The 2014 World Congress On Insulin Resistance, Diabetes, And Cardiovascular Disease

Metabolic syndrome is a collection of traits that predict both type II diabetes (adult-onset diabetes) and cardiovascular disease. The initial definition of metabolic syndrome, provided by the World Health Organization in 1998, included insulin resistance, elevated blood pressure, abnormal plasma lipids (for example, elevated plasma triglycerides or reduced plasma HDL cholesterol), impaired glucose tolerance, and a high waist-to-hip ratio.¹ Many other definitions of metabolic syndrome have been given, with newer ones including markers of chronic inflammation.¹ Some scientists challenge the idea that there exists such an entity as “metabolic syndrome.”^2,3

The concept of metabolic syndrome was inspired by a 1988 paper by the physician/scientist Gerald Reaven, who described a collection of traits he believed are caused by insulin resistance, and which he said predict cardiovascular disease.⁴ Dr. Reaven called the collection of traits “Syndrome X.” He did not include obesity or inflammation as traits of Syndrome X.

Insulin resistance was the centerpiece of Syndrome X. Insulin resistance most often refers to the reduced ability of insulin to cause glucose to enter muscle and fat cells, but insulin resistance can also affect the liver, brain, immune system cells, endothelial cells, the beta cells of the pancreas that produce insulin, and other tissues. In 2003, Dr. Reaven co-organized a World Congress on Insulin Resistance. Subsequent conferences have been called the “World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.” From November 20-22, 2014, I attended the 12^th Congress in Los Angeles, California.

Central Obesity May Not Always Predict Heart Disease

Gerald Reaven, MD, (Professor of Medicine, Stanford University) cited studies (particularly from Asian countries) demonstrating that central (abdominal) obesity is not an essential feature for metabolic syndrome, nor for predicting ischemic heart disease^5,6 or insulin resistance.⁷

BMI (Body Mass Index) measures obesity based on the ratio of weight to height (kg/m²). Although BMI has been criticized because it does not distinguish between fat and muscle, possibly because so few people are muscular, BMI has proven to be a convenient measure of obesity in population studies. Dr. Reaven cited studies showing that BMI is equal to or better than waist circumference or wrist-to-hip ratio as a measure of obesity,⁸ insulin resistance,⁹ and diabetes.¹⁰

When other risk factors are available, such as plasma lipids, blood pressure, and history of diabetes, none of the measures of obesity improve prediction of cardiovascular disease.¹¹ Nonetheless, abdominal obesity is a frequent cause of metabolic syndrome¹² and type II diabetes.¹³

Obesity Treatments

Samuel Klein, MD, (Professor of Medicine, Washington University, St. Louis, Missouri) has attempted a variety of interventions to address the problems of obesity, type II diabetes, and metabolic syndrome. Overweight subjects who lost weight through diet and exercise showed a reduction in blood pressure, blood glucose, and blood triglycerides in proportion to the amount of their weight loss.¹⁴ Type II diabetics placed on a very calorie-restricted diet (600 calories per day) for eight weeks showed normalization of plasma glucose, liver insulin sensitivity, and insulin production by the pancreas.¹⁵

Dr. Klein studied the effect of a low-carbohydrate diet. Although LDL cholesterol leads to atherosclerosis, small LDL particles do so much more than large LDL particles.¹⁶ A low-carbohydrate diet reduces blood triglycerides while increasing the size of LDL particles.¹⁷ The amount of small LDL particles increase in direct proportion to the percent of carbohydrate in the diet.¹⁷ When Dr. Klein put obese patients on a calorie-restricted diet that was either low in fat or low in carbohydrate, both groups lost weight, but the low-carbohydrate group had a greater reduction in triglycerides and blood pressure.¹⁸

Abdominal (visceral) fat is associated with chronic inflammation and insulin resistance. Surgical removal of abdominal fat (liposuction) from obese patients had no effect on blood pressure, insulin resistance, plasma glucose, or chronic inflammation.^19,20

