Abstract
The opposite effects of insulin and glucagon in fuel homeostasis, the paracrine/endocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes (T2D) have long been recognized. Inappropriately increased alpha-cell function importantly contributes to hyperglycemia and reflects the loss of tonic restraint normally exerted by high local concentrations of insulin on alpha-cells, possibly as a result of beta-cell failure and alpha-cell insulin resistance, but additional mechanisms, such as the participation of incretin hormones in this response, have also been suggested. Three classes of drugs already available for clinical use address the abnormalities of glucagon secretion in T2D, namely, the GLP-1 receptor agonists (GLP-1RA), the inhibitors of dipeptidyl peptidase-4 (DPP-4i) and the amylin agonist pramlintide; it has been proposed that the glucagonostatic and insulinotropic effects of GLP-1RA equally contribute to their hypoglycemic efficacy. In this review, the control of glucagon secretion and its participation in T2D pathogenesis are summarized.
Highlights
The opposite effects of insulin and glucagon in fuel homeostasis, the paracrine/endocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes (T2D) have long been recognized
De Marinis et al reported the expression of glucagon-like peptide-1 (GLP-1) receptors in alpha-cells is
The reduction of the incretin effect in T2D patients is an epi-phenomenon of chronic hyperglycemia, irrespective of primary defects in glucose-dependent insulinotropic peptide (GIP) or GLP-1 action [24], which is consistent with the finding of loss of GIP insulinotropic efficacy in patients with diabetes of other etiologies, such as secondary to chronic pancreatitis, monogenic diabetes caused by HNF1 alpha mutations, and autoimmune diabetes with preserved beta-cell function [25]
Summary
The opposite effects of insulin and glucagon in fuel homeostasis, the paracrine/endocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes (T2D) have long been recognized. Glucagon secretion is stimulated by the incretin hormone glucose-dependent insulinotropic peptide (GIP)
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