Leptin therapy as a substitute for insulin replacement in experimental models of diabetes: Clinical implications in humans

Abstract

Multidisciplinary approaches undertaken to elucidate the control of leptin secretion from white adipose tissue and its neurobiology in energy homeostasis has serendipitously uncovered the obligatory participation of leptin via the hypothalamus in glucose homeostasis, independent of its well-known role in appetite control. The salient features of this discovery are the following: Glucose homeostasis, sustained through the operation of a tight feedback relationship between pancreatic insulin and adipocyte leptin, is mediated through an interconnected network of leptin receptor producing neurons in the hypothalamus that relays afferent regulatory information along distinct pathways to peripheral targets involved in insulin secretion and glucose metabolism. A break down in optimal leptin communication with these hypothalamic targets due to leptin insufficiency resulting from either leptinopenia or hypoleptinemia after loss of pancreatic beta cells, or evoked by hyperleptinemia associated attenuated leptin entry across the blood–brain barrier, underlies diabetes type 1(T1DM) and diabetes type 2 (T2DM). Leptin replenishment by injection or gene therapy, systemically or directly into the hypothalamus, stably reinstated euglycemia in all rodent paradigms of T1DM. In contrast, leptin delivery only directly to hypothalmic targets either by central infusion or gene therapy reestablished glucose homeostasis in obese and aging T2DM animal paradigms. Clinical evaluations along similar lines to establish glucose homeostasis for extended periods in response to leptin delivered systemically was also successful in leptinopenic congenital or acquired lipodystrophic subjects. Evidently, leptin therapy is a new treatment modality with the potential to replace insulin monotherapy for T1DM when delivered either systemically or centrally, but for T2DM only when delivered centrally. The current global rise in the incidence of diabetes underscores an urgent need for rigorous clinical testing of leptin to determine the optimal delivery procedure and long-term consequences.