By contrast, bariatric surgery (surgical procedures to reduce the size of the stomach and/or small intestine) was shown to produce substantial weight loss for at least 10 years. This weight loss was accompanied by improved insulin sensitivity, reduced chronic inflammation, and reversal of factors leading to nonalcoholic fatty liver disease, in addition to reducing death rate.^21-24

Gastric bypass is superior to binding methods of bariatric surgery, leading to 25% weight loss after 10 years compared to 16% or less for binding.²⁵ Gastric bypass for type II diabetes more often greatly reduces hemoglobin glycation than sleeve gastronomy.²⁶ Death in the first 30 days after bariatric surgery is rare (0.3%), mostly due to pre-surgical health conditions.²⁷ Complications due to bariatric surgery are largely dependent upon the skillfulness of the surgeon.²⁸ The website of the American Society of Metabolic and Bariatric Surgery (https://asmbs.org) has a search tool for finding a quality local provider of bariatric surgery.

Appetite Suppression With Leptin Hormone

Christos Mantzoros, MD, DSc, (Professor of Medicine, Harvard Medical School) is an expert on leptin, the “satiety hormone” that curbs appetite. Leptin is produced by fat cells. Leptin exerts its appetite-satiating effects by acting on the brain, mainly in the hypothalamus. Although blood levels of leptin increase with obesity due to an increase in fat, obese individuals experience less of leptin’s appetite-suppressing effects, a condition known as leptin resistance.²⁹ Leptin administration to obese individuals has not resulted in weight loss.³⁰ A study conducted by Dr. Mantzoros showed that sleep deprivation decreases plasma leptin levels, lending credence to the idea that eating a``t night can make a substantial contribution to obesity.³¹

Leptin is opposed by ghrelin, a “hunger hormone” that stimulates appetite. Ghrelin is mostly produced by the gut and, like leptin, exerts its effects on appetite by its action on the hypothalamus of the brain. When individuals lose weight, ghrelin blood levels rise. But weight loss due to bariatric surgery greatly reduces ghrelin levels.³²

Leptin is only one of several substances released by fat cells, leading to the concept that fat is an endocrine organ.³³ Adiponectin, an anti-inflammatory hormone that increases insulin sensitivity, is another major hormone produced by fat cells.³³ Pro-inflammatory factors produced by fat cells include TNF-alpha and even leptin, which contribute to the chronic inflammation associated with obesity.³⁴ Nonetheless, leptin is important for brain development, memory formation, protection against age-related brain atrophy, and for removal of the amyloid-beta protein that accumulates in Alzheimer’s disease.³⁵

Artificial Sweeteners Promote Weight Gain

Yanina Pepino, PhD, (Research Assistant Professor, Washington University School of Medicine, St. Louis, Missouri) studies the effects of artificial sweeteners. The worldwide share of artificial sweeteners is aspartame (27.9%), sucralose (27.9%), cyclamate ( 15.7%), saccharin (13.1%), acesulfame-K (5.2%), and neotame (1.4%).³⁶

In some short-term studies, the use of artificial sweeteners rather than sugar has been shown to slightly reduce weight gain³⁷ or slightly increase weight loss.³⁸ But a 14-year study showed that the consumption of either sugar-sweetened beverages or artificially sweetened beverages was associated with a higher risk of type II diabetes than consumption of fruit juice.³⁹

Similarly, a study lasting seven to eight years found that consumption of artificially sweetened beverages was associated with a nearly 50% greater change in BMI than was seen in non-consumers.⁴⁰ The authors suggested that subjects prone to weight gain might be more inclined to drink diet beverages. The authors also suggested that artificial sweeteners might increase food intake or increase the appeal of sweetness. Obese subjects given the artificial sweetener sucralose showed increased insulin levels and insulin resistance.⁴¹ Insulin levels were also raised in type II diabetics given sucralose and acesulfame-K.⁴² Mice given the artificial sweeteners aspartame and erythritol showed increased insulin levels and insulin resistance, which was believed to be due to increased plasma triglycerides.⁴³ By contrast, the natural sweetener stevia lowered insulin levels in obese subjects who showed increased insulin following aspartame and sucrose consumption.⁴⁴

A study of both humans and mice showed that the artificial sweeteners sucralose, aspartame, and saccharin had a substantial effect on gut bacteria that increased glucose intolerance.⁴⁵ The effect was greater with saccharin than with sucralose or aspartame.

