Leptin Therapy Reverses Hyperglycemia in Mice With Streptozotocin-Induced Diabetes, Independent of Hepatic Leptin Signaling

Abstract

OBJECTIVELeptin 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.RESEARCH DESIGN AND METHODSAfter 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.RESULTSHyperleptinemia 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.CONCLUSIONSThese 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.

Lymphocytes in obesity-related adipose tissue inflammation

“…Interestingly, recent studies have described a beneficial role of leptin administration in type 1 diabetes. Although this is an apparent contradiction to the aforementioned reduced susceptibility of leptin-deficient mice to type 1 diabetes, the studies by Wang et al and Denroche et al in insulin-deficient and streptozotocin-treated diabetic mice, respectively [71,72], have demonstrated that leptin therapy prevents hyperglycaemia, improves lipid metabolism and reduces glucagon secretion. According to a recent paper, the majority of these effects are probably CNS-dependent [73].…”

Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol

“…Alternatively, leptin can stimulate glucose uptake in the peripheral tissues of rodent models of type 1 diabetes [6,7]. However, glucose utilisation in white adipose and some skeletal muscle groups is unaltered in response to leptin [6,7], and other studies report that glucose uptake or disposal is not substantially augmented by leptin therapy [1,4]. Considered with the profound fasting intolerance in the current study, these findings suggest that energy-yielding substrate depletion plays an important role in the glucose-lowering action of leptin.…”

“…Administration of the adipose-derived hormone leptin can ameliorate hyperglycaemia and hyperketonaemia in rodent models of insulin-deficient type 1 diabetes, without raising circulating insulin levels, and independent of food intake [1][2][3][4]. Several mechanisms have been proposed for this glucose-lowering action, including suppressed glucagon and improved insulin sensitivity [1][2][3][4][5], and central leptin therapy was shown to inhibit hepatic glucose production [6] and enhance glucose uptake in brown adipose tissue [7].…”

“…Several mechanisms have been proposed for this glucose-lowering action, including suppressed glucagon and improved insulin sensitivity [1][2][3][4][5], and central leptin therapy was shown to inhibit hepatic glucose production [6] and enhance glucose uptake in brown adipose tissue [7]. With the plethora of metabolic changes that occur with leptin administration in rodent models of type 1 diabetes, the precise mechanism of leptin action in type 1 diabetes remains unclear.…”

Alpha cell function in type 1 diabetes

“…[62][63][64] In animal studies, circulating glucagon is decreased following therapy with ghrelin antagonists, and with leptin agonists. 65,66 These therefore have therapeutic potential, and the leptin analogue metreleptin has now entered phase 1 clinical trials in patients with type 1 diabetes mellitus. 67 A group of novel drugs that target the GPR119 receptor have shown promise in protecting mouse alpha and beta cells from streptozotocin-induced apoptosis 68 and may therefore improve glycaemic control through preservation of these cells.…”