Leptin treatment confers clinical benefit at multiple stages of virally induced type 1 diabetes in BB rats.
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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Conference Paper: Array processing using parametric signal models[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 signalsAcoustics, Speech, and Signal Processing, 1995. ICASSP-95., 1995 International Conference on; 06/1995
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ABSTRACT: Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes. After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted. Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes. These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.Diabetes 04/2011; 60(5):1414-23. DOI:10.2337/db10-0958 · 8.47 Impact Factor
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ABSTRACT: Leptin is a 167 amino acid cytokine- like hormone that is primarily manufactured by white adipose tissue. Brown adipose tissue, the stomach, ovaries, placenta, the liver, skeletal muscle, bone marrow, and pituitary also have been demonstrated to produce leptin (1). This hormone acts through at least six splice isoform receptors with similar extracellular but differing intracellular domains. Through these receptors, leptin has pleiotropic effects including suppression of appetite in the hypothalamus as well as modulation of energy homeostasis in the neuroendocrine system, immune function, and bone metabolism (1). Despite advances in the treatment of type 1 diabetes (T1D), insulin therapy is not curative. Recently, an interesting study in the nonobese diabetic (NOD) animal model for T1D mice was reported showing that the administration of leptin to recently diagnosed animals - either as monotherapy or with low- dose insulin - reversed hyperglycemia primarily through suppression of hyperglucagonemia (2). Unlike insulin, leptin therapy lowered lipogenic and cholesterologenic transcription factors thereby reducing lipid levels. Another animal model for T1D is the biobreeding diabetes- resistant (BB- DR) rat. These animals do not normallyPediatric Diabetes 09/2011; 13(1):74-6. DOI:10.1111/j.1399-5448.2011.00796.x · 2.13 Impact Factor