Dana Small, PhD, (Associate Professor of Psychiatry, Yale School of Medicine) has done research on the effects of artificial sweeteners on behavior and the brain. Experiments on rats have shown that appetite results not only from the area of the brain that communicates with hormones (the hypothalamus), but with the area of the brain associated with learning (the hippocampus).⁴⁶ Dr. Small has shown that this also applies to humans.⁴⁷ She has shown that learned association occurs between food flavors and the ability of those foods to change blood glucose.⁴⁸

Rats given foods with artificial sweeteners learn that those foods are not providing calories associated with sweeteners―and compensate by eating more food and becoming obese.⁴⁹ Mice prefer sucrose over sucralose (which is 600 times sweeter than sucrose) because of an area of the brain that responds to sucrose.⁵⁰ There is considerable evidence that artificial sweeteners contribute to weight gain in people.⁵¹

Calories cause the small intestine to release the hormone glucagon-like peptide 1, which reduces appetite by its effects on the brain. Glucagon-like peptide 1 also increases insulin sensitivity. Rats fed artificial sweetener show reduced glucagon-like peptide 1 secretion and increased food consumption.⁵² Mice fed the artificial sweetener acesulfame-K showed impaired memory due to disruption of functioning neurons in the hippocampus.⁵³

Vitamin D3 Deficiency Promotes Insulin Resistance

Carlos Bernal-Mizrachi, MD, (Associate Professor of Cell Biology and Physiology, Washington University, St. Louis, Missouri) has shown that there is a vicious cycle between insulin resistance in the immune system cells (macrophages) that contribute to atherosclerosis and endoplasmic reticulum stress in those cells.⁵⁴

The endoplasmic reticulum is the organelle in cells that synthesizes proteins, fats, and other macromolecules. By preventing synthesis of vital cell components, endoplasmic reticulum stress disrupts cell function, increases macrophage insulin resistance, and increases atherosclerotic foam cell formation.⁵⁴

Vitamin D3 deficiency activates endoplasmic reticulum stress in macrophages^55,56 and increases blood pressure.⁵⁷ Persons with low vitamin D levels have higher risk for insulin resistance and metabolic syndrome.⁵⁸ A review of studies of vitamin D supplementation failed to show prevention of cardiovascular disease, but noted that the dose used in the largest trial was low (400 IU) and had compliance problems.⁵⁹ A vitamin D3 dose of 2,000 IU daily has been shown to reduce symptoms in patients at risk for diabetes.⁶⁰ A review of studies showed a direct relationship between vitamin D blood levels and risk of type II diabetes.⁶¹

Endothelial Cell Function And Dysfunction

Mark Kearney, MD, (Professor of Cardiology, University of Leeds, Leeds, UK) has done much research on endothelial dysfunction. The endothelium is the layer of cells covering the walls of blood vessels. Among the most important functions of endothelial cells is to dilate blood vessels by releasing nitric oxide.

Aging and other conditions cause the production of nitric oxide by endothelial cells to decline, a condition described as endothelial dysfunction. Failure of blood vessels to dilate leads to high blood pressure.⁶² Failure of the coronary arteries of the heart to dilate can lead to a heart attack. For that reason, nitroglycerin tablets (which cause nitric oxide production) are taken to relieve angina and prevent immediate heart attack.⁶³ Increases in free radicals and chronic inflammation associated with aging leads to endothelial dysfunction,^64,65 which contributes to atherosclerosis.⁶⁶ Smoking leads to endothelial dysfunction, which can be somewhat reversed by smoking cessation.⁶⁷

Dr. Kearney’s team has established that insulin resistance in endothelial cells leads to endothelial dysfunction,⁶⁸ a result that has been confirmed by others.⁶⁹ His team has shown that reducing free radicals reduces endothelial dysfunction.

