Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

Abstract

The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

Leptin therapy, insulin sensitivity, and glucose homeostasis

“…Besides being a potentially safe and effective antidiabetic therapy, these results clearly demonstrate that leptin regulates the glucose-insulin homeostasis in the hypothalamus, independent of its peripheral actions. [7071]…”

A case for new therapy for diabetes, is it leptin?

“…This is readily correctable by reinstating leptin sufficiency by circumventing BBB with replenishment directly in the hypothalamus. [2621] …”

“…In toto, the worldwide epidemic of diabetes and attending co-morbidities, together with the knowledge of the relatively higher rates of the incidence of diabetes in developing countries,[2–421] should catalyze a global search for newer and unconventional therapeutic strategies that can curb this alarming pandemic without the well-known shortcomings of insulin therapy, such as its failure to reproduce and sustain normoglycemia over a 24-h period, roller coaster pattern of glycemia interspersed with episodes of severe hypoglycemia, attendant obesity, metabolic and neural comorbidities, and the sky-rocketing treatment costs.…”

“…In fact, leptin gene therapy consisting of a single peripheral, central, or site-specific hypothalamic injection of recombinant adeno-associated virus (rAAV) vector encoding the leptin gene is highly advantageous over other modes of delivery, because it can impose long-lasting euglycemia and mitigate comorbidities. [9102126] rAAV is a relatively nonpathogenic and nonimmunogenic vector as amply documented by numerous ongoing clinical trials for various neural diseases. [293738] Consequently, leptin therapy is potentially a suitable new strategy for physicians that provide an additional armament to subserve as an efficient alternative or a supplement to the current insulin monotherapy.…”

“…Since the clinical safety and benefits of leptin therapy for long-term amelioration of T1D and T2D have not yet been fully ascertained, it is timely and pertinent to undertake rigorous clinical trials to evaluate and refine the leptin treatment regimen, to determine the efficient mode of delivery—systemic, nasal, or central route—and to assess the efficacy of a stable supply of biologically active leptin with the aid of gene therapy. [21293940] A search for newer long-acting leptin mimetics that can cross the BBB and reinstate hypothalamic control of glucose homeostasis also has the potential to pave the way in providing new antidiabetic drugs.…”