2018年6月29日星期五
2017年1月4日星期三
What Is LDL-P and Apolipoprotein B (apoB) ?
LDL-C is usually calculated using the Friedewald equation. However, this measure can underestimate LDL-C level as triglycerides increase. Direct LDL-C measurements are also available and better reveal individual issues, but are less often promoted or done due to slightly higher costs.
LDL-C reflects the total content or concentration of cholesterol within LDL-C particles in mg/ml or mmol/L. Since the amount of cholesterol in each particle may vary, measuring LDL-C does not necessarily reflect the actual number of particles.
LDL-P (LDL particle number) measures the actual number of LDL particles (particle concentration, nmol/L). It appears that LDL-P may be a stronger predictor of cardiovascular events than LDL-C.
Low LDL-P is a much stronger predictor of low risk than low LDL-C. In fact, about 30 – 40% of those with low LDL-C may have elevated LDL-P. Therefore you can have low LDL-C but still be at risk for CVD, particularly if your LDL-P is elevated. Discordance is when LDL-C differs from LDL-P.
Lipoproteins play an essential role for the initiation and progression of atherosclerosis. Therefore it is very important for us to understand what regulates the production and clearance of atherogenic lipoprotein particles and how these mechanisms may be influenced.
LDL-C is only a measure of the cholesterol mass within LDL-particles. Thus, LDL-C only indirectly reflects the atherogenic potential of LDL particles. Apolipoprotein B (apoB) and LDL-P on the other hand reflect the number of atherogenic particles, with no mention of cholesterol mass. Therefore apoB and LDL-P are believed to be better risk predictors than LDL-C.
Reference Range for LDL-P
LDL-P is measured by a so-called NMR lipid profile test. A value of less than 1.000 is considered ideal. Above 2.000 is considered very high.
Apolipoprotein B (apoB)
Apolipoprotein B (ApoB) is an important component of many lipoproteins that are involved in atherosclerosis and cardiovascular disease.
Lipoproteins are the particles that transport cholesterol and triglycerides in the blood stream.
Lipoproteins are comprised of proteins (apolipoproteins), phospholipids, triglycerides and cholesterol. The lipoproteins vary in the major lipoprotein present, and the relative contents of the different lipid components. ApoB is an important component of many of the most atherogenic lipoprotein particles.
ApoB occurs in 2 main forms, apoB 48 and apoB 100. ApoB 48 is synthesized mainly by the small intestine. ApoB 100 is the apolipoprotein found in lipoproteins synthesized by the liver. Therefore, from the viewpoint of atherosclerosis and cardiovascular risk, apoB100 is the important one. ApoB 48 is primarily found in chylomicrons.
ApoB 100 is found in chylomicrons, VLDL, IDL, LDL and LP(a) particles. All these particles are atherogenic. Each of these particles contains a single apoB molecule. Therefore, measurements of apoB represent the total burden of the main lipoprotein particles involved in the atherosclerotic process.
Usually, 85-90 percent of apoB represent LDL particles. Thus, apoB reflects particle concentration, similar to LDL-P. Although measurements of apoB are not widely available, the assay has been standardized and does not require a fasting sample.
Apo B containing lipoproteins are the ones that are most likely to enter the wall of the arteries. They are capable of trafficking cholesterol into the artery wall, and if present in increased numbers they may be the main initiating factor in atherosclerosis. Retention of ApoB containing lipoprotein particles within the arterial wall is an essential part of the process.
The normal range for apoB is 40-125 mg/dL.
Usually less than 100 mg/dL is considered desirable in low or intermediate risk individuals.
Less than 80 mg/dL is desirable in high risk individuals, such as those with cardiovascular disease or diabetes.
LDL-C reflects the total content or concentration of cholesterol within LDL-C particles in mg/ml or mmol/L. Since the amount of cholesterol in each particle may vary, measuring LDL-C does not necessarily reflect the actual number of particles.
LDL-P (LDL particle number) measures the actual number of LDL particles (particle concentration, nmol/L). It appears that LDL-P may be a stronger predictor of cardiovascular events than LDL-C.
Low LDL-P is a much stronger predictor of low risk than low LDL-C. In fact, about 30 – 40% of those with low LDL-C may have elevated LDL-P. Therefore you can have low LDL-C but still be at risk for CVD, particularly if your LDL-P is elevated. Discordance is when LDL-C differs from LDL-P.
Lipoproteins play an essential role for the initiation and progression of atherosclerosis. Therefore it is very important for us to understand what regulates the production and clearance of atherogenic lipoprotein particles and how these mechanisms may be influenced.
LDL-C is only a measure of the cholesterol mass within LDL-particles. Thus, LDL-C only indirectly reflects the atherogenic potential of LDL particles. Apolipoprotein B (apoB) and LDL-P on the other hand reflect the number of atherogenic particles, with no mention of cholesterol mass. Therefore apoB and LDL-P are believed to be better risk predictors than LDL-C.
Reference Range for LDL-P
LDL-P is measured by a so-called NMR lipid profile test. A value of less than 1.000 is considered ideal. Above 2.000 is considered very high.
Apolipoprotein B (apoB)
Apolipoprotein B (ApoB) is an important component of many lipoproteins that are involved in atherosclerosis and cardiovascular disease.
Lipoproteins are the particles that transport cholesterol and triglycerides in the blood stream.
Lipoproteins are comprised of proteins (apolipoproteins), phospholipids, triglycerides and cholesterol. The lipoproteins vary in the major lipoprotein present, and the relative contents of the different lipid components. ApoB is an important component of many of the most atherogenic lipoprotein particles.
ApoB occurs in 2 main forms, apoB 48 and apoB 100. ApoB 48 is synthesized mainly by the small intestine. ApoB 100 is the apolipoprotein found in lipoproteins synthesized by the liver. Therefore, from the viewpoint of atherosclerosis and cardiovascular risk, apoB100 is the important one. ApoB 48 is primarily found in chylomicrons.
ApoB 100 is found in chylomicrons, VLDL, IDL, LDL and LP(a) particles. All these particles are atherogenic. Each of these particles contains a single apoB molecule. Therefore, measurements of apoB represent the total burden of the main lipoprotein particles involved in the atherosclerotic process.
Usually, 85-90 percent of apoB represent LDL particles. Thus, apoB reflects particle concentration, similar to LDL-P. Although measurements of apoB are not widely available, the assay has been standardized and does not require a fasting sample.
Apo B containing lipoproteins are the ones that are most likely to enter the wall of the arteries. They are capable of trafficking cholesterol into the artery wall, and if present in increased numbers they may be the main initiating factor in atherosclerosis. Retention of ApoB containing lipoprotein particles within the arterial wall is an essential part of the process.
The normal range for apoB is 40-125 mg/dL.
Usually less than 100 mg/dL is considered desirable in low or intermediate risk individuals.
Less than 80 mg/dL is desirable in high risk individuals, such as those with cardiovascular disease or diabetes.
2016年12月25日星期日
Statins Linked to Raised Risk of Type 2 Diabetes
Large Finnish study found a nearly 50 percent increase in people taking cholesterol-lowering drugs
WEDNESDAY, March 4, 2015 (HealthDay News) -- Cholesterol-lowering statin drugs may significantly increase a person's risk of developing type 2 diabetes, a new study from Finland suggests.
Researchers found that statins were associated with an almost 50 percent higher risk of developing type 2 diabetes, even after adjusting for other factors.
Statins appear to increase the risk of type 2 diabetes in several ways, the researchers said. One is that the drugs can increase a person's insulin resistance, and the other is that the cholesterol-lowering drugs seem to impair the ability of the pancreas to secrete insulin, according to the report.
Commenting on the study, Dr. Ronald Goldberg, director of the Lipid Disorder Clinic and associate director of the Diabetes Research Institute at the University of Miami, said the researchers "show evidence that statins increased insulin resistance, and that the people who developed diabetes appeared to have less ability to respond to the insulin resistance by making more insulin."
The study authors noted, however, that their research only found an association between statin use and diabetes risk. And since the study was limited to white men, it's not clear if the findings would apply to women or other racial groups.
More than 29 million people in the United States have diabetes, according to the American Diabetes Association (ADA). Type 2 diabetes occurs when the body becomes resistant to insulin, a hormone needed to process the sugars found in foods. To compensate, the body produces more insulin. Excess weight and a sedentary lifestyle are two important risk factors for type 2 diabetes, according to the ADA.
Prior studies have indicated that statins may increase a person's risk of diabetes, the authors said in background information in the study. However, these earlier studies were focused mainly on statins' role in preventing heart disease, not on their potential diabetes risk.
In this new study, University of Eastern Finland researchers tracked the effects of statin treatment in almost 9,000 men without diabetes over the course of six years. The men were between 45 and 73 years old. One in four of the men was taking a statin at the beginning of the study.
The health of the men was followed for nearly six years. During that time, 625 men were newly diagnosed with type 2 diabetes, the researchers said. Even after other risk factors were accounted for, people treated with statins were 46 percent more likely to develop diabetes than those not treated with statins.
The diabetes risk increased with the dosage taken of the statin drugs simvastatin (Zocor) and atorvastatin (Lipitor), the researchers said.
Digging a little deeper, the investigators found that statins decreased insulin sensitivity by 24 percent, and insulin secretion by 12 percent. The more simvastatin and atorvastatin that people took, the more their ability to use and produce insulin suffered.
High-dose simvastatin was associated with a 44 percent increased risk of developing diabetes, while for low-dose simvastatin the increased risk was 28 percent. High-dose atorvastatin was linked to a 37 percent increased diabetes risk, the study found.
Based on these findings, physicians will have to weigh risks versus benefits before prescribing statins, said Dr. Al Powers, director of the division of diabetes, endocrinology and metabolism at Vanderbilt University Medical Center.
Patients with pre-diabetes will need particular consideration, given that they are already on the verge of developing type 2 diabetes, Powers said.
"That's a situation where the physician and the patient must weigh the risks and benefits and decide what to do," Powers said.
On the other hand, statins can be prescribed without concern to people already diagnosed with type 2 diabetes, since they are already being treated for the condition, he added. "Those patients should continue their statin treatment," Powers said.
Goldberg expects that most heart patients who need statins will continue to receive them, but with close monitoring of their blood sugar levels.
"If your risk for heart disease is high, the benefit of statin therapy is so important that most physicians and most patients, when it's explained to them, will be willing to incur the increased risk of diabetes in favor of the added benefit to preventing heart attack and stroke," Goldberg said.
Dr. Alan Garber, a professor at Baylor College of Medicine, said that statin users with blood sugar levels beginning to creep up can likely head off type 2 diabetes through diet and exercise. Garber is the editor of the journal Diabetes, Obesity and Metabolism.
"The solution is lifestyle modification with diet and exercise. You should do that for high cholesterol, anyway," Garber said. "There's no simple cure-all for all the risk factors in life. It's clear that a single pill isn't going to supplant individual self-management. Patients have to learn to take care of themselves."
The findings were published March 4 in Diabetologia, the journal of the European Association for the Study of Diabetes.
2016年10月19日星期三
Extreme Nutrition: The Diet of Eskimos
The carnivorous diet of traditional Eskimo inhabitants of the frozen, northern, circumpolar regions of planet Earth (Siberia, Alaska, Canada, and Greenland), serves as a testament to the strengths and adaptability of the human species. The foods consumed by these hardy people are in "polar" opposition to those recommended by me (the McDougall Diet of starches, vegetables, and fruits): a carnivore vs. an herbivore diet. Unfortunately, misinformation surrounding the all-meat diet of the Eskimo has promoted dangerous eating habits to the modern-day general public.
For more than 6,000 years, natives of the frozen North have lived with almost no contact with the rest of the world. Not until the mid-1800s were reliable records made of their daily lives, their diets, and their health. Early reports describe these people as looking beautiful and athletic when they were young, but then they aged quickly, and "men and women who appeared to be 60 or over were rare."
Rumors have since circulated that traditional Eskimos have lived free of heart disease, cancer, and most other chronic diseases affecting western civilizations these days. Research published in the mid-1970s tried to explain this "Eskimo paradox" of living healthy with very few plant foods, on a high-fat, high-cholesterol, no-dietary-fiber diet. The omega-3 fish fats were noted as the miracle ingredient providing protection. Dietetic and medical experts have uncritically accepted this theory in the face of libraries filled with incriminating evidence to the contrary. They tell patients to eat more fish, poultry, and even red meat—like the Eskimos – and plenty of fish oil - in order to stay healthy.
Pushing the Nutritional Envelope
Hunted animals, including birds, caribou, seals, walrus, polar bears, whales, and fish provided all the nutrition for the Eskimos for at least 10 months of the year. And in the summer season people gathered a few plant foods such as berries, grasses, tubers, roots, stems, and seaweeds. Frozen snow-covered lands were unfit for the cultivation of plants. Animal flesh was, by necessity, the only food available most of the time.
The fat, not the protein, from animal foods provided most of the 3,100 calories required daily for these active people. Plants are the primary source of all carbohydrates, including digestible sugars and non-digestible dietary fibers. Eating raw meat indirectly provided Eskimos with enough carbohydrates in the form of glycogen (found in the muscles and liver of animals) to meet their necessary nutrient requirements and keep them out of a starvation condition called ketosis. Muscle tissue contains almost no calcium, and as a result the daily intake was about 120 mg/day versus the 800 mg and more commonly recommended for good health. Plants (not people) synthesize Vitamin C, yet the Eskimo was able to avoid scurvy with the 30 mg of vitamin C consumed daily found in land and sea animals. Recommendations for vitamin C are 60 mg/day and higher daily. Low levels of sunlight, and preformed vitamin D from fish, met the "sunshine D vitamin" requirement for Eskimo health. By the grace of environmental design, Nature made sure there was just enough nutrition for the Eskimo to survive.
