Article

Leptin treatment confers clinical benefit at multiple stages of virally induced type 1 diabetes in BB rats

Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Autoimmunity (Impact Factor: 2.75). 03/2011; 44(2):137-48. DOI: 10.3109/08916934.2010.482116
Source: PubMed

ABSTRACT The adipokine, leptin, regulates blood glucose and the insulin secretory function of beta cells, while also modulating immune cell function. We hypothesized that the dual effects of leptin may prevent or suppress the autoreactive destruction of beta cells in a virally induced rodent model of type 1 diabetes. Nearly 100% of weanling BBDR rats treated with the combination of an innate immune system activator, polyinosinic:polycytidylic acid (pIC), and Kilham rat virus (KRV) become diabetic within a predictable time frame. We utilized this model to test the efficacy of leptin in preventing diabetes onset, remitting new onset disease, and preventing autoimmune recurrence in diabetic rats transplanted with syngeneic islet grafts. High doses of leptin delivered via an adenovirus vector (AdLeptin) or alzet pump prevented diabetes in>90% of rats treated with pIC+KRV. The serum hyperleptinemia generated by this treatment was associated with decreased body weight, decreased non-fasting serum insulin levels, and lack of islet insulitis in leptin-treated rats. In new onset diabetics, hyperleptinemia prevented rapid weight loss and diabetic ketoacidosis, and temporarily restored euglycemia. Leptin treatment also prolonged the survival of syngeneic islets transplanted into diabetic BBDR rats. In diverse therapeutic settings, we found leptin treatment to have significant beneficial effects in modulating virally induced diabetes. These findings merit further evaluation of leptin as a potential adjunct therapeutic agent for treatment of human type 1 diabetes.

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    • "In agreement with this, plasma insulin was significantly reduced by STZ, and leptin did not increase insulin levels compared with STZ-vehicle mice (Fig. 1C). This is not surprising given the numerous studies showing that leptin inhibits insulin secretion (7,18–22). "
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    • "Perhaps the most compelling evidence of the profound effect of leptin on glucose homeostasis is that leptin administration can normalize blood glucose levels in non‐obese rodent models of insulin deficient, type 1 diabetes. Leptin infusion or gene therapy, can reverse hyperglycemia without a detectable rise in circulating insulin levels in streptozotocin (STZ)‐treated rats48–54 and mice55–57, non‐obese diabetic (NOD) mice49,58, insulin deficient Akita mice59,60 and BioBreeding rats with virally‐induced β‐cell destruction61. Leptin therapy also normalizes water intake and urine output, and reverses glycosuria, hyperketonemia and hyperphagia in insulin deficient rodents50,52,54,58, indicating improved overall health of these animals. "
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