Increasing Prevalence of Obesity and Diabetes
From 1960 to 1980 about 15% of American adults were obese (BMI 30 or greater), but by the year 2002 that figure had doubled to over 30%.1 The prevalence of American children and adolescents classified as overweight roughly tripled between 1980 and 2000.1 But the problem is not restricted to the United States, as obesity and overweight diagnoses are increasing worldwide. Prevalence of childhood obesity in Brazil and India were recently estimated to be 22%, and for Mexico nearly 42%.2 Along with the increase in global obesity there has been a rise in type II diabetes 3 (formerly called adult-onset diabetes before it affected so many children).
How Type II Diabetes Develops
Diabetes is generally defined as a condition of elevated glucose. Insulin, which is secreted from islet cells in the pancreas, helps glucose enter many body tissues. In type I diabetes, a person typically has little or no insulin production. More than 90% of all diabetics have type II rather than type I diabetes, however.4 Obesity often leads to insulin resistance, wherein it becomes more difficult for insulin to cause glucose uptake by cells. As a result of increasing insulin resistance, the pancreas increases insulin production and release in an attempt to get enough glucose into cells. Eventually pancreatic insulin production ceases, and type II diabetes progresses to an advanced stage.5,6
Although insulin resistance is the best predictor for the development of type II diabetes, experts have different opinions concerning the mechanisms causing insulin resistance.
Keystone Symposia is a nonprofit organization that holds many scientifically prestigious conferences on a variety of topics in molecular and cellular biology. From January 27 to February 1, 2013, a symposium was held in Keystone, Colorado, on the subjects of diabetes and adipose tissue biology, organized and attended by leading scientific researchers in the field.
Insulin Resistance from Fat
Possibly no one has studied insulin resistance harder and longer than Gerald Shulman, MD, PhD (Professor of Medicine, Yale University, New Haven, Connecticut). Shulman’s favorite hypothesis is that excessive fat from the diet (or fat generated by high levels of fructose consumption) accumulates in cells, interfering with the cell-signaling involved in the pathway between a cell’s insulin receptor and uptake of glucose by the cell.7-9 In particular, the protein that transports glucose into a cell (GLUT4 protein) is prevented by fat from reaching the cell surface.10 When I asked Dr. Shulman about the effect of fat saturation (saturated fat) and chain-length of fatty acids on insulin resistance, he told me that these properties of fat do not matter (excluding fish oil, which he said has special signaling capabilities).
Kitt Petersen, MD (Professor of Medicine, Yale University, New Haven, Connecticut) has long been Dr. Shulman’s understudy and has co-authored many papers with him. Dr. Petersen has been focused on the role of exercise and mitochondria in insulin resistance. She has shown that exercise and weight loss increase insulin sensitivity.11,12 She has found evidence that age-associated decline of mitochondrial function is associated with defective fat metabolism, leading to fat accumulation and insulin resistance.13,14 Like Shulman, she believes that inflammation is a consequence rather than a cause of insulin resistance.15 When I asked her about the molecular mechanism behind insulin resistance in smokers, she told me that there are probably many mechanisms of insulin resistance and there is much to be learned about the subject.16,17
Insulin Resistance from Inflammation
Alan Saltiel, PhD (Director, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan) favors the view that inflammation is the link between obesity and insulin resistance. He has shown that mice that are genetically modified to not release the pro-inflammatory molecule NF-κB when fed a high-fat diet are protected from insulin resistance.18 He later showed that normal mice are similarly protected from insulin resistance due to a high-fat diet when given a chemical inhibitor that blocks NF-κB activation.19
Tal Pecht (PhD student, Ben-Gurion University, Beer-Sheva, Israel) believes that inflammation from body fat (especially visceral fat) leads to insulin resistance. She cited studies indicating that necrotic cell death of fat cells attracts macrophages which may lead to insulin resistance. 20-22 With her supervisor, Pecht demonstrated that macrophages in visceral fat form foam cells such as those found in atherosclerotic plaques, which results in inflammation and possibly insulin resistance.23
Nutrients that health conscious people take today like curcumin, cinnamon, silymarin, and genistein (an isoflavone found in soybeans) suppress the pro-inflammatory molecule NF-κB.24-28
Distribution of Body Fat
Susan Fried, PhD (Professor, Boston University School of Medicine, Boston, Massachusetts) has studied the relationship between body fat distribution and diabetes or cardiovascular disease. With increasing obesity, men become “apples” (round, more abdominal fat), whereas women become “pears” (more fat in the hips and thighs). Only abdominal fat is associated with increased cardiovascular disease and diabetes.29,30 After menopause, however, women accumulate more abdominal fat.31
The Effect of When You Eat
Paolo Sassone-Corsi, PhD (Director, Center for Epigenetics and Metabolism, University of California, Irvine) presented evidence that disruption of biological clocks associated with the sleep-wake cycle and feeding can lead to cardiovascular disease and insulin resistance.32,33 Similar effects are seen for mice as for human shift-workers. Mice subjected to light at night have more body mass and less glucose tolerance than mice under normal light/dark conditions, despite equivalent food intake and activity.34 He said that when you eat can be as important as what you eat.
