2103-P: Glucose-Dependent Insulinotropic Polypeptide (GIP) Protects against Cytokine-Induced Cell Death and Exerts Both Insulinotropic and Glucagonotropic Effects in Human Islets

Abstract

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted from enteroendocrine K cells following food intake and potentiates glucose-stimulated insulin secretion from β-cells. Recent studies suggest that GIP also has glucagonotropic properties under euglycemic and hypoglycemic conditions in humans. GIP may therefore be exploited as a safeguard against hypoglycemia in patients with type 1 diabetes (T1D). However, a direct glucagonotropic effect of GIP on human α-cells has not yet been investigated. In this study, we investigated the effects of GIP on glucagon and insulin secretion in isolated human islets during 30-min exposures to low (2 mM) and high (20 mM) D-glucose concentrations. We further investigated the potency of GIP to protect human islets from cell death induced by a 48-h exposure to pro-inflammatory cytokines (50 U/mL interleukin-1β + 1,000 U/mL interferon-γ) known to contribute to islet destruction in T1D. GIP (2.5 nM) significantly (P=0.048, n=4) increased glucagon secretion by 48% at 2 mM glucose in isolated human islets as compared to 2 mM glucose alone. At 20 mM glucose, GIP did not affect glucagon secretion, but potentiated insulin secretion by 45% (P=0.015, n=4). Further, cytokine-induced human islet cell death was decreased by 50% by co-treatment with GIP (P=0.001, n=3). Our findings demonstrate that GIP protects against cytokine-induced islet death and possesses glucagonotropic and insulinotropic effects on human islets at low and high glucose, respectively. These findings support GIP as a bifunctional blood glucose-stabilizer that might be exploited to treat T1D. Disclosure A. Jørgensen: None. M. Egeskov: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. J. Størling: None.