The Twin Epidemics of Obesity and Diabetes

Zachary T. Bloomgarden, MD

Disclosures

June 18, 2004

Editorial Collaboration

Medscape &

Allen M Spiegel, MD,[1] Director, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Maryland, discussed the National Institutes of Health (NIH) research agenda for the prevention of the twin epidemics of diabetes and obesity. "Even though we typically use the term 'epidemic' for infectious diseases," he noted, the sharp increase in diabetes allows one to use this term for diabetes as well. There will be almost 30 million people in the United States with diabetes by the year 2030, with similar increases around the world,[2] "so the burden is enormous, and yet much is preventable." The epidemic of diabetes is paralleled by the epidemic of obesity, which Dr. Spiegel described as an "absolute crisis." Obesity is associated with other morbidities besides type 2 diabetes, including heart disease, hypertension, stroke, sleep apnea, and certain malignancies.

Promising New Developments in Diabetes

"The path from discovery to research is long and hard," Dr. Spiegel said. Despite great enthusiasm attending the explosive increase in knowledge of the human genome, there has been difficulty translating this knowledge into pharmacologic products.[3] Dr. Spiegel reviewed several promising new developments. A growing understanding of the processes leading to angiogenesis, initially pursued in malignancy research, is relevant to the complications of diabetes. Biochemical insights from the pathogenesis of maturity-onset diabetes of the young (MODY) have led to an understanding of allosteric activators of glucokinase, which may have potential in diabetes therapy, both facilitating insulin release by the beta cell and acting to decrease hepatic glucose output.[4] The Beta Cell Biology Consortium (BCBC) has been created to facilitate interdisciplinary approaches that will advance the understanding of pancreatic islet development and function. The goal of the BCBC is to develop a cell-based therapy for insulin delivery, which may be applicable to type 2 as well as to type 1 diabetes. The importance of the binding of endogenous lipids to peroxisome proliferator activated receptor (PPAR) nuclear receptors is now being appreciated, and has led to the development of new candidate drugs, although there are potential adverse effects such as colonic polyps being found in some models.

"What is the root cause of insulin resistance in type 2 diabetes?" Dr. Spiegel asked. AMP-sensitive kinase, which is critically sensitive to cellular energy and influences oxidative metabolism in mitochondria, is an enzyme present in liver, muscle, and brain, where it has an effect on hypothalamic energy balance. Downregulation of genes of oxidative metabolism has been documented in persons with insulin resistance[5] and in those with diabetes. An example is peroxisome-proliferator-activated receptor-gamma coactivator 1 beta, which has been shown to be associated with the impaired mitochondrial activity of insulin-resistant offspring of parents with type 2 diabetes.

An important focus of research has been the adipocyte as an endocrine organ responsible for the conversion of cortisone to cortisol via 11 beta hydroxysteroid dehydrogenase (HSD)-1 and the production of inflammatory mediators such as tumor necrosis factor (TNF) alpha and interleukin (IL) 6, and cytokines such as resistin and leptin. These findings have led to the concept of obesity as an inflammatory state, with monocytes attracted by activated adipocytes adding to the inflammatory milieu. Markers of endothelial dysfunction appear to be related to the state of inflammation and are increased among persons at risk of developing type 2 diabetes.[6]

The natural history of type 2 diabetes, Dr. Spiegel noted, encompasses the person who is genetically predisposed, the state of prediabetes, and diabetes itself. Evidence is accumulating that intervention is possible at all levels. In the area of cardiovascular disease (CVD) research, the Bypass Angioplasty Revascularization Investigation (BARI)-2D is focusing on both the early use of coronary revascularization procedures and the value of treating with an insulin-sensitizing agent vs an insulin-providing therapy. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is focusing on the prevention of major cardiovascular events (heart attack, stroke, or cardiovascular death) in adults with type 2 diabetes using intensive glycemic control, intensive blood pressure control, and intensive lipid management. Look AHEAD (Action for Health in Diabetes) is a trial examining the effects of a lifestyle intervention designed to achieve and maintain weight loss through decreased caloric intake and exercise, with a focus on type 2 diabetes and cardiovascular disease. Useful resources for diabetes treatment and prevention can be found at NIH Web sites.[7,8]

Responding to the Obesity Crisis

In response to the obesity crisis, the NIH has developed a strategic plan for the support of obesity research.[9] Yet, Dr. Spiegel noted, "what the Diabetes Prevention Program (DPP) shows is ... a modest weight loss is all that's needed." He cited a recent paper[10] that describes a potential approach to childhood obesity -- "yanking soda machines and carbonated beverages out of schools." It is crucial to be aware of ethnic differences in obesity. Certain Asian groups, for example, have a much lower threshold at which excess body weight causes diabetes. Dr. Spiegel pointed out that "obesity is really an economic issue as well," so that financial incentives might be made available to increase consumption of fruits and vegetables.

