Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Abstract

Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies

“…high glucose levels or hydrogen peroxide [20, 21, 86-90] (Table 1 ). However, the observed effects on apoptosis in a number of these studies may not strictly be attributed to effects via OS, as GLP-1 per se activates antiapoptotic genes and thus independently decreases apoptosis [91]. But in general, in vitro studies have reported decreased levels of ROS [20, 21, 76, 84, 88-90, 92-99], NOX subunits or activity [20, 21, 84], malondialdehyde (MDA) [90, 95, 100] and increased levels of antioxidants and/or genes involved in antioxidant activity [21, 86, 87, 90, 92, 95, 100-103] following GLP-1 exposure.…”

Gluco-Incretins Regulate Beta-Cell Glucose Competence by Epigenetic Silencing of Fxyd3 Expression

“…They potentiate glucose-induced insulin secretion (GIIS) [1], [2], induce beta-cell proliferation [3], [4], protect these cells against cytokine- or glucolipotoxicity-induced apoptosis [5], [6], and increase their glucose competence [7]. Their actions depend on their binding to specific Gs protein-coupled receptors [8], [9], which induce the production of cAMP leading to activation of protein kinase A, or of the cAMP binding protein Epac2 [10].…”

Combined insulin detemir and liraglutide therapy in type 2 diabetic patients: a base for an alliance

“…Препараты инсулина спо-собствуют улучшению функции β-клеток за счет норма-лизации уровня гликемии натощак, ликвидации эффекта глюкозотоксичности и уменьшения нагрузки на β-клетку. Инкретиновая терапия также способна ингибировать апоптоз [14] и улучшать функцию β-клеток [41,42]. Складывается впечатление о том, что гипотеза «отдыха β-клетки», сформулированная на основании данных применения инсулинотерапии в дебюте СД2 [43], приоб-ретает большую актуальность в условиях своевременной комбинации левемира и лираглутида.…”

“…Рецепторы ГПП-1 экспрессируются также дру-гими клетками, что объясняет внепанкреатические эф-фекты ГПП-1: замедление опорожнения желудка [12], индукцию чувства насыщения посредством центральных эффектов на гипоталамус [13], что крайне важно для кон-троля массы тела и гликемии у пациентов с СД2 на фоне ожирения. ГПП-1 также способен защищать β-клетки путем ингибирования их апоптоза [14], предполагая за-медление прогрессирования заболевания.…”