Insulin Sensitive Obesity

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This week, I am hosting Matthias Blüher, Professor of Endocrinology from the University of Leipzig, Germany, who yesterday, presented a seminar on the topic of “Insulin Sensitive Obesity” at the Alberta Diabetes Institute. As most readers will know, excess weight is typically associated with insulin resistance, which has been suggested to be a major underlying factor in the development of the metabolic syndrome. However, as Blüher and other have shown before, there is a significant subset of individuals with excess weight, who are quite insulin sensitive and lack any sign or evidence for metabolic abnormalities. These individuals have also been described as being “metabolically healthy obese”. Blüher’s group in Leipzig has performed extensive studies on this interesting group of subjects, which make up around 10-25% of individuals with severe obesity. Using euglycemic insulin clamp studies (the gold-standard for measuring insulin sensitivity), Blüher and colleagues identified 30 individuals with typical insulin resistance and 30 individuals with atypical insulin sensitivity – both groups of subjects had a mean BMI of around 45 or severe obesity. Among the many differences between the two groups, the best predictor of insulin resistance included more liver fat and increased visceral fat. As reported previously, insulin resistant individuals had higher levels of glucose, HbA1c (although diabetic patients were excluded from the study), lower levels of HDL choldesterol, higher levels of CRP, larger adipocytes, greater macrophage infiltration of adipose tissue, and a higher leptin-to-adiponectin ratio. Expression studies on fat tissue from both groups showed higher expression of various adipokines and biomarkers including AGT, MCP-1, PAI-1, Nampt (visfatin) endocannabinoids, ceramide, and oxidative stress in the insulin resistant group than the insulin sensitive controls. In contrast, adipose tissue of the insulin sensitive subjects expressed higher levels of FTO, UCP-1, and adiponectin. Blüher and colleagues were particularly thrilled to also see increased expression of vaspin (Visceral adipose tissue – derived serpin A12) in the insulin sensitive group, an enzyme that has been shown to increase insulin sensitivity and reduce food intake in animal studies. This molecule may provide a “drugable” target for treating obesity or related metabolic complications in the future. Much of this work was undertaken as part of the newly funded Integrated Research and Management Centre for Obesity, which was recently funded by the German federal government in Leipzig. As we discussed during Blüher’s meeting, we very much look forward to developing and expanding collaborations between the University of… Read More »

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Leptin and the New Biology of Obesity

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Yesterday, I co-chaired and spoke at a session on obesity management at the 25th Annual Scientific Meeting of the American Society of Hypertension in New York. Later in the afternoon, Jeff Friedman, who played a prominent role in the discovery of leptin, thereby hearkening in the modern era of adipocyte and appetite physiology, presented an update on the potential role of this system in the therapeutic management of obesity and diabetes. While leptin has therapeutic efficacy in rare cases of genetic leptin deficiency, its use in non-genetic “garden-variety” obesity has proven disappointing. Indeed, there appears to be more evidence that leptin plays an important role in defending against weight loss, than to support its roled in the prevention of weight gain. Thus, the dramatic decline in sympathetic activity, fall in metabolic rate and increased hunger that follows weight loss is likely due to the decrease in the leptin signal that unleashes the biological drive to rapidly regain weight and defend against further weight loss. Indeed in most obese individuals, leptin levels increase in proportion to weight gain, while at the same time these individuals display leptin resistance, rendering these increased levels of leptin as biologically ineffective (a notion akin to the hyperinsulinemia associated with insulin resistance in patients with type 2 diabetes mellitus). This state of affairs limits the use of leptin for the treatment of obesity, as the high doses of leptin that would be required to overcome the leptin resistance are poorly tolerated. But recent research points to another possible use of leptin (or leptin analogues) in weight management, namely as a way to prevent weight regain after weight loss. The basic idea here is to substitute leptin after weight loss in an attempt to trick the body into thinking that it still has as much body fat as it had before. Studies that have combined the peptide pramlinitide (which induces weight loss) with metreleptin (a long-acting analogue of leptin) are showing promise in terms of long-term weight loss maintenance (albeit at the cost of injections). Friedman also discussed new data showing that leptin may have potent antidiabetogenic effects independent of any effects on weight loss or food intake. Some of this action may be mediated by leptin’s ability to increase plasma levels of Insulin-like Growth Factor Binding Protein 2 (IGFBP2), which has profound inhibitory effects on hepatic glucose output. Several studies to further exploring the interaction between… Read More »

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