Dr. Spiegel noted that "it is not clear if there is actually any data or any evidence whether a low-fat diet is better than a low-carbohydrate diet." Leibel's inpatient isocaloric studies suggested that "a calorie is a calorie is a calorie."[11] Citing other studies performed by Dr. Rudy Leibel, Dr. Spiegel noted that a difference between energy intake and output of approximately 3.6% will lead to obesity. However, once a person becomes obese and then loses weight, the caloric restriction necessary to maintain that weight loss is considerably greater than it would have been if the person had never been obese.

"Evolutionary biology is stacked against us," Dr. Spiegel noted, with evolution favoring energy storage and avoidance of starvation. If "the tendency to gain weight when the environment is permissive" is our genetic heritage, however, pharmacologic treatment may well be appropriate,[12] and Dr. Spiegel suggested that our increasingly detailed understanding of appetite regulation[13] bodes well for such endeavors. Leptin changes "the wiring diagram of the brain in the arcuate nucleus," so eating behavior is biologically influenced.[14] Early in life, however, leptin appears to exert trophic actions on hypothalamic neurons that regulate feeding, suggesting neonatal brain programming that may not be reversible later in life.[15] "All of this research has yielded a rich pipeline," Spiegel noted, and our important task is the development of an integrated approach encompassing genetics, biochemistry, and the environment.

Adipose Tissue as an Endocrine Organ

Christos Mantzoros, MD,[16] Beth Israel Deaconess Medical Center, Boston, Massachusetts, discussed adipose tissue as an endocrine organ, and reviewed the clinical importance of leptin and 3 other adipokines -- resistin, tumor necrosis factor (TNF) alpha, and adiponectin.

Leptin

When first discovered in 1994, leptin was proposed as a link between obesity and diabetes, with leptin deficiency leading to weight gain and hyperglycemia. But the vast majority of obese persons do produce sufficient leptin, and, in general, obese persons have high leptin levels, suggesting leptin resistance. Leptin is produced by adipose tissue in an amount proportional to the number of calories stored in fat, and shows acute changes relative to caloric intake. Cleared by the kidneys, it circulates in free and bound form and activates a specific receptor in the brain and in the periphery. In the rare children with inactivating leptin or leptin receptor mutations (comprising approximately 1% of severe pediatric obesity; about another 10% have mutations downstream from leptin), there are a number of neuroendocrine abnormalities affecting the thyroid, growth hormone, and reproductive axes. Leptin administration can cause modest weight loss in obese persons, although there is huge variability. Perhaps 10% of the obese population has relative hypoleptinemia and the potential for greater response.[17] In leptin-deficient children, exogenous leptin leads to the initiation of puberty.[18]

Teleologically, one would imagine that starvation would decrease reproductive ability. Leptin, then, can be seen as a signal informing the brain as to whether there is sufficient energy stored in fat. Anorexia nervosa and strenuous exercise are associated with hypothalamic amenorrhea. Leptin treatment of this syndrome leads to follicle development; increase in luteinizing hormone, estrogen, and progesterone; and improvement in bone metabolism markers such as osteocalcin and bone alkaline phosphatase, further suggesting that leptin deficiency may be an important explanatory factor. Long-term studies in progress address the potential effects of leptin in these conditions on bone density and risk of fracture. Similarly, the fall in thyroxin and in metabolic rate with starvation is partially normalized by leptin administration.[19]

Another state of relative leptin deficiency is lipoatrophy, both in the congenital form and the form associated with retroviral therapy for HIV. Lipoatrophy is associated with hypertriglyceridemia, poorly controlled diabetes, and fatty liver, all of which improve with leptin administration to a degree related to the baseline level of leptin deficiency. Thus, Dr. Mantzoros stated, hypoleptinemia may be seen as an important new clinical entity having a distinct neuroendocrine phenotype, including reproductive immaturity. The spectrum of leptin deficiency ranges from partial to complete and may also include leptin resistance, for which it may be possible to develop leptin sensitizers.

