Alpha cell function in health and disease: influence of glucagon-like peptide-1

Abstract

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

“…As discussed in a recent review [12], the effects of glucagon-like peptide-1 do not appear to be limited to suppression of glucagon release in the presence of hyperglycaemia; rather, during hypoglycaemia, activation of the glucagon-like peptide-1 receptor (by agonists such as exenatide) increases glucagon levels, enhancing the stimulatory effect of low glucose levels on the alpha cell [13].…”

“…Potential participants attended a screening visit (Week −4), during which inclusion/exclusion criteria were assessed. Eligible patients were randomised at Week 0 to receive vildagliptin (50 mg twice daily) or placebo, subsequently attending five additional visits (Weeks 4,8,12,16 and 24). For the patient disposition, see Fig.…”

Effect of the amino acid alanine on glucagon secretion in non-diabetic and type 1 diabetic subjects during hyperinsulinaemic euglycaemia, hypoglycaemia and post-hypoglycaemic hyperglycaemia

“…For example, it is possible that the initially greater stimulation of beta cell function by amino acids results in a greater fall in intra-islet insulin concentration during hypoglycaemia, at least in normal non-diabetic subjects [24]. In addition, it is possible that amino acids modulate the glucose-sensing ability of alpha cells through glucagon-like peptide 1 [25].…”

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…In fact, islet dysfunction is a key event underlying development of type 2 diabetes, as manifested by impaired insulin secretion and increased secretion of glucagon (Dunning et al, 2005;Wajchenberg 2007). Recently, it has also been proposed that reduced β cell mass is associated with type 2 diabetes (Butler et al, 2003;Wajchenberg 2007).…”