Insulin resistance in the endothelial cells precedes insulin resistance in the liver and muscles.⁷⁰ Dr. Kearney noted that endothelial dysfunction is highly associated with metabolic syndrome.⁷¹ Type II diabetes has the effect of 15 years of additional aging on blood vessels.⁷² An estimated 25% of chronic heart failure patients have type II diabetes.⁷³

Lipoprotein(a) As A Cardiovascular Disease Risk Factor

Sotirios Tsimikas, MD, (Director of Vascular Medicine, San Diego Health Center) is concerned with the effect of lipoprotein(a) on cardiovascular disease risk. Lipoprotein(a) is a special kind of LDL particle that can cause atherosclerosis independently of other LDL particles.^74,75

Lipoprotein(a) consists of an LDL particle that is bound to the glycoprotein (sugared-protein) apoprotein(a).⁷⁶ Some genetic variants of lipoprotein(a) are associated with greater cardiovascular risk than others.⁷⁷ Lipoprotein(a) binds strongly both to the proteoglycans in blood vessel walls and to oxidized phospholipids.^78-80

Niacin has been reported to slightly reduce plasma lipoprotein(a),^81,82 but niacin has not been shown to reduce cardiovascular events in patients receiving statin theapy.⁸³ The most effective therapy is apheresis (removal of lipoprotein(a) by filtering the blood). Apheresis that reduced LDL-cholesterol by 65% and lipoprotein(a) by 73% reduced major cardiac events by 86%, a result that cannot be explained by the LDL reduction alone.⁷⁸

Metabolic Syndrome Factors

Ele Ferrannini, MD, (Professor of Internal Medicine, University of Pisa, Pisa, Italy) studies correlation of factors associated with metabolic syndrome. In one study, Dr. Ferrannini showed that there is a direct association between insulin resistance and endothelial function in patients with type II diabetes.⁸⁴ The same study found insulin resistance in type II diabetes to be associated with chronic inflammation and with an impaired ability to prevent blood clots (impaired fibrinolysis), even in persons who were not obese.⁸⁴

As obesity increases, fat cells become larger, and larger fat cells become more insulin resistant. As abdominal obesity increases, glucose uptake is reduced in both skeletal muscle and fat.⁸⁵ Other studies by Dr. Ferrannini showed that insulin resistance increases in direct proportion to waist circumference⁸⁶ and blood pressure.⁸⁷ Glucose tolerance measures how rapidly glucose is reduced in the bloodstream after being administered. A person has poor glucose tolerance if glucose is not rapidly reduced. Dr. Ferrannini showed that impaired glucose tolerance is directly related to insulin resistance of the insulin-producing beta cells of the pancreas.⁸⁸

Atherosclerosis In Childhood

Olli Raitakari, MD, PhD, (Professor of Cardiovascular Medicine, University of Turku, Turku, Finland) began his talk by referring to the fact that more than three-quarters of American soldiers killed and autopsied in the Korean War (with an average age of 22) had gross signs of atherosclerosis.⁸⁹

Dr. Raitakari has found that children with risk factors for cardiovascular disease (based on lipids and blood pressure) typically will develop atherosclerosis as adults.⁹⁰

Based on his research, screening children for atherosclerosis (thickness in the intima-media of blood vessels) beginning at the age of 9 could identify children who would most benefit from therapies to prevent cardiovascular disease.⁹¹ Dr. Raitakari has found that obese children who become nonobese as adults have a similar cardiovascular risk as those who were never obese.⁹² He also found that having both parents smoke had the effect of increasing blood vessel age by an average of 3.3 years.⁹³

Cancer Due To Obesity And Diabetes

Derek LeRoith, MD, PhD, (Director of Diabetes Research, Rambam Health Care Campus, Haifa, Israel) studies the effect of obesity and diabetes on cancer. In the US, cancer deaths due to overweight and obesity are estimated to be 14% for men and 20% for women.⁹⁴