There Is No Eskimo Paradox
The human being is designed to thrive on a diet of starches, vegetables and fruits. The Eskimo experience serves as a testament to the miraculous strengths and adaptability of our bodies. We can survive on raw and cooked meat, but we thrive on starches, vegetables and fruits. These hardy people survived living at the edge of the nutritional envelope, but not in good health. Here are some of the health costs they paid:
Eskimos Suffer from Atherosclerosis
Claims that Eskimos were free of heart (artery) disease are untrue. A thorough review of the evidence concludes that "Eskimos have a similar prevalence of CAD (coronary artery disease) as non-Eskimo populations, they have excessive mortality due to cerebrovascular strokes, their overall mortality is twice as high as that of non-Eskimo populations, and their life expectancy is approximately 10 years shorter than the Danish population."
Mummified remains of Eskimos dating back 2,000 years have shown extensive hardening of the arteries throughout their brains, hearts and limbs; as a direct consequence of following a carnivorous diet of birds, caribou, seals, walrus, polar bears, whales, and fish. The June 1987 issue of National Geographic magazine carried an article about two Eskimo women, one in her twenties and the other in her forties, frozen for five centuries in a tomb of ice. When discovered and medically examined they both showed signs of severe osteoporosis and also suffered extensive atherosclerosis, "probably the result of a heavy diet of whale and seal blubber."
Eskimos Suffer from Severe Bone Loss
Their low-calcium diet and lack of sunshine (vitamin D) are only minor factors contributing to the extensive osteoporosis found in recent and ancient Eskimos. Alaskan Eskimos older than age 40 have been found to have a 10% to 15% greater deficit in bone mineral density compared to Caucasians in the US. This research published in 1974 on 107 elderly people concluded, "Aging bone loss, which occurs in many populations, has an earlier onset and greater intensity in the Eskimos. Nutritional factors of high protein, high nitrogen, high phosphorus, and low calcium intakes maybe implicated."
Protein, and especially animal protein, consumed in excess of our needs places serious burdens on the body. The liver and kidneys work hard to process the excess protein and excrete its byproducts along with the urine. As a result of this extra work, Eskimos have been reported to have an enlarged liver while living on meat, and to produce larger than average volumes of urine in order to excrete the byproducts of protein metabolism. The bones also play a role in managing excess animal protein (acidic by nature) by neutralizing large amounts of dietary acids. In this process bone structure and bone mineral content are lost through the kidney system, depleting the bones into a condition called osteoporosis.
Eskimos Are Infected with Parasites
Diseases of animals are readily transmitted to humans when eaten. One example is trichinosis (an infection with the roundworm Trichinella spiralis), which is found in about 12% of older Eskimos; a result of eating raw and infected walrus, seal, and polar bear meat. In most cases this parasite infestation causes no symptoms, but illness and death can result.
Meat-derived Chemical Pollution
Since the 1970s the diet of the Eskimo has contained high levels of toxic, organic pollutants and heavy metals. These lipophilic chemicals are attracted to and concentrated in the fatty-tissues of land and sea animals. As a direct result of the traditional Eskimo diet (now contaminated by industry wastes), the bodies of these Arctic people contain the highest human concentrations of environmental chemicals found anywhere on Earth: "levels so extreme that the breast milk and tissues of some Greenlanders could be classified as hazardous waste." Eskimo women have been found to have levels of PCBs in their breast milk five to ten times higher than women in southern Canada. These chemicals cause and promote many forms of cancer and cause brain diseases, including Parkinson's disease.
Nutrition Has Gone Downhill for the Eskimo
The notion that consuming meat, fish, and fish oil will promote health and healing has captured the attention of the scientific community in large part because of the misinterpretation** of the Eskimo experience. But life has gotten worse for the Eskimo. Over the past 50 years their traditional diet has been further modified with the addition of western foods. Rather than using a hook, spear, or club to catch their meal, as in the past, people living in this part of the world use the "green lure" (the dollar bill) and catch their meals through an open car window at the local fast-food restaurant. Obesity, type-2 diabetes, tooth decay, and cancers of the breast, prostate, and colon have been added to the Eskimo's traditional health problems of artery disease, bone loss, and infectious diseases.
People living in the frozen north these days have heated homes and drive around in comfortable SUVs. The challenging environment their ancestors barely survived through required a carnivorous diet. Those days of needing 3100 calories a day to counter the freezing cold and hunt for dinner are gone. The idea that current epidemics of obesity and sickness in these Northern people would be best fixed by returning to the old ways of carnivorous diet would not work unless they also returned to living in igloo homes and hunted their lands for every meal. Physicians and dietitians now caring for these people suffering from the western diet with the addition of too much traditional food (ancestral meat) should be prescribing a starch-based diet to help them lose excess weight and cure common dietary diseases.
*The term "Eskimo" comes from a Native American word that may have meant "eater of raw meat." The word "Eskimo" has come to be considered offensive, especially in Canada. Many prefer the name "Inuit," which means "the people" or "real people." However, "Eskimo" is the term used in the scientific and historical literature and will be used here.
**Misinterpretation is easy to spread because:
1) People love to hear good news about their bad habits.
2) Nutritional "facts," even when false and harmful, are used to sell meat, fish, and other foods.
3) The media loves headlines that sell their products, like "The Eskimo Diet proves Meat's Good."
For more than 6,000 years, natives of the frozen North have lived with almost no contact with the rest of the world. Not until the mid-1800s were reliable records made of their daily lives, their diets, and their health. Early reports describe these people as looking beautiful and athletic when they were young, but then they aged quickly, and "men and women who appeared to be 60 or over were rare."
Rumors have since circulated that traditional Eskimos have lived free of heart disease, cancer, and most other chronic diseases affecting western civilizations these days. Research published in the mid-1970s tried to explain this "Eskimo paradox" of living healthy with very few plant foods, on a high-fat, high-cholesterol, no-dietary-fiber diet. The omega-3 fish fats were noted as the miracle ingredient providing protection. Dietetic and medical experts have uncritically accepted this theory in the face of libraries filled with incriminating evidence to the contrary. They tell patients to eat more fish, poultry, and even red meat—like the Eskimos – and plenty of fish oil - in order to stay healthy.
Pushing the Nutritional Envelope
Hunted animals, including birds, caribou, seals, walrus, polar bears, whales, and fish provided all the nutrition for the Eskimos for at least 10 months of the year. And in the summer season people gathered a few plant foods such as berries, grasses, tubers, roots, stems, and seaweeds. Frozen snow-covered lands were unfit for the cultivation of plants. Animal flesh was, by necessity, the only food available most of the time.
The fat, not the protein, from animal foods provided most of the 3,100 calories required daily for these active people. Plants are the primary source of all carbohydrates, including digestible sugars and non-digestible dietary fibers. Eating raw meat indirectly provided Eskimos with enough carbohydrates in the form of glycogen (found in the muscles and liver of animals) to meet their necessary nutrient requirements and keep them out of a starvation condition called ketosis. Muscle tissue contains almost no calcium, and as a result the daily intake was about 120 mg/day versus the 800 mg and more commonly recommended for good health. Plants (not people) synthesize Vitamin C, yet the Eskimo was able to avoid scurvy with the 30 mg of vitamin C consumed daily found in land and sea animals. Recommendations for vitamin C are 60 mg/day and higher daily. Low levels of sunlight, and preformed vitamin D from fish, met the "sunshine D vitamin" requirement for Eskimo health. By the grace of environmental design, Nature made sure there was just enough nutrition for the Eskimo to survive.
There Is No Eskimo Paradox
The human being is designed to thrive on a diet of starches, vegetables and fruits. The Eskimo experience serves as a testament to the miraculous strengths and adaptability of our bodies. We can survive on raw and cooked meat, but we thrive on starches, vegetables and fruits. These hardy people survived living at the edge of the nutritional envelope, but not in good health. Here are some of the health costs they paid:
Eskimos Suffer from Atherosclerosis
Claims that Eskimos were free of heart (artery) disease are untrue. A thorough review of the evidence concludes that "Eskimos have a similar prevalence of CAD (coronary artery disease) as non-Eskimo populations, they have excessive mortality due to cerebrovascular strokes, their overall mortality is twice as high as that of non-Eskimo populations, and their life expectancy is approximately 10 years shorter than the Danish population."
Mummified remains of Eskimos dating back 2,000 years have shown extensive hardening of the arteries throughout their brains, hearts and limbs; as a direct consequence of following a carnivorous diet of birds, caribou, seals, walrus, polar bears, whales, and fish. The June 1987 issue of National Geographic magazine carried an article about two Eskimo women, one in her twenties and the other in her forties, frozen for five centuries in a tomb of ice. When discovered and medically examined they both showed signs of severe osteoporosis and also suffered extensive atherosclerosis, "probably the result of a heavy diet of whale and seal blubber."
Eskimos Suffer from Severe Bone Loss
Their low-calcium diet and lack of sunshine (vitamin D) are only minor factors contributing to the extensive osteoporosis found in recent and ancient Eskimos. Alaskan Eskimos older than age 40 have been found to have a 10% to 15% greater deficit in bone mineral density compared to Caucasians in the US. This research published in 1974 on 107 elderly people concluded, "Aging bone loss, which occurs in many populations, has an earlier onset and greater intensity in the Eskimos. Nutritional factors of high protein, high nitrogen, high phosphorus, and low calcium intakes maybe implicated."
Protein, and especially animal protein, consumed in excess of our needs places serious burdens on the body. The liver and kidneys work hard to process the excess protein and excrete its byproducts along with the urine. As a result of this extra work, Eskimos have been reported to have an enlarged liver while living on meat, and to produce larger than average volumes of urine in order to excrete the byproducts of protein metabolism. The bones also play a role in managing excess animal protein (acidic by nature) by neutralizing large amounts of dietary acids. In this process bone structure and bone mineral content are lost through the kidney system, depleting the bones into a condition called osteoporosis.
Eskimos Are Infected with Parasites
Diseases of animals are readily transmitted to humans when eaten. One example is trichinosis (an infection with the roundworm Trichinella spiralis), which is found in about 12% of older Eskimos; a result of eating raw and infected walrus, seal, and polar bear meat. In most cases this parasite infestation causes no symptoms, but illness and death can result.
Meat-derived Chemical Pollution
Since the 1970s the diet of the Eskimo has contained high levels of toxic, organic pollutants and heavy metals. These lipophilic chemicals are attracted to and concentrated in the fatty-tissues of land and sea animals. As a direct result of the traditional Eskimo diet (now contaminated by industry wastes), the bodies of these Arctic people contain the highest human concentrations of environmental chemicals found anywhere on Earth: "levels so extreme that the breast milk and tissues of some Greenlanders could be classified as hazardous waste." Eskimo women have been found to have levels of PCBs in their breast milk five to ten times higher than women in southern Canada. These chemicals cause and promote many forms of cancer and cause brain diseases, including Parkinson's disease.
Nutrition Has Gone Downhill for the Eskimo
The notion that consuming meat, fish, and fish oil will promote health and healing has captured the attention of the scientific community in large part because of the misinterpretation** of the Eskimo experience. But life has gotten worse for the Eskimo. Over the past 50 years their traditional diet has been further modified with the addition of western foods. Rather than using a hook, spear, or club to catch their meal, as in the past, people living in this part of the world use the "green lure" (the dollar bill) and catch their meals through an open car window at the local fast-food restaurant. Obesity, type-2 diabetes, tooth decay, and cancers of the breast, prostate, and colon have been added to the Eskimo's traditional health problems of artery disease, bone loss, and infectious diseases.
People living in the frozen north these days have heated homes and drive around in comfortable SUVs. The challenging environment their ancestors barely survived through required a carnivorous diet. Those days of needing 3100 calories a day to counter the freezing cold and hunt for dinner are gone. The idea that current epidemics of obesity and sickness in these Northern people would be best fixed by returning to the old ways of carnivorous diet would not work unless they also returned to living in igloo homes and hunted their lands for every meal. Physicians and dietitians now caring for these people suffering from the western diet with the addition of too much traditional food (ancestral meat) should be prescribing a starch-based diet to help them lose excess weight and cure common dietary diseases.
*The term "Eskimo" comes from a Native American word that may have meant "eater of raw meat." The word "Eskimo" has come to be considered offensive, especially in Canada. Many prefer the name "Inuit," which means "the people" or "real people." However, "Eskimo" is the term used in the scientific and historical literature and will be used here.
**Misinterpretation is easy to spread because:
1) People love to hear good news about their bad habits.
2) Nutritional "facts," even when false and harmful, are used to sell meat, fish, and other foods.
3) The media loves headlines that sell their products, like "The Eskimo Diet proves Meat's Good."
2016年10月6日星期四
Walter Kempner, MD Founder of the Rice Diet
Walter Kempner, medical doctor and research scientist, is the father of modern day diet therapy and creator of the Rice Diet. All who have followed in his footsteps, including Nathan Pritikin, Dean Ornish, Neal Barnard, Caldwell Esselstyn, and myself, owe homage to this man and his work.
Kempner's Rice Diet program began at Duke University in Durham, North Carolina in 1939. The treatment was a simple therapy of white rice, fruit, juice, and sugar, and was reserved for only the most seriously ill patients. Although low-tech, the benefits of the Rice Diet far exceed those of any drug or surgery ever prescribed for chronic conditions, including coronary artery disease, heart and kidney failure, hypertension, diabetes, arthritis, and obesity.
Originally used for only short time periods and under close supervision due to concerns about nutritional deficiencies, subsequent research proved the Rice Diet to be safe and nutritionally adequate for the vast majority of patients.
A major breakthrough occurred by accident in 1942 when one of Dr. Kempner's patients, a 33-year-old North Carolina woman with chronic glomerulonephritis (kidney disease) and papilledema (eye disease) failed to follow his instructions. Because of Dr. Kempner's heavy German accent she misunderstood his instructions to return in two weeks, and after two months, she finally returned, with no signs of deficiency, but rather with robust health. The woman had experienced a dramatic reduction of her blood pressure, from 190/120 to 124/84 mmHg, resolution of eye damage (retinal hemorrhages and papilledema), and a noticeable decrease in heart size.
After this experience Dr. Kempner began treating his patients for extended periods of time, and expanded the indications from only serious troubles (glomerulonephritis and malignant hypertension) to patients with relatively minor illnesses, such as routine hypertension (160/100 mmHg), headaches, chronic fatigue, chest pains, edema, xanthoma, pseudo tumor cerebri, and psoriasis.