Genetic Causes of Obesity and Type II Diabetes
Ronald Kahn, MD (Professor of Medicine, Harvard Medical School, Boston, Massachusetts) has been studying genetic factors that influence obesity and type II diabetes in humans and mice. High metabolic rate and high levels of energy-generating brown fat are genetic influences that protect against obesity. 35,36 Kahn has demonstrated in mice that genetic background also governs the degree to which obesity will lead to inflammation or insulin resistance.37 Dr. Kahn is currently following leads that the type of bacteria in the intestine influences the development of insulin resistance and type II diabetes.38
FGF21 and Longevity
David Mangelsdorf, PhD (Professor and Chairman of the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas) has been studying Fibroblast Growth Factor 21 (FGF21), a growth factor secreted in the liver during fasting that has been shown to increase liver insulin sensitivity in rats made obese by a high-fat diet.39 Dr. Mangelsdorf has created mice that secrete more-than-normal amounts of FGF21 and live 30-40% longer without any calorie restriction.40 Like Snell and Ames dwarf mice (which also live longer than normal mice) the FGF21 transgenic mice are small, are more growth-hormone resistant, and are more insulin sensitive than normal mice.40,41
Inflammation from Aging Rather Than from Fat
James Kirkland, MD, PhD (Professor of Medicine, Mayo Clinic, Rochester, Minnesota) has observed that although insulin resistance, type II diabetes, and inflammation continually increase with age, obesity begins to decline in late middle age. Although the inflammation associated with obesity mainly comes from macrophages, the inflammation associated with aging mainly comes from fat cells.42 Obesity is associated with fat deposition in tissues other than fat cells, which is believed to cause insulin resistance and fat toxicity.43 Saturated fats have been shown to kill heart cells. 44 Fat toxicity impedes the function of and can even kill the insulin-producing cells of the pancreas.45,46 Dr. Kirkland has shown that aging increases susceptibility to fat toxicity.47 Certain saturated fats have been shown to kill cells by increasing synthesis of the waxy fats or by other means.48-50 Certain waxy fats can cause insulin resistance.51
Dr. Kirkland believes that much of the chronic inflammation associated with aging and type II diabetes is due to inflammatory proteins (cytokines) secreted from senescent (old or damaged) fat cells, noting that fat is the largest organ in the body for an increasing percentage of the population.52,53 Dr. Kirkland initiated a study which showed that partial rejuvenation results from eliminating senescent cells in a mouse with accelerated aging. 54 He is currently seeking to replicate that study in normal mice.
Binge Drinking and Type II Diabetes
Christoph Buettner, MD, PhD (Director, Laboratory for Metabolism and Diabetes, Mount Sinai School of Medicine, New York City, New York) was inspired by human epidemiological evidence that binge drinking leads to chronic insulin resistance or diabetes55-57 to investigate the molecular mechanisms in rats. He found that ethanol dosing in rats that simulates human binge drinking is toxic to the hypothalamus, and thereby induces insulin resistance. 58 Short-term insulin resistance lasts for days after all the ethanol has been metabolized.58 Dr. Buettner is concerned that binge drinking continues to increase among college students.59 Adolescents are particularly vulnerable to brain damage from binge drinking. 60
I had made it a priority to attempt to gain from this conference an understanding of the mechanism by which insulin resistance is induced. I was surprised that opinions on this subject could be so different, but I believe that some of the reason for the divergence of views is that there is more than one mechanism involved. In particular, I think that in some cases inflammation can induce insulin resistance, whereas in other cases fat directly impedes cell signaling between the insulin receptor and the glucose transporter.