Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes

Abstract

OBJECTIVEDepletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.RESEARCH DESIGN AND METHODSAdult male Wistar rats remained nondiabetic or were injected with the β-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 μg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.RESULTSPhysiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.CONCLUSIONSWe conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.

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

“…While leptin therapy suppresses glucagon levels in STZdiabetic mice [2-5, 7, 19], leptin therapy can reverse hyperglycaemia prior to glucagon suppression [11], and can reverse hyperglucagonaemia without normalising glycaemia in STZ-diabetic rats [5]; this suggests that glucagon suppression alone cannot sufficiently account for the glucoselowering action of leptin. Our finding that, during prolonged fasting, STZ-leptin mice showed a trend towards elevated plasma glucagon, but were hypoglycaemic, supports this notion.…”

“…First, this demonstrates that the level of glycaemic normalisation achieved by leptin is dependent on fasting duration, which should be taken into account when comparing results across studies. Differences in fasting duration could account for discrepancies between studies as to whether physiological leptin doses reverse hyperglycaemia in STZ-diabetic rodents [5,11,20], and why studies examining free-feeding or 2 h fasted rodents have not reported leptin-induced hypoglycaemia [2,3,7,19]. Second, the hypoketotic hypoglycaemia observed during prolonged fasting suggests that leptin therapy may carry hypoglycaemic risk in type 1 diabetes.…”

“…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.…”

A Review of the Leptin Hormone and the Association with Obesity and Diabetes Mellitus

“…Given that obesity can be a result of leptin resistance, leptin resistance is likely to be involved in the development of the disease. Like Leptin resistance, leptin deficiency is significant in the pathogenesis of severe insulin resistance in uncontrolled insulin deficient diabetes mellitus [26].…”

“…[25] 2004 Leptin level increases with sleep [7] 2010 Leptin is significant in the pathogenesis of insulin resistance in uncontrolled insulindeficient diabetic rats [26] 2016…”