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: 2.71). 03/2011; 44(2):137-48. DOI: 10.3109/08916934.2010.482116
Source: PubMed


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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    ABSTRACT: Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose response study revealed that leptin reverses STZ-diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia, but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose, but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice transplanted with 50 or 125 islets. While these islet doses were insufficient to ameliorate hyperglycemia alone, co-administration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-diabetic mice.
    Diabetes 05/2013; 62(8). DOI:10.2337/db12-1684 · 8.10 Impact Factor
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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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    ABSTRACT: The fat-derived hormone, leptin, is well known to regulate body weight. However, there is now substantial evidence that leptin also plays a primary role in the regulation of glucose homeostasis, independent of actions on food intake, energy expenditure or body weight. As such, leptin might have clinical utility in treating hyperglycemia, particularly in conditions of leptin deficiency, such as lipodystrophy and diabetes mellitus. The mechanisms through which leptin modulates glucose metabolism have not been fully elucidated. Leptin receptors are widely expressed in peripheral tissues, including the endocrine pancreas, liver, skeletal muscle and adipose, and both direct and indirect leptin action on these tissues contributes to the control of glucose homeostasis. Here we review the role of leptin in glucose homeostasis, along with our present understanding of the mechanisms involved. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00203.x, 2012).
    03/2012; 3(2):115-129. DOI:10.1111/j.2040-1124.2012.00203.x
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    • "In addition, leptin inhibits the oversecretion of glucagon associated with insulin deficiency, stimulates insulin signaling, activates the muscular IGF1 receptor [72], and reduces the amount of liver triglycerides [73] in insulin-deficient animals. A recent study evidenced that high doses of leptin could also modulate the autoreactive destruction of beta cells in a virally induced rodent model of type 1 diabetes, and prevent hyperglycaemia [74]. "
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    ABSTRACT: Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.
    Biochimie 03/2012; 94(10):2116-25. DOI:10.1016/j.biochi.2012.03.013 · 2.96 Impact Factor
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