Cancer cells avidly consume glucose, and insulin is a growth factor that enhances cancer growth (many cancer cells have insulin receptors).⁹⁵ People with insulin resistance, such as type II diabetics, and people with metabolic syndrome have high blood plasma levels of both glucose and insulin, which accelerates cancer growth.⁹⁵ Women without diabetes who have had surgery for early-stage breast cancer have a greatly increased risk of cancer recurrence if their plasma insulin levels are high.⁹⁶

Type II diabetics show a steady decline in insulin production by their pancreas such that after 10 years, half of these diabetics require insulin injections.⁹⁷ Diabetics receiving insulin or insulin analogs have an increased risk of cancer in proportion to the size of the dose of insulin or insulin analog.⁹⁸

But type II diabetics receiving metformin have reduced plasma glucose and insulin, which reduces their incidence of cancer.⁹⁹ By one estimate, the overall reduction in cancer risk with metformin is 31%.¹⁰⁰ Gastric bypass surgery of severely obese subjects has reduced cancer risk by 60%.¹⁰¹

Diabetic Neuropathy

Allen Jacobs, Doctor of Podiatric Medicine, (private practice, St. Louis, Missouri) is concerned with medical conditions resulting from high blood glucose of persons with type II diabetes, especially with the condition of neuropathy.

Neuropathy is damage to nerves, which impairs sensation, movement, and other functions.

Diabetic neuropathy is present in 8% of newly diagnosed type II diabetics, and in over 40% of diabetics who have had the disease for more than 10 years.¹⁰² Diabetic neuropathy is the major cause of kidney disease, and is the most common cause of blindness in middle-aged adults.¹⁰³ More than half of all foot amputations are due to diabetes.¹⁰⁴

The antidiabetic drug metformin lowers blood levels of vitamin B12, which may worsen neuropathy.¹⁰⁵ Oral administration of vitamin B12 in the form of Methyl-B12 (methylcobalamin) has been shown to relieve symptoms of diabetic neuropathy.¹⁰⁶

Obesity And Alzheimer’s Disease

Suzanne Craft, PhD, (Professor of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina) is concerned about metabolic syndrome and the risk of dementia, especially Alzheimer’s disease.

Above the age of 40, obesity is associated with a reduction of gray matter (neurons) in the brain.¹⁰⁷ A study of non-demented elderly found that high insulin levels were associated with subsequent higher incidence of Alzheimer’s disease.¹⁰⁸ High insulin levels in the elderly are associated with less gray matter in the areas of the brain most associated with Alzheimer’s disease,¹⁰⁹ and is associated with reduced metabolic rate in those areas.¹¹⁰

Mouse experiments indicate that insulin deficiency or insulin resistance can increase aggregation of the amyloid-beta,¹¹¹ or tau¹¹² proteins associated with Alzheimer’s disease. Conversely, insulin has been shown to reduce amyloid-beta binding and protect synapses.^113,114 Dr. Craft has shown that moderate doses of insulin improved cognitive function in adults with mild cognitive impairment or mild-to-moderate Alzheimer’s disease.¹¹⁵ Higher or lower doses of insulin did not improve cognitive function.

Conclusions

The annual Southern California World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease has much in common with the annual South Florida Cardiovascular Disease Prevention Symposium, described in the July 2014 issue of Life Extension^® magazine. Both are conferences that attract several hundred people, where most of the presenters are MDs. These physicians do not discuss disease without discussing both prevention and treatment. The Congress has a greater emphasis on insulin resistance, diabetes, and obesity, but cardiovascular disease is the major cause of death for these conditions.

Some key points in this Congress include the substantial beneficial effects that bariatric surgery can have for reducing obesity and the health consequences of obesity; artificial sweeteners lead to weight gain, rather than weight loss; and that obesity and metabolic syndrome can lead to not only diabetes and cardiovascular disease but cancer, neuropathy, and Alzheimer’s disease.

If you have any questions on the scientific content of this article, please call a Life Extension^® Health Advisor at 1-866-864-3027.

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