Leptin-controlled gene can reverse diabetes

Researchers developed a set of conditions in which leptin treatment potently improves diabetes independent of its ability to correct weight and food intake. The new findings confirm what some at least had already suspected: that leptin’s antidiabetic effects are independent of the hormone’s well-known ability to reduce body weight. Researchers have found that even a very little bit of the fat hormone leptin goes a long way when it comes to correcting diabetes. The hormone controls the activity of a gene known as IGFBP2 in the liver, which has antidiabetic effects in animals and could have similar therapeutic effect in humans. “It was surprising to me how potent leptin was in treating diabetes,” said Jeffrey Friedman of Rockefeller University. “It had a highly significant impact at plasma levels that were undetectable.”

Cell Metabolism journal – Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene

We tested whether leptin can ameliorate diabetes independent of weight loss by defining the lowest dose at which leptin treatment of ob/ob mice reduces plasma glucose and insulin concentration. We found that a leptin dose of 12.5 ng/hr significantly lowers blood glucose and that 25 ng/hr of leptin normalizes plasma glucose and insulin without significantly reducing body weight, establishing that leptin exerts its most potent effects on glucose metabolism. To find possible mediators of this effect, we profiled liver mRNA using microarrays and identified IGF Binding Protein 2 (IGFBP2) as being regulated by leptin with a similarly high potency. Overexpression of IGFBP2 by an adenovirus reversed diabetes in insulin-resistant ob/ob, Ay/a, and diet-induced obese mice, as well as insulin-deficient streptozotocin-treated mice. Hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity following IGFBP2 treatment of ob/ob mice. These results show that IGFBP2 can regulate glucose metabolism, a finding with potential implications for the pathogenesis and treatment of diabetes

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