Walter Kempner's Medical Records
During his career, fellow professionals wanted Dr. Kempner to set up randomized, controlled studies. However in studies designed this way, half of the patients are treated and half go untreated. His medical ethics would not allow him to deny his proven diet therapy to anyone; therefore, he declined. Furthermore, he correctly pointed out that each patient served as his own control.
Dr. Kempner documented the benefits of his treatments by tracking their changes in cholesterol, blood pressure, blood sugar, and body weight, as well as with pictures. For example, his records showed that 93% of patients with an elevated cholesterol benefited with an average reduction from 273 mg/dL before treatment to 177 mg/dL after. These reductions in cholesterol are greater than those usually seen with powerful statin drugs, and without the costs and risks. His numbers also showed how a high-carbohydrate diet improved blood sugars and often cured type-2 diabetes.
Reducing Massive Obesity:
In one article the results of 106 massively obese patients treated as outpatients with the Rice Diet, exercise, and motivational enhancement under daily supervision were reported. The average weight loss was 63.9 kg (141 pounds). Normal weight was achieved by 43 of the patients.
Curing Severe Hypertension.
In the beginning, Dr. Kempner treated only patients with near-fatal conditions, like malignant hypertension (blood pressures in the 220/120 mmHg range). In this emergency condition people often suffered from heart and kidney failure, and eye damage (with retinal hemorrhages, exudates, and papilledema). Today such patients are treated with powerful medications and laser eye surgery, with far greater risks and costs, and far fewer benefits. The safe and effective Rice Diet treatment for eye damage and kidney damage has been largely forgotten.
Stopping Hemorrhages and Exudates.
The eyes are a window to the condition of the blood vessel system and major organs throughout the body. By looking (with an ophthalmoscope) into the back of the eye (retina) a physician can actually see ongoing damage, which is not limited to the eye, but is also happening in the kidneys and all other tissues. Photos of the retina show how the Rice Diet stops the bleeding (hemorrhages) and leaking (exudates) from blood vessels. This serves as a dramatic demonstration of the body's ability to heal given the supportive environment of a healthy diet.
Reversing Heart Disease.
Narrowing of heart (coronary) arteries due to atherosclerosis (a result of the Western diet) causes chest pains (angina) and changes in the electrocardiogram (EKGs showing inverted "T" waves). The Rice Diet relieves chest pains and corrects EKG abnormalities. In other words, the Rice Diet can cure common heart disease, which affects more than half of Americans. Modern-day heart doctors routinely prescribe heart surgery for blocked arteries, with far greater costs and risks, and far fewer benefits.
Treating Heart and Kidney Failure.
In late stages of disease, the Western diet causes the failure of major organs, including the heart, kidneys, liver, and brain. Enlargement of the heart, as seen on a chest x-ray, is a classic sign of heart failure. The Rice Diet causes enlarged (failing) hearts to revert to normal size and function. Kidney function also dramatically improves, as does the patient in general.
The Rice Diet Components
*Dry rice of 250 to 350 grams daily forms the basis of the diet. Any kind of rice is used as long as it contains no milk or salt. The rice is boiled or steamed in plain water or fruit juice, without salt, milk or fat. (One cup of dry white rice weighs about 200 grams, and contains about 13 grams of protein, 150 grams of carbohydrate, 1 gram of fat, and 700 calories.)
*Calorie intake is usually 2,000 to 2,400 calories daily. Intake varies based upon the patient's condition: underweight people are fed more calories, and vice versa.
*Fruit and fruit juices are allowed.
*Dried fruits can be used as long as nothing but sugar has been added.
*White sugar may be used as desired (ad libitum); on average a patient takes in about 100 grams daily (400 calories) but, if necessary (to maintain body weight), as much as 500 grams (2000 calories) daily has been used.
*No avocados, dates, or nuts.
*No tomato or vegetable juices.
*Supplementary vitamins are added in the following amounts: vitamin A 5,000 units, vitamin D 1,000 units, thiamine chloride 5 mg, riboflavin 5 mg, niacinamide 25 mg, calcium pantothenate 2 mg. (However, none of the Rice Diet patients during five months of treatment showed any signs (epithelial, neural or metabolic) to make one suspect any vitamin deficiency.
*Adaptation to the diet takes about two months.
*Exercise is encouraged. Bed rest is only advised with severe conditions.
*Water intake is restricted in some severely ill patients to less than 1.5 liters (6 cups) a day to prevent water intoxication and electrolyte imbalances.
*A few patients with kidney disease cannot tolerate the diet because of their inability to retain minerals.
*Once the patient's health has returned, then small amounts of non-leguminous vegetables, potatoes, lean meat or fish (all prepared without salt or fat) may be added. However, if these additions result in adverse consequences (elevated blood pressure, enlargement of the heart, abnormal EKG changes, worsening kidney or eye conditions, etc.), then the basic Rice Diet, without modification, must be continued.
*A physician competent in diet therapy should follow anyone in need of the Rice Diet. Sicker patients need closer supervision.
The nutrient breakdown is about 2,000 to 2,400 calories per day (depending on the patient's body weight): 95% carbohydrate, 4 to 5% protein (20 to 25 grams), 2 to 3% fat (rice is relatively high in the essential fat linoleic acid), 140 milligrams of calcium, and 150 milligrams of sodium daily. For more rapid and effective weight loss, the calories are restricted.
Why White Rice And Table Sugar?
One reason Kempner chose rice was because he believed that rice proteins were easily assimilated and there was no concern about getting sufficient amounts of the essential amino acids. (This adequacy and completeness of protein is not limited to rice, and is true for all starches, including corn, potatoes, and sweet potatoes.) He chose rice rather than another starch because in his day, nearly half of the world's population consumed large amounts of rice (sometimes rice made up 80% to 90% of their diet).
White rice, as opposed to brown whole-grain rice, was used because it was considered more palatable to the general public and was more readily available. Plain white rice contains about 8% of calories as protein. The addition of simple sugars brings the protein content of the Rice Diet down to 5% or fewer of total calories. The body only needs a small amount of protein daily (fewer than 5% of calories from food). The liver and kidneys must process and excrete any protein consumed beyond the basic requirements, causing extra work and often organ damage.
The addition of white table sugar adds calories without protein and fat. Fruits and juices are also high in sugar (carbohydrate) calories and low in fat and protein. The primary benefits of the Rice Diet are accomplished by easing the workload on compromised tissues and organs by providing them with clean-burning energy from carbohydrates and avoiding common dietary poisons such as salt, fat, cholesterol, and animal protein. In such a supportive environment the body's healing powers can outpace the damages once caused by unhealthy foods. Dr. Kempner added multivitamins, which may be necessary because of all the refined foods served. Using whole foods (specifically the McDougall starch-based diet), rather than white rice and sugar, provides all necessary vitamins and minerals. No supplements are recommended other than vitamin B12.
The Rice Diet Today
After nearly 70 years, in 2002 Duke University severed its relationship with the Rice Diet. The Rice Diet program, however, continued to run independently until the fall of 2013 under the direction of Robert Rosati, MD, when it closed for business. Kitty Rosati (with her husband, Robert) has published several national best selling books on the Rice Diet.
Francis Neelon, MD, the Rice Diet's former medical director, has joined with business interests to reestablish the Rice Diet, and they plan to open an outpatient facility in Durham, NC beginning in February of 2014.
One of Dr. Kempner's closest collaborators, Barbara Newborg, MD, recently published an extensive biography on the father of modern day diet therapy, Walter Kempner and the Rice Diet: Challenging Conventional Wisdom.
The McDougall Diet vs. The Rice Diet
Walter Kempner, MD was very influential on my career. His published work showed me the power of diet therapy and that nutritional deficiencies do not occur with simple plant-based diets (even with the addition of lots of sugar). Even before I was born, Dr. Kempner had disproven concepts that are still held as true by most medical doctors today, such as, "diet has little to do with heart disease," "additional protein improves health," and "carbohydrates cause diabetes."
I find myself recommending the Rice Diet several times a year to the few patients I see who are on the verge of complete heart or kidney failure. Otherwise, I recommend the McDougall Diet (a starch-based diet with fruits and non-starchy-vegetables along with some salt and sugar for flavorings) to almost all of my patients.
No apology needs to be made for serving pasta and marinara sauce, bean burritos, or rice and Chinese vegetables. The diet I recommend, the McDougall Diet, is for the living. The Rice Diet is one that I reserve for the "nearly dead." I am grateful every day for Walter Kempner's contributions to medical science. Unfortunately, because profits, rather than patients' welfare, dictate common medical practice, diet therapy remains unappreciated and practically unknown.
Kempner's Rice Diet program began at Duke University in Durham, North Carolina in 1939. The treatment was a simple therapy of white rice, fruit, juice, and sugar, and was reserved for only the most seriously ill patients. Although low-tech, the benefits of the Rice Diet far exceed those of any drug or surgery ever prescribed for chronic conditions, including coronary artery disease, heart and kidney failure, hypertension, diabetes, arthritis, and obesity.
Originally used for only short time periods and under close supervision due to concerns about nutritional deficiencies, subsequent research proved the Rice Diet to be safe and nutritionally adequate for the vast majority of patients.
A major breakthrough occurred by accident in 1942 when one of Dr. Kempner's patients, a 33-year-old North Carolina woman with chronic glomerulonephritis (kidney disease) and papilledema (eye disease) failed to follow his instructions. Because of Dr. Kempner's heavy German accent she misunderstood his instructions to return in two weeks, and after two months, she finally returned, with no signs of deficiency, but rather with robust health. The woman had experienced a dramatic reduction of her blood pressure, from 190/120 to 124/84 mmHg, resolution of eye damage (retinal hemorrhages and papilledema), and a noticeable decrease in heart size.
After this experience Dr. Kempner began treating his patients for extended periods of time, and expanded the indications from only serious troubles (glomerulonephritis and malignant hypertension) to patients with relatively minor illnesses, such as routine hypertension (160/100 mmHg), headaches, chronic fatigue, chest pains, edema, xanthoma, pseudo tumor cerebri, and psoriasis.
Walter Kempner's Medical Records
During his career, fellow professionals wanted Dr. Kempner to set up randomized, controlled studies. However in studies designed this way, half of the patients are treated and half go untreated. His medical ethics would not allow him to deny his proven diet therapy to anyone; therefore, he declined. Furthermore, he correctly pointed out that each patient served as his own control.
Dr. Kempner documented the benefits of his treatments by tracking their changes in cholesterol, blood pressure, blood sugar, and body weight, as well as with pictures. For example, his records showed that 93% of patients with an elevated cholesterol benefited with an average reduction from 273 mg/dL before treatment to 177 mg/dL after. These reductions in cholesterol are greater than those usually seen with powerful statin drugs, and without the costs and risks. His numbers also showed how a high-carbohydrate diet improved blood sugars and often cured type-2 diabetes.
Reducing Massive Obesity:
In one article the results of 106 massively obese patients treated as outpatients with the Rice Diet, exercise, and motivational enhancement under daily supervision were reported. The average weight loss was 63.9 kg (141 pounds). Normal weight was achieved by 43 of the patients.
Curing Severe Hypertension.
In the beginning, Dr. Kempner treated only patients with near-fatal conditions, like malignant hypertension (blood pressures in the 220/120 mmHg range). In this emergency condition people often suffered from heart and kidney failure, and eye damage (with retinal hemorrhages, exudates, and papilledema). Today such patients are treated with powerful medications and laser eye surgery, with far greater risks and costs, and far fewer benefits. The safe and effective Rice Diet treatment for eye damage and kidney damage has been largely forgotten.
Stopping Hemorrhages and Exudates.
The eyes are a window to the condition of the blood vessel system and major organs throughout the body. By looking (with an ophthalmoscope) into the back of the eye (retina) a physician can actually see ongoing damage, which is not limited to the eye, but is also happening in the kidneys and all other tissues. Photos of the retina show how the Rice Diet stops the bleeding (hemorrhages) and leaking (exudates) from blood vessels. This serves as a dramatic demonstration of the body's ability to heal given the supportive environment of a healthy diet.
Reversing Heart Disease.
Narrowing of heart (coronary) arteries due to atherosclerosis (a result of the Western diet) causes chest pains (angina) and changes in the electrocardiogram (EKGs showing inverted "T" waves). The Rice Diet relieves chest pains and corrects EKG abnormalities. In other words, the Rice Diet can cure common heart disease, which affects more than half of Americans. Modern-day heart doctors routinely prescribe heart surgery for blocked arteries, with far greater costs and risks, and far fewer benefits.
Treating Heart and Kidney Failure.
In late stages of disease, the Western diet causes the failure of major organs, including the heart, kidneys, liver, and brain. Enlargement of the heart, as seen on a chest x-ray, is a classic sign of heart failure. The Rice Diet causes enlarged (failing) hearts to revert to normal size and function. Kidney function also dramatically improves, as does the patient in general.
The Rice Diet Components
*Dry rice of 250 to 350 grams daily forms the basis of the diet. Any kind of rice is used as long as it contains no milk or salt. The rice is boiled or steamed in plain water or fruit juice, without salt, milk or fat. (One cup of dry white rice weighs about 200 grams, and contains about 13 grams of protein, 150 grams of carbohydrate, 1 gram of fat, and 700 calories.)
*Calorie intake is usually 2,000 to 2,400 calories daily. Intake varies based upon the patient's condition: underweight people are fed more calories, and vice versa.
*Fruit and fruit juices are allowed.
*Dried fruits can be used as long as nothing but sugar has been added.
*White sugar may be used as desired (ad libitum); on average a patient takes in about 100 grams daily (400 calories) but, if necessary (to maintain body weight), as much as 500 grams (2000 calories) daily has been used.
*No avocados, dates, or nuts.
*No tomato or vegetable juices.
*Supplementary vitamins are added in the following amounts: vitamin A 5,000 units, vitamin D 1,000 units, thiamine chloride 5 mg, riboflavin 5 mg, niacinamide 25 mg, calcium pantothenate 2 mg. (However, none of the Rice Diet patients during five months of treatment showed any signs (epithelial, neural or metabolic) to make one suspect any vitamin deficiency.
