Elsevier

Peptides

Volume 30, Issue 10, October 2009, Pages 1957-1963
Peptides

Review
Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation

https://doi.org/10.1016/j.peptides.2009.07.021Get rights and content

Abstract

Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin–hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs – liver, skeletal muscle and brown adipose tissue – to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae – hyperinsulinemia, insulin resistance and hyperglycemia – in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.

Introduction

Insulin produced by pancreactic β-cells facilitates glucose homeostasis by promoting glucose uptake and storage in skeletal muscle, liver and fat cells. Either lack or inefficient use of insulin by these peripheral targets coalesces into diabetes, a chronic disease characterized by hyperglycemia which over time may inflict a spectrum of metabolic and neural diseases and shorten life-span [33], [34], [53], [55], [67], [72]. Diabetics suffer from either type 1 or type 2 diabetes. Type 1 diabetes is a debilitating autoimmune disease caused by T-cell-mediated gradual destruction of β-cells, leading to either insufficient or complete lack of insulin production [17], [29], [33], [34], [72], [82]. Insulin replacement regimens aimed at reproducing the physiological range of blood glucose levels are the treatment of choice for these patients [72], [82]. Type 2 diabetes is a progressive chronic disease that can manifest at any age due largely to persistent metabolic imbalance engendered by myriads of internal and external environmental factors, including diet and lifestyle changes [17], [29], [33], [34], [72], [82]. Increases in episodic basal and post-prandial insulin secretion initiated by these environmental shifts gradually lead to insulin receptor insensitivity, insulin resistance and diminished downstream insulin receptor signaling in target cells. The relentless compensatory insulin hypersecretion to normalize blood glucose levels under these conditions expedites β-cell dysfunction and loss that eventuates into unremitting hyperglycemia [9], [33], [35], [53], [55], [70], [71]. The onset of these pathophysiological sequalae of type 2 diabetes is highly correlated with increasing adiposity and age [29], [33], [34], [35], [53], [55], [60], [79], [80]. Interventional therapies that delay or prevent entirely the inevitable adverse health consequences of type 2 diabetes include insulin administration and injectable and orally effective antidiabetic drugs [33], [63], [72], [82]. However, current therapies for these two etiologically distinct diseases are cumbersome, as they require daily administration or continuous infusion of insulin and antidiabetic drugs, along with constant monitoring by patients and physicians for glycemic control, all of which, in aggregate, substantially escalate medical costs [29], [33], [53], [55], [63], [72], [79], [80], [82].

Historically, ever since the recognition of insulin as the indispensable signal molecule in maintaining glucose homeostasis, research has been devoted entirely to deciphering the external and internal environmental factors at the systemic, cellular and molecular levels that regulate insulin secretion and endogenous pathways that integrate glucose disposal for tight glycemic control [6], [33], [55], [72], [82]. This expanding knowledge has continued to singularly steer research towards improving ways to optimally deliver insulin and identify newer insulin mimetics. The possibility that there may exist additional endogenous signal molecules and alternate peripheral and central pathways that either on their own or in concert with insulin orchestrate homeostatic cues for tight glycemic control, and may, thus, offer novel therapeutic avenues, has received little attention in contemporary thinking (Fig. 1) [33], [34], [56], [72], [82].

Indeed, it has been known for a long time that neural signals from the brain, especially those emanating from the hypothalamus, are quite important in the dynamic operation of the insulin–glucose axis [12], [27], [37], [38], [40]. Ablation of either the ventromedial nucleus (VMN) or the paraventricular nucleus of the hypothalamus in rodents accelerated insulin secretion not only prior to the onset of hyperphagia and increased rate of fat accretion but blood insulin levels remained elevated in concert with progression towards morbid obesity [12], [27], [37], [38], [40]. These rapid and pronounced permanent shifts in the insulin–glucose axis have long been assumed as a secondary manifestation in response to unregulated ingestive behavior and adiposity. The identification of leptin, primarily produced by white adipose tissue (WAT), as a major hormonal signal in the hypothalamic integration of energy homeostasis [20], [35], [37], [38], [55], [68], [93], and subsequent unraveling of additional multiple regulatory effects of leptin exerted through the hypothalamus on various physiological systems, re-established a pivotal role of afferent neural relays in the bidirectional communication between the periphery and brain [13], [17], [21], [29], [32], [35], [40], [47], [55], [58], [59], [60], [78], [85].

Consequently, apart from a mandatory regulatory role in energy intake and expenditure [10], [35], [38], [40], [93], independent participation of leptin in the hypothalamic integration of insulin–glucose homeostasis and the new understanding that a breakdown in the cross-talk between WAT and hypothalamus is, indeed, an etiologic factor in the pathogenesis of diabetes is collated in this review. Also, within this context are detailed (i) hypothalamic relays that influence insulin secretion and glucose disposal under the direction of leptin, (ii) a critical role of antecedent leptin insufficiency in the hypothalamus in causation of pathophysiological sequalae of diabetes type 1 and 2, and (iii) interventions that reinstate central leptin sufficiency to lessen or eliminate the shortcomings of current therapies.

Section snippets

Leptin restraint on insulin secretion primarily through hypothalamic relays

That leptin exerts a dynamic regulatory restraint on insulin secretion is suggested by numerous clinical and animal studies [2], [22], [23], [24], [28], [35], [66], [68], [69], [70], [74]. Insulin is adipogenic, promotes leptin secretion and fat deposition in the body (Fig. 1, Fig. 2) [29], [33], [35], [36], [47], [55]. Since leptin can inhibit insulin efflux from β-cells, a peripheral adipo-insular feedback loop was suggested to tightly regulate leptin and insulin secretion (Fig. 1) [33], [47]

Upregulation of glucose metabolism by leptin through hypothalamic relays, independent of insulin involvement

Leptin is also a significant player in the regulation of glucose metabolism. Systemic administration of leptin to either leptin-deficient ob/ob [19], [35], [41], [61], [89] or leptinopenic lipodystrophic, diabetic humans and mice stimulated glucose metabolism and normalized blood glucose concentrations, benefits previously attributed to activation of leptin receptors on hepatocytes, islet cells, adipocytes and skeletal muscle cells [19], [29], [30], [33], [47], [53], [55]. However, these very

Amelioration of diabetes by stable leptin supply

Research in gene transfer strategies to develop interventional therapies for various neural diseases has proceeded at a rapid pace [18], [35], [36], [39], [40], [42], [46]. It is now feasible to introduce genes into cells to replace a missing gene in order to correct or augment the target gene function to cure or slow the progression of chronic diseases due to genetic abnormalities, environmental insults and metabolic imbalance. Gene transfer technology thus offers a potentially newer means to

Concluding remarks

A striking inference of these investigations is that leptin in the circulation or available centrally alone, can mimic insulin-like glucose lowering effects in the complete absence of insulin. More importantly, the outcome of the central leptin gene transfer studies illuminates a substantive leptin link in the etiology of diabetes (Fig. 2). Since stable leptin supply blocked the dire life-threatening pathophysiological consequences of diabetes, central leptin gene therapy is potentially a

Acknowledgment

The work is supported by a grant from the National Institutes of Health (DK37273).

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