Pleotropic Acute and Chronic Effects of Leptin to Reverse Type 1 Diabetes

Abstract

Recent studies have demonstrated that leptin can prolong life chronically in rats with poorlycontrolled type 1 diabetes (T1D). Multiple explanations have been proposed to explain leptin's chronic antihyperglycemic effect, including suppression of glucagon release and/or signaling, reductions in hyperphagia and ectopic lipid content, and improvements in insulin sensitivity; it is leptin's ability to reduce plasma glucose relies on all of these effects. In addition, leptin reverses hyperglycemia and diabetic ketoacidosis (DKA) acutely, within 6 hours of leptin infusion, by suppressing hypothalamic-pituitary-adrenal (HPA) axis activity in insulinopenic rats. Thus current evidence suggests that leptin's acute, insulin-independent effect to reverse DKA by suppressing HPA axis activity occurs through a different mechanism from its chronic, pleotropic, insulindependent effect to reverse hyperglycemia and prolong survival in rodents with T1D. Leptin may therefore represent an attractive therapeutic target to improve glycemic control in humans with poorly-controlled T1D. Keywordstype 1 diabetes; leptin; corticosterone; diabetic ketoacidosis; hypothalamic-pituitary-adrenal axis Type 1 diabetes (T1D) occurs when T-cell mediated destruction of the insulin-producing β-cell (1, 2) leads to insulinopenia, hyperglycemia, and ketoacidosis, which can rapidly result in coma and death if left untreated. For reasons that remain unclear, the incidence of T1D is on the rise worldwide (3, 4), and increases in diabetic ketoacidosis (DKA) rates have accompanied the increasing prevalence of T1D (5, 6). For eight decades since its discovery in the early 1920s, insulin was believed to be the only hormone capable of reversing T1D, and consequently it has been prescribed to all T1D patients as a necessary agent to extend life. However, the absolute requirement of treating T1D with insulin was first called into question in the late 1990s. Leptin, a hormone secreted by adipocytes which was first identified by Jeffrey Friedman and colleagues (7) which reduces body weight and normalizes glycemia in leptin-deficient ob/ob mice (8-10), resulted in close to normalization of blood glucose concentrations when infused subcutaneously in streptozotocin (STZ)-induced T1D rats (11).These results have clear clinical implications in humans: although studies have yielded both positive (12-16) and negative results (17)(18)(19) regarding an association of leptin with glycemic control in normoglycemic or mildly hyperglycemic T1D patients, patients in diabetic ketoacidosis (DKA) clearly have lower plasma leptin concentrations than healthy controls (20, 21). These results suggest that leptin may be regulated by insulin, an interpretation bolstered by the fact that leptin production by adipocytes rises with increasing insulin concentrations in vitro (22), during the acute treatment of DKA in T1D subjects (20) and during acute and chronic hyperinsulinemia in some studies in healthy controls (23-25). However, data are mixed regarding the ability of insulin -...

Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice

“…Although the adipokines are synthesized and secreted by the adipose tissue, the expression of adipokines and components of their signaling cascades is shown in the testes (Gurusubramanian & Roy, 2014; Rak, Mellouk, Froment, & Dupont, 2017). The plasma levels of adipokines change dramatically not only in DM2, as a result of obesity and impaired energy metabolism, but also in DM1 due to acute hyperglycemia, reduced insulin signaling and the activation of inflammation and oxidative stress (Perry, 2017; Yazıcı et al, 2012). We have also shown that the expression of visfatin was decreased in the testis of rats with alloxan‐induced DM1 (Gurusubramanian & Roy, 2014).…”

Editorial: The Transformative Age of Leptin in Diabetes Treatment

“…Dr. Perry defends these findings in the face of a recent article showing no effect of HPA axis regulation on leptin's glucose-lowering activities. She convincingly argues that the lower insulin levels and presence of sucrose water masked the activities of leptin on the hypothalamus in the contrasting study (Perry 2017). The implications of Dr. Perry's studies are profound.…”