*Adaptation to the diet takes about two months.
*Exercise is encouraged. Bed rest is only advised with severe conditions.
*Water intake is restricted in some severely ill patients to less than 1.5 liters (6 cups) a day to prevent water intoxication and electrolyte imbalances.
*A few patients with kidney disease cannot tolerate the diet because of their inability to retain minerals.
*Once the patient's health has returned, then small amounts of non-leguminous vegetables, potatoes, lean meat or fish (all prepared without salt or fat) may be added. However, if these additions result in adverse consequences (elevated blood pressure, enlargement of the heart, abnormal EKG changes, worsening kidney or eye conditions, etc.), then the basic Rice Diet, without modification, must be continued.
*A physician competent in diet therapy should follow anyone in need of the Rice Diet. Sicker patients need closer supervision.
The nutrient breakdown is about 2,000 to 2,400 calories per day (depending on the patient's body weight): 95% carbohydrate, 4 to 5% protein (20 to 25 grams), 2 to 3% fat (rice is relatively high in the essential fat linoleic acid), 140 milligrams of calcium, and 150 milligrams of sodium daily. For more rapid and effective weight loss, the calories are restricted.
Why White Rice And Table Sugar?
One reason Kempner chose rice was because he believed that rice proteins were easily assimilated and there was no concern about getting sufficient amounts of the essential amino acids. (This adequacy and completeness of protein is not limited to rice, and is true for all starches, including corn, potatoes, and sweet potatoes.) He chose rice rather than another starch because in his day, nearly half of the world's population consumed large amounts of rice (sometimes rice made up 80% to 90% of their diet).
White rice, as opposed to brown whole-grain rice, was used because it was considered more palatable to the general public and was more readily available. Plain white rice contains about 8% of calories as protein. The addition of simple sugars brings the protein content of the Rice Diet down to 5% or fewer of total calories. The body only needs a small amount of protein daily (fewer than 5% of calories from food). The liver and kidneys must process and excrete any protein consumed beyond the basic requirements, causing extra work and often organ damage.
The addition of white table sugar adds calories without protein and fat. Fruits and juices are also high in sugar (carbohydrate) calories and low in fat and protein. The primary benefits of the Rice Diet are accomplished by easing the workload on compromised tissues and organs by providing them with clean-burning energy from carbohydrates and avoiding common dietary poisons such as salt, fat, cholesterol, and animal protein. In such a supportive environment the body's healing powers can outpace the damages once caused by unhealthy foods. Dr. Kempner added multivitamins, which may be necessary because of all the refined foods served. Using whole foods (specifically the McDougall starch-based diet), rather than white rice and sugar, provides all necessary vitamins and minerals. No supplements are recommended other than vitamin B12.
The Rice Diet Today
After nearly 70 years, in 2002 Duke University severed its relationship with the Rice Diet. The Rice Diet program, however, continued to run independently until the fall of 2013 under the direction of Robert Rosati, MD, when it closed for business. Kitty Rosati (with her husband, Robert) has published several national best selling books on the Rice Diet.
Francis Neelon, MD, the Rice Diet's former medical director, has joined with business interests to reestablish the Rice Diet, and they plan to open an outpatient facility in Durham, NC beginning in February of 2014.
One of Dr. Kempner's closest collaborators, Barbara Newborg, MD, recently published an extensive biography on the father of modern day diet therapy, Walter Kempner and the Rice Diet: Challenging Conventional Wisdom.
The McDougall Diet vs. The Rice Diet
Walter Kempner, MD was very influential on my career. His published work showed me the power of diet therapy and that nutritional deficiencies do not occur with simple plant-based diets (even with the addition of lots of sugar). Even before I was born, Dr. Kempner had disproven concepts that are still held as true by most medical doctors today, such as, "diet has little to do with heart disease," "additional protein improves health," and "carbohydrates cause diabetes."
I find myself recommending the Rice Diet several times a year to the few patients I see who are on the verge of complete heart or kidney failure. Otherwise, I recommend the McDougall Diet (a starch-based diet with fruits and non-starchy-vegetables along with some salt and sugar for flavorings) to almost all of my patients.
No apology needs to be made for serving pasta and marinara sauce, bean burritos, or rice and Chinese vegetables. The diet I recommend, the McDougall Diet, is for the living. The Rice Diet is one that I reserve for the "nearly dead." I am grateful every day for Walter Kempner's contributions to medical science. Unfortunately, because profits, rather than patients' welfare, dictate common medical practice, diet therapy remains unappreciated and practically unknown.
2016年9月4日星期日
LOW-CALORIE DIET FOR TYPE 2 DIABETES
In 2013, we awarded our largest ever research grant of £2.4 million to understand the impact of a low calorie diet on Type 2 diabetes.
Professor Roy Taylor at Newcastle University and Professor Mike Lean at the University of Glasgow are comparing the long-term effects of a new weight management approach to the best diabetes care currently available.
The aim is to find out if an intensive weight management plan can help people put their Type 2 diabetes into remission for the long term.
The DiRECT study
What is the background to this research?
Not everyone with Type 2 diabetes is overweight, but weight gain and obesity are the most important risk factors for Type 2 diabetes and the reason why Type 2 has become a global epidemic that affects overweight people of all ages.
Surgical operations, such as gastric banding and gastric bypass, are potential solutions because they lead to dramatic weight loss, which can put Type 2 diabetes into remission for up to 80% of patients. But these treatments are expensive, invasive and carry a risk of surgical complications, which mean they can only be offered as a last resort.
What do we know already about low-calorie diets?
In 2011, a Diabetes UK research trial at Newcastle University tested a low-calorie diet in 11 people with Type 2 diabetes, which helped us to understand how Type 2 diabetes can be put into remission.
After the 8-week diet, volunteers had reduced the amount of fat in their liver and pancreas. This helped to restore their insulin production and put their Type 2 diabetes into remission. Three months later, some had put weight back on, but most still had normal blood glucose control.
This study was only a first step. It was designed to tell us about the underlying biology of Type 2 diabetes, and it followed the participants for only three months.
Another study, published in 2016, confirmed these findings and showed (in 30 people) that Type 2 diabetes could be kept in remission 6 months after the low-calorie diet was completed. It also suggested that the diet was effective in people that had had Type 2 diabetes for up to 10 years.
Both of these studies were very small, and were carried out in a research environment. We don't yet understand the long-term effects of these diets, or how a low-calorie diet might be used to bring about and maintain Type 2 diabetes remission in a real-life setting, as part of routine GP care.
What is the aim of the current research?
The DiRECT (Diabetes Remission Clinical Trial) study aims to find out if intensive weight control can bring about the remission of Type 2 diabetes and be maintained long-term through routine NHS care.
The trial will compare the long-term effects of a low-calorie diet and weight management programme to bsst available care for Type 2 diabetes.
What will the research involve?
A number of GP practices across Scotland and Tyneside are recruiting people aged 20-65 who are overweight and have been diagnosed with Type 2 diabetes in the last six years. Participants at half of the practices will receive the current best-available Type 2 diabetes care, while those at the other half will receive a low-calorie diet for between 8 and 20 weeks.
Afterwards, those on the low-calorie diet will be gradually re-introduced to normal food over a period of two to eight weeks and will receive expert support to help them maintain their weight loss in the long term.
Participants receiving best-available care will get weight loss support in accordance with the latest clinical guidelines, but won't receive the low-calorie diet.
The researchers will test metabolisms and measure fat deposits inside the body, to reveal exactly how major weight loss can put Type 2 diabetes into remission. They'll also carry out psychological assessments with the participants and healthcare professionals taking part in the study, to work out how this approach to weight management might form part of routine GP care.
Where is the research taking place?
This study will take place at around 30 GP practices in Scotland and Tyneside. The research will be carried out and the data analysed by researchers at the University of Glasgow and at Newcastle University.
Who can take part?
Only people invited to take part by their GP practice can get involved in this study. Recruitment is only taking place at selected GP practices in Scotland and Tyneside. Individual patients are not being recruited.
How will it benefit people with diabetes?
If this study shows that a low-calorie diet can safely put Type 2 diabetes into remission for the long-term, it could completely transform the way this condition is viewed and treated.
If the diet can be used practically and effectively, it could lead to significant changes in the way that Type 2 diabetes is managed by the NHS. It could also help people with this condition live for longer, improving quality of life and reducing the risk of serious health complications, without the need for invasive weight loss surgery.
If a low-calorie diet can be used within routine GP care , it could ultimately be of enormous benefit to millions of people living with Type 2 diabetes in the UK.
When will results be available?
This study will last until October 2018, and the overall results will be released once all of the data has been analysed. We'll report the results in Diabetes UK publications and on the website.
The low-calorie diet
What will the diet used consist of?
The diet used in DiRECT will last for between 8 and 20 weeks and provide around 800 calories a day. It will consist of four diet soups or shakes per day, providing all essential vitamins and minerals and lots of fluids.
Will the diet cure Type 2 diabetes?
The diet being studied isn't a 'quick fix' for Type 2 diabetes. It should help people taking part in the study to lose weight – specifically, the fat in and around their liver and pancreas. This should, in turn, help to put their Type 2 diabetes into remission.
It's likely that some people who take part in the research will find the diet challenging, and every participant will have to work hard to keep weight off in the long-term to maintain Type 2 diabetes remission.
Is the diet used in this research available now?
Low-calorie diet foods are not available on prescription from the NHS. They're marketed by a range of private companies, but can be expensive and come with limited evidence of long-term benefit.
This research is the only way to tell if weight management using a low-calorie diet is practical and more effective than the current best-available treatments for Type 2 diabetes.
Should people with Type 2 diabetes follow the diet used in this research?
Until we have evidence that a low-calorie diet is more effective than the current best-available treatment, Diabetes UK recommend that people with Type 2 diabetes only attempt to lose weight in this way after they have spoken to their GP.
We're confident that DiRECT will answer important questions and give the NHS enough evidence to decide whether low-calorie diets should be offered as a routine treatment option. People with diabetes should always consult their GP before making changes to the way that they manage their condition.
What diet does Diabetes UK recommend for people with Type 2?
Diabetes UK recommends that people with Type 2 diabetes eat a healthy, balanced diet that is low in sugar, salt and fat and includes plenty of fruits and vegetables. For information on living a healthy lifestyle and eating well with Type 2 diabetes please see our guide to diabetes.
Professor Roy Taylor at Newcastle University and Professor Mike Lean at the University of Glasgow are comparing the long-term effects of a new weight management approach to the best diabetes care currently available.
The aim is to find out if an intensive weight management plan can help people put their Type 2 diabetes into remission for the long term.
The DiRECT study
What is the background to this research?
Not everyone with Type 2 diabetes is overweight, but weight gain and obesity are the most important risk factors for Type 2 diabetes and the reason why Type 2 has become a global epidemic that affects overweight people of all ages.
Surgical operations, such as gastric banding and gastric bypass, are potential solutions because they lead to dramatic weight loss, which can put Type 2 diabetes into remission for up to 80% of patients. But these treatments are expensive, invasive and carry a risk of surgical complications, which mean they can only be offered as a last resort.
What do we know already about low-calorie diets?
In 2011, a Diabetes UK research trial at Newcastle University tested a low-calorie diet in 11 people with Type 2 diabetes, which helped us to understand how Type 2 diabetes can be put into remission.
After the 8-week diet, volunteers had reduced the amount of fat in their liver and pancreas. This helped to restore their insulin production and put their Type 2 diabetes into remission. Three months later, some had put weight back on, but most still had normal blood glucose control.
This study was only a first step. It was designed to tell us about the underlying biology of Type 2 diabetes, and it followed the participants for only three months.
Another study, published in 2016, confirmed these findings and showed (in 30 people) that Type 2 diabetes could be kept in remission 6 months after the low-calorie diet was completed. It also suggested that the diet was effective in people that had had Type 2 diabetes for up to 10 years.
Both of these studies were very small, and were carried out in a research environment. We don't yet understand the long-term effects of these diets, or how a low-calorie diet might be used to bring about and maintain Type 2 diabetes remission in a real-life setting, as part of routine GP care.
What is the aim of the current research?
The DiRECT (Diabetes Remission Clinical Trial) study aims to find out if intensive weight control can bring about the remission of Type 2 diabetes and be maintained long-term through routine NHS care.
The trial will compare the long-term effects of a low-calorie diet and weight management programme to bsst available care for Type 2 diabetes.
What will the research involve?
A number of GP practices across Scotland and Tyneside are recruiting people aged 20-65 who are overweight and have been diagnosed with Type 2 diabetes in the last six years. Participants at half of the practices will receive the current best-available Type 2 diabetes care, while those at the other half will receive a low-calorie diet for between 8 and 20 weeks.
Afterwards, those on the low-calorie diet will be gradually re-introduced to normal food over a period of two to eight weeks and will receive expert support to help them maintain their weight loss in the long term.
Participants receiving best-available care will get weight loss support in accordance with the latest clinical guidelines, but won't receive the low-calorie diet.
The researchers will test metabolisms and measure fat deposits inside the body, to reveal exactly how major weight loss can put Type 2 diabetes into remission. They'll also carry out psychological assessments with the participants and healthcare professionals taking part in the study, to work out how this approach to weight management might form part of routine GP care.
Where is the research taking place?
This study will take place at around 30 GP practices in Scotland and Tyneside. The research will be carried out and the data analysed by researchers at the University of Glasgow and at Newcastle University.
Who can take part?
Only people invited to take part by their GP practice can get involved in this study. Recruitment is only taking place at selected GP practices in Scotland and Tyneside. Individual patients are not being recruited.
How will it benefit people with diabetes?
If this study shows that a low-calorie diet can safely put Type 2 diabetes into remission for the long-term, it could completely transform the way this condition is viewed and treated.
If the diet can be used practically and effectively, it could lead to significant changes in the way that Type 2 diabetes is managed by the NHS. It could also help people with this condition live for longer, improving quality of life and reducing the risk of serious health complications, without the need for invasive weight loss surgery.
If a low-calorie diet can be used within routine GP care , it could ultimately be of enormous benefit to millions of people living with Type 2 diabetes in the UK.
