Incretins

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.

Glucagon receptor signalling – backwards and forwards

“…As summarized in the excellent review in the recent issue of Expert Opin Investig Drugs [8], interruptions of glucagon receptor (GCGr) signalling, including inactivating mutations, knockouts, and antagonism by selective small molecules, monoclonal antibodies, or antisense oligonucleotides, are associated with α-cell hyperplasia, leading to dramatic hypersecretion of proglucagon-derived products, including glucagon and GLP-1. By contrast, the reduction in plasma glucagon induced with GLP-1r agonists and DPP-4 inhibitors is modest (20-50%) and does not appear to be associated with an overt hypertrophic effect on α-cells [7].…”

“…Not surprisingly, glucagon secretion is increased substantially by blockade of GLP-1r signalling using exendin9-39, and suppressed by GLP-1r agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (the latter markedly delay the degradation of active GLP-1). By contrast, exogenous GIP stimulates glucagon secretion despite its insulinotropic actions, which counteracts the glucagonostatic action of GLP-1 [7].…”

“…There is compelling evidence linking the gut-derived incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), to the regulation of glucagon secretion. GLP-1 exhibits both insulinotropic and glucagonostatic effects [7]; the latter may be mediated by activation of GLP-1r on α-cells and/or secondary to the stimulation of insulin from β-cells and/or somatostatin from δ-cells [7]. Not surprisingly, glucagon secretion is increased substantially by blockade of GLP-1r signalling using exendin9-39, and suppressed by GLP-1r agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (the latter markedly delay the degradation of active GLP-1).…”

“…GLP-1 mimetics and DPP-4 inhibitors) or action (e.g. metformin) [7]. These effects are generally modest and, probably for this reason, not associated with the adverse effects seen with GCGr antagonism.…”

Incretins role in Latent autoimmune diabetes of adults pathogenesis, the possibility of therapy with combination of glucagon-like peptide-1 agonist (GLP-1) and insulin.

“…ГПП-1 глюкозозависимо снижает секрецию глюкагона, сти-мулирует секрецию инсулина, индуцирует увеличение содержания (запаса) инсулина в β-клетках. Кроме того, ГПП-1 замедляет опорожнение желудка и способствует ускорению чувства насыщения [2].Испытания на жи-вотных демонстрируют участие ГПП-1 в β-клеточной пролиферации, повышении неогенеза и снижении апоптоза β-клеток, что способствует их регенерации и повышению массы [3,4].Имеющиеся на сегодняшний день исследования по изучению секреции инкретинов при аутоиммунном СД немногочисленны, и их результаты неоднозначны. Ряд исследователей указывают на сниженную секре-цию инкретинов и неадекватную супрессию глюка-гона при СД1 и LADA [5,6].…”