Abstract
Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic β-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of α-cells glucagon secretion to IGF-1. Herein, we evaluated the association between plasma IGF-1 and glucagon levels in 116 nondiabetic adults. After adjusting for age gender and BMI, fasting glucagon levels were positively correlated with 2-h post-load glycaemia, HOMA index and fasting insulin, and were negatively correlated with IGF-1 levels. In a multivariable regression, the variables independently associated to fasting glucagon were circulating IGF-1 levels, HOMA index and BMI, explaining 20.7% variation. To unravel the molecular mechanisms beneath IGF-1 and glucagon association, we investigated whether IGF-1 directly modulates glucagon expression and secretion in an in vitro model of α-cells. Our data showed that IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion via activation of the phosphatidylinositol-3-kinase/Akt/FoxO1 pathway.Collectively, our results suggest a new regulatory role of IGF-1 on α-cells biological function.
Highlights
Glucagon is the major hyperglycaemic hormone of the body counteracting insulin effects when blood glucose falls to dangerously low levels [1]
We found that even when age, gender and BMI, 2-h post-load glucose levels, and the HOMA index were included in the model, the variables independently associated to fasting glucagon levels were circulating IGF-1 levels (β= -0.255, P=0.03), HOMA index (β=0.289, P=0.04) and BMI (β= -0.267, P=0.05) explaining 20.7% of variation of fasting glucagon levels
Glucagon secretion is regulated by the fine interaction of several elements, including glucose, insulin, incretin hormones, somatostatin, amino-acids, and fatty acids [31,32,33,34]
Summary
Glucagon is the major hyperglycaemic hormone of the body counteracting insulin effects when blood glucose falls to dangerously low levels [1]. Glucagon secretion by pancreatic α cells is a complex and highly regulated process, involving a combination of paracrine, autocrine, hormonal, as well as autonomic neural mechanisms [2]. Glucagon secretion is mainly regulated by insulin and glucose both acting as inhibitors. Impaired suppression of glucagon by insulin and glucose have been proposed as potential mechanisms for the hyperglucagonemia observed in individuals with type 2 diabetes (T2DM) [3, 4]. Glucagon suppression upon oral glucose challenge is reduced in individuals with impaired glucose tolerance (IGT) [5,6,7]. It is important to consider the complex interplay among metabolic, paracrine, autocrine, and hormonal factors when studying glucagon secretion in vivo
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