When will results be available?
This study will last until October 2018, and the overall results will be released once all of the data has been analysed. We'll report the results in Diabetes UK publications and on the website.
The low-calorie diet
What will the diet used consist of?
The diet used in DiRECT will last for between 8 and 20 weeks and provide around 800 calories a day. It will consist of four diet soups or shakes per day, providing all essential vitamins and minerals and lots of fluids.
Will the diet cure Type 2 diabetes?
The diet being studied isn't a 'quick fix' for Type 2 diabetes. It should help people taking part in the study to lose weight – specifically, the fat in and around their liver and pancreas. This should, in turn, help to put their Type 2 diabetes into remission.
It's likely that some people who take part in the research will find the diet challenging, and every participant will have to work hard to keep weight off in the long-term to maintain Type 2 diabetes remission.
Is the diet used in this research available now?
Low-calorie diet foods are not available on prescription from the NHS. They're marketed by a range of private companies, but can be expensive and come with limited evidence of long-term benefit.
This research is the only way to tell if weight management using a low-calorie diet is practical and more effective than the current best-available treatments for Type 2 diabetes.
Should people with Type 2 diabetes follow the diet used in this research?
Until we have evidence that a low-calorie diet is more effective than the current best-available treatment, Diabetes UK recommend that people with Type 2 diabetes only attempt to lose weight in this way after they have spoken to their GP.
We're confident that DiRECT will answer important questions and give the NHS enough evidence to decide whether low-calorie diets should be offered as a routine treatment option. People with diabetes should always consult their GP before making changes to the way that they manage their condition.
What diet does Diabetes UK recommend for people with Type 2?
Diabetes UK recommends that people with Type 2 diabetes eat a healthy, balanced diet that is low in sugar, salt and fat and includes plenty of fruits and vegetables. For information on living a healthy lifestyle and eating well with Type 2 diabetes please see our guide to diabetes.
2016年6月28日星期二
Low cardiorespiratory fitness and poor muscle strength increase their risk for type 2 diabetes
For adolescents, low cardiorespiratory fitness and poor muscle strength increase their risk for type 2 diabetes later in life, regardless of body weight, according to a study of young men in Sweden.
“Not only were both low aerobic and muscular fitness linked with a higher long-term risk of diabetes, but this was true even among those with normal body mass index,” said lead author Dr. Casey Crump of the Icahn School of Medicine at Mount Sinai in New York City.
These risk factors had a synergistic effect. In other words, the combination of low aerobic and muscular fitness increased diabetes risk more than the sum of the two individual risks, Crump told Reuters Health by email.
The researchers used data on more than one million 18-year-old military conscripts in Sweden between 1969 and 1997, without a history of diabetes.
The researchers followed these men until 2012, identifying type 2 diabetes diagnoses using national hospital and outpatient registries.
About 2%, or 34,000 men, were diagnosed with diabetes during follow-up, which lasted into middle age for most. Half were diagnosed after age 46.
Those who were least fit as 18-year olds were three times more likely to be diagnosed with diabetes than those with better measures of aerobic capacity and strength, even for young men with a healthy body mass index, as reported in the Annals of Internal Medicine, March 7.
“This study showed that fitness traits were important for the prediction of future diabetes at any body weight so it should not be ignored,” said Peter T. Katzmarzyk of Pennington Biomedical Research Center in Baton Rouge, Louisiana, who wrote an editorial accompanying the study.
But “every study uses a different definition of ‘fitness’ and it is not really possible to come up with a single number that can define fitness level, especially given the known difference across ages and between men and women,” he told Reuters Health by email.
Activity level and genetics are major determinants of physical fitness, but activity level is the most important modifiable factor, Crump said.
“More studies will be needed that measure physical fitness as well as diet and BMI at other time points across the lifespan to examine age windows of susceptibility to these factors in relation to diabetes,” he said.
These should include women and other populations, he said.
“Young people should maintain regular exercise and both aerobic and muscular fitness, and avoid barriers to this such as screen time,” Crump said.
Current guidelines recommend 60 minutes of exercise daily, most of which should be aerobic activity, but should also include muscle-strengthening activities at least three days per week, he said, but only about half of U.S. children and youth meet these guidelines.
“Not only were both low aerobic and muscular fitness linked with a higher long-term risk of diabetes, but this was true even among those with normal body mass index,” said lead author Dr. Casey Crump of the Icahn School of Medicine at Mount Sinai in New York City.
These risk factors had a synergistic effect. In other words, the combination of low aerobic and muscular fitness increased diabetes risk more than the sum of the two individual risks, Crump told Reuters Health by email.
The researchers used data on more than one million 18-year-old military conscripts in Sweden between 1969 and 1997, without a history of diabetes.
The researchers followed these men until 2012, identifying type 2 diabetes diagnoses using national hospital and outpatient registries.
About 2%, or 34,000 men, were diagnosed with diabetes during follow-up, which lasted into middle age for most. Half were diagnosed after age 46.
Those who were least fit as 18-year olds were three times more likely to be diagnosed with diabetes than those with better measures of aerobic capacity and strength, even for young men with a healthy body mass index, as reported in the Annals of Internal Medicine, March 7.
“This study showed that fitness traits were important for the prediction of future diabetes at any body weight so it should not be ignored,” said Peter T. Katzmarzyk of Pennington Biomedical Research Center in Baton Rouge, Louisiana, who wrote an editorial accompanying the study.
But “every study uses a different definition of ‘fitness’ and it is not really possible to come up with a single number that can define fitness level, especially given the known difference across ages and between men and women,” he told Reuters Health by email.
Activity level and genetics are major determinants of physical fitness, but activity level is the most important modifiable factor, Crump said.
“More studies will be needed that measure physical fitness as well as diet and BMI at other time points across the lifespan to examine age windows of susceptibility to these factors in relation to diabetes,” he said.
These should include women and other populations, he said.
“Young people should maintain regular exercise and both aerobic and muscular fitness, and avoid barriers to this such as screen time,” Crump said.
Current guidelines recommend 60 minutes of exercise daily, most of which should be aerobic activity, but should also include muscle-strengthening activities at least three days per week, he said, but only about half of U.S. children and youth meet these guidelines.
2016年5月12日星期四
AN OLD IDEA, REVIVED: STARVE CANCER TO DEATH
In the early 20th century, the German biochemist Otto Warburg believed that tumors could be treated by disrupting their source of energy. Hisidea was dismissed for decades — until now.
The story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes; whatever caused cancer, he surmised, had something to do with chromosomes.
Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer. But in the following decades, Warburg’s discovery would largely disappear from the cancer narrative, his contributions considered so negligible that they were left out of textbooks altogether.
Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.
Warburg’s discovery, later named the Warburg effect, is estimated to occur in up to 80 percent of cancers. It is so fundamental to most cancers that a positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer, works simply by revealing the places in the body where cells are consuming extra glucose. In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.
In the years following his breakthrough, Warburg became convinced that the Warburg effect occurs because cells are unable to use oxygen properly and that this damaged respiration is, in effect, the starting point of cancer. Well into the 1950s, this theory — which Warburg believed in until his death in 1970 but never proved — remained an important subject of debate within the field. And then, more quickly than anyone could have anticipated, the debate ended. In 1953, James Watson and Francis Crick pieced together the structure of the DNA molecule and set the stage for the triumph of molecular biology’s gene-centered approach to cancer. In the following decades, scientists came to regard cancer as a disease governed by mutated genes, which drive cells into a state of relentless division and proliferation. The metabolic catalysts that Warburg spent his career analyzing began to be referred to as “housekeeping enzymes” — necessary to keep a cell going but largely irrelevant to the deeper story of cancer.
“It was a stampede,” says Thomas Seyfried, a biologist at Boston College, of the move to molecular biology. “Warburg was dropped like a hot potato.” There was every reason to think that Warburg would remain at best a footnote in the history of cancer research. (As Dominic D’Agostino, an associate professor at the University of South Florida Morsani College of Medicine, told me, “The book that my students have to use for their cancer biology course has no mention of cancer metabolism.”) But over the past decade, and the past five years in particular, something unexpected happened: Those housekeeping enzymes have again become one of the most promising areas of cancer research. Scientists now wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms.
There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t. The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.
Even James Watson, one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. At his office at the Cold Spring Harbor Laboratory in Long Island, Watson, 88, sat beneath one of the original sketches of the DNA molecule and told me that locating the genes that cause cancer has been “remarkably unhelpful” — the belief that sequencing your DNA is going to extend your life “a cruel illusion.” If he were going into cancer research today, Watson said, he would study biochemistry rather than molecular biology.
“I never thought, until about two months ago, I’d ever have to learn the Krebs cycle,” he said, referring to the reactions, familiar to most high-school biology students, by which a cell powers itself. “Now I realize I have to.”
Born in 1883 into the illustrious Warburg family, Otto Warburg was raised to be a science prodigy. His father, Emil, was one of Germany’s leading physicists, and many of the world’s greatest physicists and chemists, including Albert Einstein and Max Planck, were friends of the family. (When Warburg enlisted in the military during World War I, Einstein sent him a letter urging him to come home for the sake of science.) Those men had explained the mysteries of the universe with a handful of fundamental laws, and the young Warburg came to believe he could bring that same elegant simplicity and clarity to the workings of life. Long before his death, Warburg was considered perhaps the greatest biochemist of the 20th century, a man whose research was vital to our understanding not only of cancer but also of respiration and photosynthesis. In 1931 he won the Nobel Prize for his work on respiration, and he was considered for the award on two other occasions — each time for a different discovery. Records indicate that he would have won in 1944, had the Nazis not forbidden the acceptance of the Nobel by German citizens.
That Warburg was able to live in Germany and continue his research throughout World War II, despite having Jewish ancestry and most likely being gay, speaks to the German obsession with cancer in the first half of the 20th century. At the time, cancer was more prevalent in Germany than in almost any other nation. According to the Stanford historian Robert Proctor, by the 1920s Germany’s escalating cancer rates had become a “major scandal.” A number of top Nazis, including Hitler, are believed to have harbored a particular dread of the disease; Hitler and Joseph Goebbels took the time to discuss new advances in cancer research in the hours leading up to the Nazi invasion of the Soviet Union. Whether Hitler was personally aware of Warburg’s research is unknown, but one of Warburg’s former colleagues wrote that several sources told him that “Hitler’s entourage” became convinced that “Warburg was the only scientist who offered a serious hope of producing a cure for cancer one day.”
Although many Jewish scientists fled Germany during the 1930s, Warburg chose to remain. According to his biographer, the Nobel Prize-winning biochemist Hans Krebs, who worked in Warburg’s lab, “science was the dominant emotion” of Warburg’s adult life, “virtually subjugating all other emotions.” In Krebs’s telling, Warburg spent years building a small team of specially trained technicians who knew how to run his experiments, and he feared that his mission to defeat cancer would be set back significantly if he had to start over. But after the war, Warburg fired all the technicians, suspecting that they had reported his criticisms of the Third Reich to the Gestapo. Warburg’s reckless decision to stay in Nazi Germany most likely came down to his astonishing ego. (Upon learning he had won the Nobel Prize, Warburg’s response was, “It’s high time.”)
“Modesty was not a virtue of Otto Warburg,” says George Klein, a 90-year-old cancer researcher at the Karolinska Institute in Sweden. As a young man, Klein was asked to send cancer cells to Warburg’s lab. A number of years later, Klein’s boss approached Warburg for a recommendation on Klein’s behalf. “George Klein has made a very important contribution to cancer research,” Warburg wrote. “He has sent me the cells with which I have solved the cancer problem.” Klein also recalls the lecture Warburg gave in Stockholm in 1950 at the 50th anniversary of the Nobel Prize. Warburg drew four diagrams on a blackboard explaining the Warburg effect, and then told the members of the audience that they represented all that they needed to know about the biochemistry of cancer.
Warburg was so monumentally stubborn that he refused to use the word “mitochondria,” even after it had been widely accepted as the name for the tiny structures that power cells. Instead Warburg persisted in calling them “grana,” the term he came up with when he identified those structures as the site of cellular respiration. Few things would have been more upsetting to him than the thought of Nazi thugs chasing him out of the beautiful Berlin institute, modeled after a country manor and built specifically for him. After the war, the Russians approached Warburg and offered to erect a new institute in Moscow. Klein recalls that Warburg told them with great pride that both Hitler and Stalin had failed to move him. As Warburg explained to his sister: “Ich war vor Hitler da” — “I was here before Hitler.”
Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal,” Warburg wrote in 1956, responding to a criticism of his hypothesis that cancer is a problem of energy. “A man who knows nothing at all about engines, their structure and their purpose may discover the difference. He may, for example, smell it.”
The “complete combustion,” in Warburg’s analogy, is respiration. The “incomplete combustion,” turning nutrients into energy without oxygen, is known as fermentation. Fermentation provides a useful backup when oxygen can’t reach cells quickly enough to keep up with demand. (Our muscle cells turn to fermentation during intense exercise.) Warburg thought that defects prevent cancer cells from being able to use respiration, but scientists now widely agree that this is wrong. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warburg effect opens the gates for more and more trucks to deliver building materials (in the form of glucose molecules) to make “daughter” cells.
If this theory can explain the “why” of the Warburg effect, it still leaves the more pressing question of what, exactly, sets a cell on the path to the Warburg effect and cancer. Scientists at several of the nation’s top cancer hospitals have spearheaded the Warburg revival, in hopes of finding the answer. These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients.
Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism. In Thompson’s analogy, the Warburg effect can be thought of as a social failure: a breakdown of the nutrient-sharing agreement that single-celled organisms signed when they joined forces to become multicellular organisms. His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide. Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin. But Thompson’s search for those mutations didn’t lead to an entirely new discovery. Instead, it led him to AKT, a gene already well known to molecular biologists for its role in promoting cell division. Thompson now believes AKT plays an even more fundamental role in metabolism.
The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat; it instead stuffs itself with glucose. Thompson discovered he could induce the “full Warburg effect” simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible. When Thompson presents his research to high-school students, he shows them a slide of mold spreading across a piece of bread. The slide’s heading — “Everyone’s first cancer experiment” — recalls Warburg’s observation that cancer cells will carry out fermentation at almost the same rate of wildly growing yeasts.