Resistin levels are higher in women but do not correlate with obesity, central adiposity, or insulin resistance. Therefore, the peptide may not be a systemic factor, although Dr. Mantzoros suggested that it may have a paracrine effect. Although structurally similar, TNF alpha and adiponectin appear to act in functionally opposite ways. TNF alpha is secreted by macrophages, endothelial cells, muscle, and adipocytes, the latter accounting for approximately 30% of circulating levels. TNF alpha acts mainly in the liver, increases inflammatory markers, and is associated with insulin resistance. Concentrations are, however, very low and turnover is rapid, so clinical studies have proven difficult. The soluble TNF alpha receptor (sTNFR) can be more readily measured. In men, studies have shown that both HbA1c and sTNFR are independently associated with serum leptin levels.[20] In a study of approximately 1000 women with type 2 diabetes, both sTNFR and A1C were associated with risk of CVD, with sTNFR independent of other risk factors. Those persons with both low A1C and low TNF-system activation had a longer congestive heart disease (CHD) event-free survival, while increases in both factors were associated with greater CHD rates.

Adiponectin is structurally similar to TNF alpha, circulating in trimers, hexamers, and higher-order oligomers, with higher circulating concentrations than those of any other known hormone. Adiponectin activates 2 different receptors -- one mainly in muscle, the other mainly in liver -- with the system regulated at the level of these receptors. There is diurnal variation of adiponectin, with levels peaking early in the morning.[21] Central body fat distribution, low HDL, and higher estradiol levels are independently associated with lower levels of serum adiponectin.[22] Levels of adiponectin are lower in persons with diabetes, particularly in those with CHD, correlating negatively with insulin levels and increased by thiazolidinediones, which also improve insulin sensitivity. In persons with HIV infection and antiretroviral-induced metabolic syndrome with body fat redistribution, pioglitazone improves insulin sensitivity and lipids, and raises adiponectin levels,[23] further suggesting that "adiponectin may be the missing link between diabetes, inflammatory markers, and cardiovascular disease."

Dr. Mantzoros noted that insulin resistance is associated with malignancies, and he asked whether low levels of adiponectin might play a role in this process. In a case-control study[24] of women with endometrial cancer, low adiponectin level was found to be significantly associated with the risk of endometrial cancer in women younger than 65 years of age. Prospective studies in progress appear to show similar results with breast and colon cancer.

Dr. Mantzoros summarized by saying that leptin reflects total fat mass and communicates information to the brain, appearing to be particularly important in low leptin states, although also possibly having peripheral effects. Adiponectin and TNF alpha act in the periphery with opposing effects on insulin action, free fatty acid levels, and inflammation. Perhaps, Dr. Mantzoros concluded, "the discovery of these molecules will offer new opportunities for prevention and treatment" of diabetes and CVD.

References
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  2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047-1053.

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  5. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664-671.

  6. Meigs JB, Hu FB, Rifai N, Manson JE. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA. 2004;291:1978-1986.

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  8. National Diabetes Education Program. Available at:
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  9. National Institutes of Health. NIH Obesity Research. Available at:
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  16. Mantzoros C. Adipose tissue as an endocrine organ: the clinical significance of leptin and other adipokines Program and abstracts of the American Association of Clinical Endocrinologists 13th Annual Meeting; April 28-May 2, 2004: Boston, Massachusetts.

  17. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282:1568-1575.

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  20. Chu NF, Spiegelman D, Rifai N, Hotamisligil GS, Rimm EB. Glycemic status and soluble tumor necrosis factor receptor levels in relation to plasma leptin concentrations among normal weight and overweight US men. Int J Obes Relat Metab Disord. YEAR;24:1085-1092.

  21. Gavrila A, Peng CK, Chan JL, Mietus JE, Goldberger AL, Mantzoros CS. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab. 2003;88:2838-2843

  22. Gavrila A, Chan JL, Yiannakouris N, et al. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab. 2003;88:4823-4831.

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