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.

  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 8.47 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper attempts to assess the potential performance gain of spatial-temporal processing relative to conventional spatial processing, for signals obeying a deterministic parametric model. The Cramer-Rao bound (CRB) on the estimates of the source directions of arrival (DOA) is used to quantify this gain. Spatial-temporal processing does not yield any such gain in the single source case, or for multiple coherent signals. However, significant gains can be achieved for multiple non-coherent signals
    Acoustics, Speech, and Signal Processing, 1995. ICASSP-95., 1995 International Conference on; 06/1995
Show more