Just as Thompson has redefined the role of AKT, Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, has helped lead the cancer world to an appreciation of how one widely studied gene can profoundly influence a tumor’s metabolism. In 1997, Dang became one of the first scientists to connect molecular biology to the science of cellular metabolism when he demonstrated that MYC — a so-called regulator gene well known for its role in cell proliferation — directly targets an enzyme that can turn on the Warburg effect. Dang recalls that other researchers were skeptical of his interest in a housekeeping enzyme, but he stuck with it because he came to appreciate something critical: Cancer cells can’t stop eating.
Unlike healthy cells, growing cancer cells are missing the internal feedback loops that are designed to conserve resources when food isn’t available. They’re “addicted to nutrients,” Dang says; when they can’t consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer: It’s not that other types of alterations can’t arise first, but rather that, when they do, the incipient tumors lack the access to the nutrients they need to grow. Dang uses the analogy of a work crew trying to put up a building. “If you don’t have enough cement, and you try to put a lot of bricks together, you’re going to collapse,” he says.
Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions.
Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells and, at least in rats and rabbits, wipe out advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. Dang says the hope is not necessarily to find a cure but rather to keep cancer at bay in a “smoldering quiet state,” much as patients treat their hypertension.
Warburg, too, appreciated that a tumor’s dependence upon a steady flow of nutrients might eventually prove to be its fatal weakness. Long after his initial discovery of the Warburg effect, he continued to research the enzymes involved in fermentation and to explore the possibility of blocking the process in cancer cells. The challenge Warburg faced then is the same one that metabolism researchers face today: Cancer is an incredibly persistent foe. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but tumors tend to find another way. “You block glucose, they use glutamine,” Dang says, in reference to another primary fuel used by cancers. “You block glucose and glutamine, they might be able to use fatty acids. We don’t know yet.”
Given Warburg’s own story of historical neglect, it’s fitting that what may turn out to be one of the most promising cancer metabolism drugs has been sitting in plain sight for decades. That drug, metformin, is already widely prescribed to decrease the glucose in the blood of diabetics (76.9 million metformin prescriptions were filled in the United States in 2014). In the years ahead, it’s likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking. Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do.
Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows, and used a centrifuge at his lab to make his cream and butter.
Warburg’s personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer.
The insulin hypothesis can be traced to the research of Lewis Cantley, the director of the Meyer Cancer Center at Weill Cornell Medical College. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell. Cantley now refers to insulin and a closely related hormone, IGF-1 (insulinlike growth factor 1), as “the champion” activators of metabolic proteins linked to cancer. He’s beginning to see evidence, he says, that in some cases, “it really is insulin itself that’s getting the tumor started.” One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway “gone awry — it’s cells behaving as though insulin were telling it to take up glucose all the time and to grow.” Cantley, who avoids eating sugar as much as he can, is currently studying the effects of diet on mice that have the mutations that are commonly found in colorectal and other cancers. He says that the effects of a sugary diet on colorectal, breast and other cancer models “looks very impressive” and “rather scary.”
Elevated insulin is also strongly associated with obesity, which is expected soon to overtake smoking as the leading cause of preventable cancer. Cancers linked to obesity and diabetes have more receptors for insulin and IGF-1, and people with defective IGF-1 receptors appear to be nearly immune to cancer. Retrospective studies, which look back at patient histories, suggest that many people who develop colorectal, pancreatic or breast cancer have elevated insulin levels before diagnosis. It’s perhaps not entirely surprising, then, that when researchers want to grow breast-cancer cells in the lab, they add insulin to the tissue culture. When they remove the insulin, the cancer cells die.
“I think there’s no doubt that insulin is pro-cancer,” Watson says, with respect to the link between obesity, diabetes and cancer. “It’s as good a hypothesis as we have now.” Watson takes metformin for cancer prevention; among its many effects, metformin works to lower insulin levels. Not every cancer researcher, however, is convinced of the role of insulin and IGF-1 in cancer. Robert Weinberg, a researcher at M.I.T.’s Whitehead Institute who pioneered the discovery of cancer-causing genes in the ’80s, has remained somewhat cool to certain aspects of the cancer-metabolism revival. Weinberg says that there isn’t yet enough evidence to know whether the levels of insulin and IGF-1 present in obese people are sufficient to trigger the Warburg effect. “It’s a hypothesis,” Weinberg says. “I don’t know if it’s right or wrong.”
During Warburg’s lifetime, insulin’s effects on metabolic pathways were even less well understood. But given his ego, it’s highly unlikely that he would have considered the possibility that anything other than damaged respiration could cause cancer. He died sure that he was right about the disease. Warburg framed a quote from Max Planck and hung it above his desk: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die.”
The story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes; whatever caused cancer, he surmised, had something to do with chromosomes.
Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer. But in the following decades, Warburg’s discovery would largely disappear from the cancer narrative, his contributions considered so negligible that they were left out of textbooks altogether.
Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.
Warburg’s discovery, later named the Warburg effect, is estimated to occur in up to 80 percent of cancers. It is so fundamental to most cancers that a positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer, works simply by revealing the places in the body where cells are consuming extra glucose. In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.
In the years following his breakthrough, Warburg became convinced that the Warburg effect occurs because cells are unable to use oxygen properly and that this damaged respiration is, in effect, the starting point of cancer. Well into the 1950s, this theory — which Warburg believed in until his death in 1970 but never proved — remained an important subject of debate within the field. And then, more quickly than anyone could have anticipated, the debate ended. In 1953, James Watson and Francis Crick pieced together the structure of the DNA molecule and set the stage for the triumph of molecular biology’s gene-centered approach to cancer. In the following decades, scientists came to regard cancer as a disease governed by mutated genes, which drive cells into a state of relentless division and proliferation. The metabolic catalysts that Warburg spent his career analyzing began to be referred to as “housekeeping enzymes” — necessary to keep a cell going but largely irrelevant to the deeper story of cancer.
“It was a stampede,” says Thomas Seyfried, a biologist at Boston College, of the move to molecular biology. “Warburg was dropped like a hot potato.” There was every reason to think that Warburg would remain at best a footnote in the history of cancer research. (As Dominic D’Agostino, an associate professor at the University of South Florida Morsani College of Medicine, told me, “The book that my students have to use for their cancer biology course has no mention of cancer metabolism.”) But over the past decade, and the past five years in particular, something unexpected happened: Those housekeeping enzymes have again become one of the most promising areas of cancer research. Scientists now wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms.
There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t. The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.
Even James Watson, one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. At his office at the Cold Spring Harbor Laboratory in Long Island, Watson, 88, sat beneath one of the original sketches of the DNA molecule and told me that locating the genes that cause cancer has been “remarkably unhelpful” — the belief that sequencing your DNA is going to extend your life “a cruel illusion.” If he were going into cancer research today, Watson said, he would study biochemistry rather than molecular biology.
“I never thought, until about two months ago, I’d ever have to learn the Krebs cycle,” he said, referring to the reactions, familiar to most high-school biology students, by which a cell powers itself. “Now I realize I have to.”
Born in 1883 into the illustrious Warburg family, Otto Warburg was raised to be a science prodigy. His father, Emil, was one of Germany’s leading physicists, and many of the world’s greatest physicists and chemists, including Albert Einstein and Max Planck, were friends of the family. (When Warburg enlisted in the military during World War I, Einstein sent him a letter urging him to come home for the sake of science.) Those men had explained the mysteries of the universe with a handful of fundamental laws, and the young Warburg came to believe he could bring that same elegant simplicity and clarity to the workings of life. Long before his death, Warburg was considered perhaps the greatest biochemist of the 20th century, a man whose research was vital to our understanding not only of cancer but also of respiration and photosynthesis. In 1931 he won the Nobel Prize for his work on respiration, and he was considered for the award on two other occasions — each time for a different discovery. Records indicate that he would have won in 1944, had the Nazis not forbidden the acceptance of the Nobel by German citizens.
That Warburg was able to live in Germany and continue his research throughout World War II, despite having Jewish ancestry and most likely being gay, speaks to the German obsession with cancer in the first half of the 20th century. At the time, cancer was more prevalent in Germany than in almost any other nation. According to the Stanford historian Robert Proctor, by the 1920s Germany’s escalating cancer rates had become a “major scandal.” A number of top Nazis, including Hitler, are believed to have harbored a particular dread of the disease; Hitler and Joseph Goebbels took the time to discuss new advances in cancer research in the hours leading up to the Nazi invasion of the Soviet Union. Whether Hitler was personally aware of Warburg’s research is unknown, but one of Warburg’s former colleagues wrote that several sources told him that “Hitler’s entourage” became convinced that “Warburg was the only scientist who offered a serious hope of producing a cure for cancer one day.”
Although many Jewish scientists fled Germany during the 1930s, Warburg chose to remain. According to his biographer, the Nobel Prize-winning biochemist Hans Krebs, who worked in Warburg’s lab, “science was the dominant emotion” of Warburg’s adult life, “virtually subjugating all other emotions.” In Krebs’s telling, Warburg spent years building a small team of specially trained technicians who knew how to run his experiments, and he feared that his mission to defeat cancer would be set back significantly if he had to start over. But after the war, Warburg fired all the technicians, suspecting that they had reported his criticisms of the Third Reich to the Gestapo. Warburg’s reckless decision to stay in Nazi Germany most likely came down to his astonishing ego. (Upon learning he had won the Nobel Prize, Warburg’s response was, “It’s high time.”)
“Modesty was not a virtue of Otto Warburg,” says George Klein, a 90-year-old cancer researcher at the Karolinska Institute in Sweden. As a young man, Klein was asked to send cancer cells to Warburg’s lab. A number of years later, Klein’s boss approached Warburg for a recommendation on Klein’s behalf. “George Klein has made a very important contribution to cancer research,” Warburg wrote. “He has sent me the cells with which I have solved the cancer problem.” Klein also recalls the lecture Warburg gave in Stockholm in 1950 at the 50th anniversary of the Nobel Prize. Warburg drew four diagrams on a blackboard explaining the Warburg effect, and then told the members of the audience that they represented all that they needed to know about the biochemistry of cancer.
Warburg was so monumentally stubborn that he refused to use the word “mitochondria,” even after it had been widely accepted as the name for the tiny structures that power cells. Instead Warburg persisted in calling them “grana,” the term he came up with when he identified those structures as the site of cellular respiration. Few things would have been more upsetting to him than the thought of Nazi thugs chasing him out of the beautiful Berlin institute, modeled after a country manor and built specifically for him. After the war, the Russians approached Warburg and offered to erect a new institute in Moscow. Klein recalls that Warburg told them with great pride that both Hitler and Stalin had failed to move him. As Warburg explained to his sister: “Ich war vor Hitler da” — “I was here before Hitler.”
Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal,” Warburg wrote in 1956, responding to a criticism of his hypothesis that cancer is a problem of energy. “A man who knows nothing at all about engines, their structure and their purpose may discover the difference. He may, for example, smell it.”
The “complete combustion,” in Warburg’s analogy, is respiration. The “incomplete combustion,” turning nutrients into energy without oxygen, is known as fermentation. Fermentation provides a useful backup when oxygen can’t reach cells quickly enough to keep up with demand. (Our muscle cells turn to fermentation during intense exercise.) Warburg thought that defects prevent cancer cells from being able to use respiration, but scientists now widely agree that this is wrong. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warburg effect opens the gates for more and more trucks to deliver building materials (in the form of glucose molecules) to make “daughter” cells.
If this theory can explain the “why” of the Warburg effect, it still leaves the more pressing question of what, exactly, sets a cell on the path to the Warburg effect and cancer. Scientists at several of the nation’s top cancer hospitals have spearheaded the Warburg revival, in hopes of finding the answer. These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients.
Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism. In Thompson’s analogy, the Warburg effect can be thought of as a social failure: a breakdown of the nutrient-sharing agreement that single-celled organisms signed when they joined forces to become multicellular organisms. His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide. Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin. But Thompson’s search for those mutations didn’t lead to an entirely new discovery. Instead, it led him to AKT, a gene already well known to molecular biologists for its role in promoting cell division. Thompson now believes AKT plays an even more fundamental role in metabolism.
The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat; it instead stuffs itself with glucose. Thompson discovered he could induce the “full Warburg effect” simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible. When Thompson presents his research to high-school students, he shows them a slide of mold spreading across a piece of bread. The slide’s heading — “Everyone’s first cancer experiment” — recalls Warburg’s observation that cancer cells will carry out fermentation at almost the same rate of wildly growing yeasts.
Just as Thompson has redefined the role of AKT, Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, has helped lead the cancer world to an appreciation of how one widely studied gene can profoundly influence a tumor’s metabolism. In 1997, Dang became one of the first scientists to connect molecular biology to the science of cellular metabolism when he demonstrated that MYC — a so-called regulator gene well known for its role in cell proliferation — directly targets an enzyme that can turn on the Warburg effect. Dang recalls that other researchers were skeptical of his interest in a housekeeping enzyme, but he stuck with it because he came to appreciate something critical: Cancer cells can’t stop eating.
Unlike healthy cells, growing cancer cells are missing the internal feedback loops that are designed to conserve resources when food isn’t available. They’re “addicted to nutrients,” Dang says; when they can’t consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer: It’s not that other types of alterations can’t arise first, but rather that, when they do, the incipient tumors lack the access to the nutrients they need to grow. Dang uses the analogy of a work crew trying to put up a building. “If you don’t have enough cement, and you try to put a lot of bricks together, you’re going to collapse,” he says.
Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions.
Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells and, at least in rats and rabbits, wipe out advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. Dang says the hope is not necessarily to find a cure but rather to keep cancer at bay in a “smoldering quiet state,” much as patients treat their hypertension.
