Hypothalamic-mediated control of glucose balance in the presence and absence of insulin

Abstract

Glucose homeostasis and LeptinThe dogma that the pancreatic-beta-cell-secreted hormone insulin is an absolute prerequisite for survival has withstood for almost a century. Precisely, since the early 1920s when insulin was first discovered and shown to rescue the lethality and part of the metabolic aberrancies caused by insulin deficiency in humans [1]. However, recent results from different groups have called into question the notion that life without insulin is incompatible. In 2008, Unger and colleagues reported that leptin overexpression is capable of rescuing the sever hyperglycemia and lethality brought on by insulin deficiency in rodents [2]. These effects are not mediated by direct action of leptin on hepatocytes [3] or pancreatic alpha cells (that are specialized in the secretion of the glycemia-rising hormone glucagon) [4,5]. Rather, these anti-diabetic and lifesaving effects are due to the action of leptin on brain neurons [4,6]. Research PerspectiveSpecifically, leptin acts on neurons endowed with the ability to express leptin receptor and also vesicular γ−aminobutyric acid (GABA) transporter (VGAT) that biochemically characterizes GABAergic neurons [7,8]. A small but important contribution is also made by direct action of leptin on hypothalamic proopiomelanocortin (POMC) neurons that belong to the central melanocortin system [9]. These results indicate that an intricate hypothalamic neurocircuitry is empowered with the ability to exert anti-diabetic actions independently to insulin.Historically, the anti-diabetic property of leptin was first shown in 1995 when results from studies aimed at testing the effect of leptin administration in insulin resistant rodents were made available [10][11][12]. Notably, the anti-diabetic effect of leptin was shown to be independent to its well-established body-weightreducing and food-intake-suppressing actions. In fact, systemic leptin administration at a dose that does not affect body weight and food intake was shown to ameliorate hyperglycemia in ob/ob mice [these mice are endowed with the ability to mediate the hyperglycemia-lowering action of the adipocyte-derived hormone leptin in an insulin-dependent and insulin-independent fashion. These results may pave the way for better anti-diabetic approaches and therefore positively impact on life expectancy of diabetic subjects.

The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice

“…We know that disruption of leptin signaling and leptin resistance plays a critical role in obesity, a major risk factor for morbidity and mortality, and obesity-related disease such as impaired glucose metabolism, cancer, and the development of cardiovascular disease. Improvements in insulin sensitivity and modulation of the IIS pathway and the subsequent increase in lifespan are much better understood with pathways conserved from worms to humans [ 142 ]. The hypothesis that CR decreases oxidative damage and increases antioxidant enzyme levels was not supported here.…”

Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates

“…We thus assessed whether these parameters could be linked to atrophy in lemurs and found that it is probably the main factor leading to pathologic hippocampal/ septal atrophy and the associated cognitive alterations in lemurs. Yet, reverse cause-effect relations are also possible [ 35 ].…”

Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?

“…The SLC2A2 level is increased in hyperglycemia and decreased in hyperinsulinemia [40]. Leptin receptor overlapping transcript (LEPROT) is involved in the expression of growth hormone and leptin receptors, which are associated with hyperglycemia [41]. Endothelial cell-specific molecule 1 (ESM1) is regulated by cytokines and could have a role in the endothelial dysfunction [42].…”

Insulin under the influence of light

“…This indicates that SIRT1, and possibly other proteins, can modulate hepatic insulin sensitivity in a diurnal fashion. Notably, while SIRT1 in SF1 neurons does not seem to be directly involved in the link between changes in photic inputs and changes in hepatic responsiveness to insulin [139], it is possible that SIRT1 in other hypothalamic neurons [9,151] controls insulin action in hepatocytes via direct and/or indirect mechanisms.…”