Leptin Improves Insulin Resistance and Hyperglycemia in a Mouse Model of Type 2 Diabetes

Abstract

Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant.

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

“…The precise mechanisms responsible for these findings are unclear, although factors including increased metabolic and physical activity may contribute [20]. The lower body weight in MKR mice is due to a reduction in lean body mass, and changes in adipose tissue mass, ranging from a slight increase to nonsignificant change, have been reported [26,27].…”

Vascular Smooth Muscle Cell Alterations Triggered by Mice Adipocytes: Role of High-Fat Diet

“…The γ1 subtype controls cellular homeostasis while PPARγ2 further controls preadipocyte differentiation and lipogenesis 12) . Among these secreted factors are leptin and adiponectin, two key factors in glucose and lipid homeostasis [13][14][15] . In addition to direct vascular consequences, adipokines may regulate VSMC proliferation, migration and viability.…”

Central leptin insufficiency syndrome: An interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions

“…it is generally held that the fat burden of obesity contributes substantially to cause hyperinsulinemia [57,64,68,69,76,89,93], acute inhibition of insulin secretion by central administration of leptin has also been reported [34,62,89,102,131]. Suppression of ultradian insulin secretion from the pancreas was consistently observed when leptin expression was selectively enhanced by leptin gene transfer in the hypothalamus or in selected hypothalamic sites such as the medial preoptic area (MPOA), paraventricular hypothalamus (PVN), ventromedial hypothalamus (VMH) or ARC [4,5,17,20,22,41,42,44,109,110,133].…”

“…Remarkably, this perseverance of euglycemia was evident even in the insulin-deficient streptozotocin treated diabetic mice and geneticallyinduced severely insulinopenic diabetic Akita mice [132,133,142, and unpublished]. Evidently, a distinct leptin-responsive hypothalamic mechanism orchestrates euglycemia by accelerating glucose metabolism in brown adipose tissue (BAT), liver, skeletal muscles and adipose tissue independent of insulin involvement [34,62,76,99,101,129,[131][132][133][134]136, Fig. 2].…”