Warburg, too, appreciated that a tumor’s dependence upon a steady flow of nutrients might eventually prove to be its fatal weakness. Long after his initial discovery of the Warburg effect, he continued to research the enzymes involved in fermentation and to explore the possibility of blocking the process in cancer cells. The challenge Warburg faced then is the same one that metabolism researchers face today: Cancer is an incredibly persistent foe. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but tumors tend to find another way. “You block glucose, they use glutamine,” Dang says, in reference to another primary fuel used by cancers. “You block glucose and glutamine, they might be able to use fatty acids. We don’t know yet.”
Given Warburg’s own story of historical neglect, it’s fitting that what may turn out to be one of the most promising cancer metabolism drugs has been sitting in plain sight for decades. That drug, metformin, is already widely prescribed to decrease the glucose in the blood of diabetics (76.9 million metformin prescriptions were filled in the United States in 2014). In the years ahead, it’s likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking. Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do.
Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows, and used a centrifuge at his lab to make his cream and butter.
Warburg’s personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer.
The insulin hypothesis can be traced to the research of Lewis Cantley, the director of the Meyer Cancer Center at Weill Cornell Medical College. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell. Cantley now refers to insulin and a closely related hormone, IGF-1 (insulinlike growth factor 1), as “the champion” activators of metabolic proteins linked to cancer. He’s beginning to see evidence, he says, that in some cases, “it really is insulin itself that’s getting the tumor started.” One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway “gone awry — it’s cells behaving as though insulin were telling it to take up glucose all the time and to grow.” Cantley, who avoids eating sugar as much as he can, is currently studying the effects of diet on mice that have the mutations that are commonly found in colorectal and other cancers. He says that the effects of a sugary diet on colorectal, breast and other cancer models “looks very impressive” and “rather scary.”
Elevated insulin is also strongly associated with obesity, which is expected soon to overtake smoking as the leading cause of preventable cancer. Cancers linked to obesity and diabetes have more receptors for insulin and IGF-1, and people with defective IGF-1 receptors appear to be nearly immune to cancer. Retrospective studies, which look back at patient histories, suggest that many people who develop colorectal, pancreatic or breast cancer have elevated insulin levels before diagnosis. It’s perhaps not entirely surprising, then, that when researchers want to grow breast-cancer cells in the lab, they add insulin to the tissue culture. When they remove the insulin, the cancer cells die.
“I think there’s no doubt that insulin is pro-cancer,” Watson says, with respect to the link between obesity, diabetes and cancer. “It’s as good a hypothesis as we have now.” Watson takes metformin for cancer prevention; among its many effects, metformin works to lower insulin levels. Not every cancer researcher, however, is convinced of the role of insulin and IGF-1 in cancer. Robert Weinberg, a researcher at M.I.T.’s Whitehead Institute who pioneered the discovery of cancer-causing genes in the ’80s, has remained somewhat cool to certain aspects of the cancer-metabolism revival. Weinberg says that there isn’t yet enough evidence to know whether the levels of insulin and IGF-1 present in obese people are sufficient to trigger the Warburg effect. “It’s a hypothesis,” Weinberg says. “I don’t know if it’s right or wrong.”
During Warburg’s lifetime, insulin’s effects on metabolic pathways were even less well understood. But given his ego, it’s highly unlikely that he would have considered the possibility that anything other than damaged respiration could cause cancer. He died sure that he was right about the disease. Warburg framed a quote from Max Planck and hung it above his desk: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die.”
2016年4月19日星期二
Hope for Reversing Type 2 Diabetes
Many experts believe Type 2 diabetes is an incurable disease that gets worse with time. But new research raises the tantalizing possibility that drastic changes in diet may reverse the disease in some people.
Recently, a small clinical trial in England studied the effects of a strict liquid diet on 30 people who had lived with Type 2 diabetes for up to 23 years. Nearly half of those studied had a remission that lasted six months after the diet was over. While the study was small, the finding offers hope to millions who have been told they must live with the intractable disease.
“This is a radical change in our understanding of Type 2 diabetes,” said Dr. Roy Taylor, a professor at Newcastle University in England and the study’s senior author. “If we can get across the message that ‘yes, this is a reversible disease — that you will have no more diabetes medications, no more sitting in doctors’ rooms, no more excess health charges’ — that is enormously motivating.”
It is not the first time that people have reversed type 2 diabetes by losing a lot of weight shortly after a diagnosis. Studies have also shown that obese individuals who have bariatric surgery frequently see the condition vanish even before they lose very much weight.
But the new study, published in Diabetes Care, proved the reversal after diet can persist for at least half a year as long as patients keep weight off, and can occur in people who have had the disease for many years.
The researchers followed the participants after they had completed an eight-week low-calorie-milkshake diet and returned to normal eating. Six months later, those who had gone into remission immediately after the diet were still diabetes-free. Though most of those who reversed the disease had had it for less than four years, some had been diabetic for more than eight years.
When Allan Tutty, 57, learned five years ago that he had Type 2 diabetes, he asked health care providers if there was a cure. “It was a case of, look, you’ve got it, deal with it, there’s no cure,” said Mr. Tutty, who manages a home for people with brain injuries in Newcastle.
Later, Mr. Tutty spotted a notice recruiting volunteers for a diabetes study that asked, “Would you like the opportunity to reverse your condition?”
Mr. Tutty said he jumped at the chance, becoming one of 30 men and women ages 25 to 80 to sign up. Mr. Tutty was one of 13 participants whose fasting plasma glucose dropped, and during the six-month follow-up remained below the seven millimole per liter (or 126 milligrams per deciliter) that defines diabetes. Although Mr. Tutty completed the study nearly three years ago, his fasting blood sugars continue to range from 5.2 to 5.6 mmol/L, he said.
Type 2 diabetes develops when the body cannot use insulin properly or make enough insulin, so the body cannot properly use or store glucose (a form of sugar) and sugar backs up into the bloodstream, raising blood sugar levels. In the United States, some 8.9 percent of adults 20 and older have been found to have diabetes, and health officials estimate that another 3.5 percent have undiagnosed diabetes.
Although no one knows exactly why the diet appeared to reverse diabetes, Dr. Taylor said the explanation may be related to how the body stores fat. Excess fat in the liver can spill into the pancreas, inhibiting insulin secretion and the liver’s response to insulin, resulting in insulin resistance and diabetes.
Going on a very-low-calorie diet may allow the body to use up fat from the liver, causing fat levels to drop in the pancreas as well. That “wakes up” the insulin-producing cells in the pancreas, normalizing blood glucose levels.
While some previous studies have shown that blood sugars can normalize after significant weight loss, endocrinologists said they were impressed by the persistence of the lower blood sugar levels for months after the diet.
“Decreasing caloric intake for any reason brings with it a rapid improvement in glucose control,” said Dr. Robert Lash, the chairman of the Endocrine Society’s clinical affairs committee and a professor of internal medicine at the University of Michigan. “What’s exciting here is that the improvements in glucose control persisted when the participants went back to eating a diet with a normal number of calories.”
While the research suggests the potential for a cure, questions remain about how long the effect will last and whether it can work for the typical patient with diabetes.
“It’s definitely doable,” said Dr. George King, the chief scientific officer at Joslin Diabetes Center and a professor at Harvard Medical School. The question, he said, is: Can people maintain the weight loss and “continue to have this reversal for many, many years?”
“That is the difficult part,” he added.
Dr. King said that even short-term remission would reduce or put off some of the serious complications associated with diabetes, like nerve damage, kidney damage, loss of vision, heart attacks and strokes. Yet structured weight loss programs are expensive and often not covered by insurance, and physicians — who are often not well-versed in nutrition — may not take the time to counsel patients about diet, Dr. King said.
The participants in the Newcastle trial, who ranged from overweight to extremely obese, were told to stop their diabetes medications and start a 600- to 700-calorie-a-day diet, consisting of three diet milkshakes a day at mealtimes and half a pound of nonstarchy vegetables a day.
Mr. Tutty, who weighed about 213 pounds before the trial, lost a little more than 30 pounds, the average weight loss in the trial. The people in the study most likely to respond to the treatment were in their early 50s on average and younger than the nonresponders, and they had had diabetes for fewer years. The responders were also healthier before the trial: They had been taking fewer medications than nonresponders, had lower fasting glucose and hemoglobin A1c before the trial, and had higher baseline serum insulin levels. Three of those who went into remission had lived with diabetes for more than eight years.
Many of the responders are still in the prediabetes zone and at risk for developing diabetes, Dr. Taylor said. “It’s not fair to say they were completely normalized, but they’re at a level of blood sugar where we don’t expect to see the serious complications associated with diabetes,” he said. “That’s why it’s such good news.”
The big challenge for dieters was returning to normal eating, and trial participants received intensive counseling from a researcher on the team about how to eat after ending the liquid diet, Dr. Taylor said.
“They would describe going back to the kitchen and almost having a panic attack,” he said. “We used that as an opportunity to instill new habits, and were very directive about how much to cook and how much to eat.”
2016年1月5日星期二
糖尿病從頭說起
造藥售藥是最賺錢的生意之一，這是眾所周知的。然則什麼類型的藥最能「吸金」？排名一至五是：抗癌藥、高血壓藥、降血脂藥、糖尿藥、止痛藥。其中糖尿藥雖然現在已經有很多，藥廠還是興致勃勃地、不停研發新藥，因為愈來愈多人患上這個病，餅縱是做多一些，也不愁沒有人吃：市場只有愈來愈大。在病人來說，一患上這病就擺脫不了；如果不妥善處理，糖尿病大可以引致白內障、失明、腎衰竭、高血壓甚至腦退化（癡呆）。最新的消息是，美國莊生藥廠（Johnson & Johnson）今年3月獲美國FDA「食物與藥物管理局」批文，准它出售一個叫Invokana（學名Canagliflozin）的糖尿病藥。此藥能令J&J每年進賬約40億美元。
糖尿病可以說是「富貴」病：是患在太多（養分），而不是患在太少；病人的血中含有過量的葡萄糖，多到「漏」進尿液。不熟悉病理的人可能會感到大惑不解：若飲水過量，腎臟自會將太多的水排出體外；同樣地，若吸收了太多葡萄糖，腎不是應該也會把多餘的葡萄糖解決掉嗎？事實上非如此。若血液中有太多葡萄糖，糖分與血液中蛋白質化合，會衍生一類「晚期糖基化終端物」（Advanced Glycation Endproducts，AGEs）；後者能損害眼角膜、視網膜、腎小球、血管和神經。在正常的情況下，當小腸將澱粉質消化，成為葡萄糖，以及把葡萄糖送到血液中之時，肌肉細胞等會快速吸收血液中的糖分。於是，血液中不會有太多的葡萄糖，也就不會出現AGEs。這個所謂「吸收」之舉，乃是由細胞主動的，血液中的葡萄糖不會自發地走入細胞中。肌肉細胞表面有一些叫Glucose Transporter-4（GLUT-4）的「葡萄糖接受體」負責把血液中的葡萄糖「拖」入細胞中。若肌肉細胞沒有足夠的GLUT-4，便會出現糖尿病。再者，所謂肌肉細胞「表面」的GLUT-4，本來是獃在細胞內的。是憑一個由胰臟分泌的「胰島素」（Insulin），透過肌肉細胞表面的「胰島素接受體」，刺激到細胞的一個酵素（又稱為「激酶」Kinase），將GLUT-4從它的細胞質（內部）搬到其細胞表面。從上述的機制可見，是有三個關鍵點主宰着糖分的物流，令有足夠的糖分能去到目的地，多餘的則能適當地被處理掉，不致於留下來，造成不當的壞後果。這三個關鍵點在於第一，有適量的胰島素；第二，有足夠的GLUT-4；第三，有「將血液中餘下來糖分」解決掉的能力。因此，目前研發出來用以對付糖尿病的藥，其藥效分別針對（一）刺激胰細胞分泌胰島素；（二）增加細胞的GLUT-4；及（三）把多餘的血糖排出體外。
胰島素的分泌
葡萄糖怎樣「由食物中產生後進入血液、再而由血液進入一般細胞內」的過程。其中涉及兩個關鍵性的操作，包括（1）胰島素如何生成，和（2）胰島素如何令細胞建立「收貨」的機制（牽涉到一個叫GLUT-4的「葡萄糖接受體」），以便能將血液中的糖分拖進細胞內。在這兩個操作中，若有阻滯或不善之處，可以令一些剩餘（細胞吸收不到的）糖分，（不當地）滯留在血液中，從而引致「血糖」過高，再彰顯成為「尿液中有糖」現象，我們稱之為「糖尿病」。身體「三個應付糖尿病的關鍵點」，包括第一，須有適量的胰島素；第二，須有足夠的GLUT-4；第三，須具足夠能力，令血液中不存有「餘下來的糖分」。從這三個關鍵點切入，西醫「如何醫理糖尿病」的原則性方向：目前已研發出來、用以對付糖尿病的藥，其藥效主要在於提升身體三個功能，分別是（一）刺激胰細胞分泌胰島素；（二）增加細胞的GLUT-4；及（三）把多餘的血糖排出體外。在其後的兩篇文章中，我岔開話題，先談及「包裝」，繼而談到「預告」系統，為的是要替「解釋胰島素如何生成」鋪路。今天可以來一個總結，言歸正傳。
胰臟中的細胞，是怎麼樣分泌胰島素的？當胰細胞製造出胰島素之後，先是把胰島素「包裝」起來，換言之，將其儲存在一些小泡（我們稱之為「囊泡」Vesicle）之中。當胰細胞受到刺激，這些小泡會黏附上（胰細胞）細胞膜的內壁。在這時候，小泡的泡膜，會與胰細胞的細胞膜，互相融合，從而產生一個「胞吐作用」（Exocytosis）。胞吐作用可令胰細胞的細胞膜生出缺口；於是小泡內的胰島素，便會被「逐出」胰細胞。然則胰細胞是受到了什麼刺激，驅使它們這樣做？刺激來自一些化學物，叫「鈣」。如果有鈣湧入細胞的內部，會刺激到細胞內的「攜鈣素」（Calmodulin），後者促使胰小泡黏附在它的細胞膜之內壁，令胰島素被送出胰細胞。再問下去：為什麼無緣無故，可令鈣湧入細胞的內部？答案是：胰細胞表面的鈣通道被打開了；而最奇妙的，是這個「鈣通道被打開」的後果，正正來自「血液中有糖分」這個原因；兩者之間，原是有直接因果關係的。具體情況是：一方面，小腸在吸收葡萄糖時會分泌一個叫GLP-1（Glucagon-Like Peptide-1）的小蛋白質。GLP-1隨血液去到胰，「預告」胰臟會有血糖接踵而來，令胰細胞表面的「鈣通道」打開；另一方面，血糖進入了胰細胞，也會開啟它的「鈣通道」。
葡萄糖怎樣「由食物中產生後進入血液、再而由血液進入一般細胞內」的過程。其中涉及兩個關鍵性的操作，包括（1）胰島素如何生成，和（2）胰島素如何令細胞建立「收貨」的機制（牽涉到一個叫GLUT-4的「葡萄糖接受體」），以便能將血液中的糖分拖進細胞內。在這兩個操作中，若有阻滯或不善之處，可以令一些剩餘（細胞吸收不到的）糖分，（不當地）滯留在血液中，從而引致「血糖」過高，再彰顯成為「尿液中有糖」現象，我們稱之為「糖尿病」。身體「三個應付糖尿病的關鍵點」，包括第一，須有適量的胰島素；第二，須有足夠的GLUT-4；第三，須具足夠能力，令血液中不存有「餘下來的糖分」。從這三個關鍵點切入，西醫「如何醫理糖尿病」的原則性方向：目前已研發出來、用以對付糖尿病的藥，其藥效主要在於提升身體三個功能，分別是（一）刺激胰細胞分泌胰島素；（二）增加細胞的GLUT-4；及（三）把多餘的血糖排出體外。在其後的兩篇文章中，我岔開話題，先談及「包裝」，繼而談到「預告」系統，為的是要替「解釋胰島素如何生成」鋪路。今天可以來一個總結，言歸正傳。
胰臟中的細胞，是怎麼樣分泌胰島素的？當胰細胞製造出胰島素之後，先是把胰島素「包裝」起來，換言之，將其儲存在一些小泡（我們稱之為「囊泡」Vesicle）之中。當胰細胞受到刺激，這些小泡會黏附上（胰細胞）細胞膜的內壁。在這時候，小泡的泡膜，會與胰細胞的細胞膜，互相融合，從而產生一個「胞吐作用」（Exocytosis）。胞吐作用可令胰細胞的細胞膜生出缺口；於是小泡內的胰島素，便會被「逐出」胰細胞。然則胰細胞是受到了什麼刺激，驅使它們這樣做？刺激來自一些化學物，叫「鈣」。如果有鈣湧入細胞的內部，會刺激到細胞內的「攜鈣素」（Calmodulin），後者促使胰小泡黏附在它的細胞膜之內壁，令胰島素被送出胰細胞。再問下去：為什麼無緣無故，可令鈣湧入細胞的內部？答案是：胰細胞表面的鈣通道被打開了；而最奇妙的，是這個「鈣通道被打開」的後果，正正來自「血液中有糖分」這個原因；兩者之間，原是有直接因果關係的。具體情況是：一方面，小腸在吸收葡萄糖時會分泌一個叫GLP-1（Glucagon-Like Peptide-1）的小蛋白質。GLP-1隨血液去到胰，「預告」胰臟會有血糖接踵而來，令胰細胞表面的「鈣通道」打開；另一方面，血糖進入了胰細胞，也會開啟它的「鈣通道」。
助胰島素分泌的藥
「糖尿病」形成的原因之一，是胰臟沒有正常的胰島素分泌；換言之，分泌量太少。一方面，小腸在吸收葡萄糖時會分泌一個叫GLP-1（Glucagon-Like Peptide-1）的小蛋白質。GLP-1隨血液去到胰，「預告」胰臟，會有血糖接踵而來，令胰細胞將它表面的「鈣通道」打開。另一方面，血中的葡萄糖（血糖）進入了胰細胞，會被其中的「粒線體」轉為能量，之後，能量被儲存起來。隨着血糖升高，能量儲存也會愈多，令胰細胞表面的「鉀通道」逐漸關掉，以致造成「電位」（Electrical Potential）的改變；此改變亦可促使細胞表面的「鈣通道」開啟。當胰細胞表面的鈣通道被打開後，會有「鈣」湧入細胞內部，從而刺激到細胞內的「攜鈣素」（Calmodulin）。後者可以促使一些胰小泡黏附在它細胞膜的內壁，令胰島素被送出胰細胞。什麼是胰小泡？這是一些「囊泡」Vesicle，好比是「袋」或「包裝物」，其中藏有胰島素。當胰細胞受到（鈣的）刺激，這些胰小泡會黏附上（胰細胞）細胞膜的內壁；接着，小泡的泡膜，會與胰細胞的細胞膜，互相融合，從而產生一個「胞吐作用」（Exocytosis），再而令胰細胞的細胞膜生出缺口；於是小泡內的胰島素，便會被「逐出」胰細胞。
上述乃分泌胰島素的過程；其中的機能若有差錯，會直接減少胰島素的分泌：「缺乏胰島素」，乃是糖尿病的主要成因之一。這方面有兩個特效藥，分別叫Diamicron（學名Gliclazide）和Januvia（學名Sitagliptin）；它們（透過不同的機制）能令「胰小泡」黏上「胰細胞細胞膜的內壁」。再進一步剖析：Diamicron做的工作是附上胰細胞表面的一個「SUR-1接受體」，為的是關掉細胞表面的「鉀通道」，從而開啟它的「鈣通道」；至於Januvia，則能更乾脆地開啟「鈣通道」。總而言之，兩者的藥效，都在於幫助胰細胞分泌胰島素。上文談及到，GLP-1亦可令胰細胞表面的「鈣通道」打開。不過，人體中自然地產生的GLP-1，可以很快被一個叫DPP-4（Dipeptidyl Peptidase-4）的酵素分解掉。有一間叫Amylin的藥廠，用人工合成方法造出了一個（能抵抗DPP-4）像GLP-1的藥，叫Byetta（學名Exenatide）。不過，這個藥有缺點，它不能口服（只能皮下注射），又可能令病人嘔吐。美國的默克藥廠（Merck）則推出了一個能抑制DPP-4的藥，叫Januvia。若DDP-4被抑制了，「負負得正」，GLP-1乃可充分發揮其功能，刺激胰細胞分泌胰島素。
胰島素抗拒
在一個人的身體中，有很多肌肉細胞，它們都需有葡萄糖，才能活下去。每當這人吃了東西，食物消化後產生很多葡萄糖，於是有糖分走進血液。但這些糖分不會自動走進細胞中。身體中有一些處於胰臟的細胞。這些胰細胞很有本領。它們有一些能「從血液中取糖」的「工具」，叫GLUT2，就生在自己細胞表面。於是胰細胞能很容易拿到血糖，正是「唾手可得」。胰細胞有了糖之後，能分泌一些叫胰島素的東西。憑這胰島素，肌肉細胞懂得利用到「私藏」起來（放在細胞內）的GLUT4，而且學胰細胞一般，懂得把GLUT4放在自己的細胞表面，於是也就能從血液中取糖分。之後GLUT4功成身退，回歸到細胞內部。待下一次血液中再次有糖分充斥時，胰細胞的胰島素，令肌肉細胞重新部署GLUT4，將血糖盡情吸收。後者若不是這樣做，它們可取不到糖分；這還是小事。葡萄糖留在血液之中，會跟隨血液全身到處遊走，去到某一些器官，可能闖禍。這情況叫糖尿病。
很多糖尿病患者的病因，在於胰細胞「分泌胰島素」的功能有缺失之處。怎樣可以補救？也有另類的糖尿病患者。他們的胰臟能正常地分泌胰島素；問題乃是在於他們的「肌肉細胞」無法將GLUT-4從細胞質搬到細胞表面，造成一個所謂「胰島素抗拒」（Insulin Resistance）現象。這種現象是可以惡性循環的。因為若是有多餘的糖分，身體會是盡可能不將其排出體外，而是會將餘下的葡萄糖以「三酸甘油脂」的形式，儲存在一些脂肪細胞內。當脂肪細胞裝滿了「三酸甘油脂」，它們會分泌一個叫TNF-Alpha的蛋白質；後者更能抑制肌肉細胞搬運GLUT-4。這就是為什麼肥胖的人更容易趨向患上糖尿病。
糖尿病藥與補健
身體「三個應付糖尿病的關鍵點」，包括第一，須有適量的胰島素（驅使細胞，起動「將血液中的糖分拖進來」的機制）；第二，須有足夠的GLUT-4（GLUT-4致「葡萄糖接受體」是細胞「吸收糖的工具」）；第三，須具足夠能力，令血液中不存有「多餘的糖分」。
從這三個關鍵點切入，如何醫理糖尿病的原則性方向：目前已研發出來、用以對付糖尿病的藥，其藥效主要在於提升身體三個功能，分別是（一）刺激胰細胞分泌胰島素；（二）增加細胞的GLUT-4；及（三）把過多的血糖排出體外。現在市面已有很多糖尿藥，但藥廠還是興致勃勃地、不停研發新藥，因為愈來愈多人患上這個病，餅縱是做多一些，也不愁沒有人吃：市場只有愈來愈大。還有，糖尿病患者一旦開始依賴藥物，大可會是一生擺脫不了；對藥商而言，無異長期飯票。糖尿病患者自應「爭氣」，想辦法「自強不息」，利身體、亦利荷包。該怎麼辦？上一篇說了，最佳方法是令糖分少入多出：包括少吃澱粉質（Starch）的食物，同時多做運動，將身體中多餘的葡萄糖消耗掉。另一方面，在藥物以外，不妨求助於一些天然補健食品。
現將之前介紹過的藥總結一下，也順便提及一些相關的「膳食補充劑」Dietary Supplements，以供參考。首先，能幫助胰島素「走出」胰細胞的西藥，有Diamicron（Gliclazide）和Januvia（Sitagliptin），這藥的功效，都在於能促使胰小泡、黏上「胰細胞」細胞膜的內壁，產生「胞吐作用」（exocytosis），從而將其內的胰島素分泌出來；這方面的「膳食補充劑」是「肉鹼」（L-Carnitine）。其次，若糖尿病患者進入了「胰島素抗拒」階段，換言之，不是缺乏胰島素，而是細胞「不為胰島素所動」，不往血液中取糖，西醫會開Glucophage（Metformin），藉提升「AMP激酶」（AMPK）抑制一個PTP酵素，從而協助肌肉細胞安排GLUT-4到它的細胞表面而進行「收貨」的工作。尚有新一代的糖尿藥Avandia（Rosiglitazone）和Actos（Pioglitazone），但有導致脂肪肝之虞。補健食品方面，洋葱素（五羥黃酮Quercetin）和苦瓜素（Triterpenoid）都能提升AMPK。第三，若血液中的糖分太多，可求助於一個叫Invokana（學名Canagliflozin）的糖尿病藥。這個藥能令體內已吸收的葡萄糖不能成單糖（於是吸收不來）；另一方面，讓體內多餘的血糖像垃圾般排走，不被「撿回來」。不過，Invokana對心臟有不良副作用，服用時不妨同時輔以「乙醯肉鹼」（Acetyl-L-Carnitine）和「精胺酸」（L-arginine）。
注意血糖水平 升糖指數(GLYCEMIC INDEX)
高升糖飲食與糖尿病 香港人食無定時，不時會因為過了正常用餐時間而感到飢餓，結果往往一下子進食太多，這樣會為身體帶來許多不良影響，例如令血糖水平急升、身體容易肥胖等，飲食習慣實在有待改善。對於期望控制體重或糖尿病者而言，除了一般飲食習慣外，就更應關注食物的「升糖指數」，以免對身體健身構成更大的壓力。
高升糖飲食與糖尿病
所謂升糖指數(Glycemic Index)，是指人體進食碳水化合物後2小時內血糖的上升幅度，升糖指數越高，血糖的升幅越大。對於不同的含醣類(碳水化合物)成分的食物，其升糖指數都各有不同，對身體的血糖水平亦會產生不同程度的影響。大體而言，食物的升糖指數可分為三級，包括最低級別的的低升糖指數（55或以下）、高一級的中升糖指數（56-69），以及最高級別的高升糖指數（70或以上）。
食物的升糖指數分級如下：
低升糖指數：55或以下
中升糖指數：56-69
高升糖指數：70或以上
當一個人進食了高升糖指數的食物進入身體後，這些食物會迅速在小腸內分解，導致血糖水平急劇上升。在此情況下，正常身體的胰島素細胞會因為受到血糖上升的刺激而大量分泌胰島素，目的是讓血糖下降至正常的水平。然而，相關的糖尿病研究指出，胰島素細胞若經常受到高血糖的刺激，其分泌功能將逐漸減弱，甚至喪失分泌功能。換言之，身體沒有足夠（或完全欠缺）胰島素來維持血糖水平的平衡，而缺乏充足的胰島素或將引致2型糖尿病。
保持穩定血糖水平
高升糖指數食物產生的另一影響是，受刺激而分泌的胰島素會抑制身體分解脂肪，同時亦加速體內脂肪囤積，引致肥胖。由於血糖水平不穩定，亦容易使人產生飢餓感，結果進食份量比平時大增，最終導致體重上升。
相反，低升糖指數食物可減慢消化速度，延長及增加飽肚感，避免過量進食，並達至管理體重的目標。另外，低升糖指數食物對血糖水平的影響較輕微，有助控制血糖的穩定性。
由此可見，糖尿病患者應多選取低升糖指數的食物，而避免進食高升糖指數的食品，並且配合均衡飲食以控制血糖水平，減少出現併發症的機會。
在注意健康的同時，當然亦希望保持飲食的樂趣，而純天然植物提煉的「日本卡宜天然糖」口味極佳，尤勝砂糖，正是糖尿病或關注體重人士的健康之選。它可以用來代替砂糖，絕不影響血糖水平，而且零卡路里。產品已獲多個世界級組織，包括：美國FDA及世衛認可其天然成分，安全可靠。無論是用於冷熱飲品、烹調煮焗及烘焙糕點，日本卡宜天然糖都十分適合。
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