The Adipocytokine Nampt and Its Product NMN Have No Effect on Beta-Cell Survival but Potentiate Glucose Stimulated Insulin Secretion

Abstract

Aims/HypothesisObesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) and its enzymatic product Nicotinamide mononucleotide (NMN), which has been associated with obesity and type 2 diabetes mellitus (T2DM) directly influence beta-cell survival and function.MethodsThe effect of Nampt and NMN on viability of INS-1E cells was assessed by WST-1 assay. Apoptosis was measured by Annexin V/PI and TUNEL assay. Activation of apoptosis signaling pathways was evaluated. Adenylate kinase release was determined to assess cytotoxicity. Chronic and acute effects of the adipocytokine Nampt and its enzymatic product NMN on insulin secretion were assessed by glucose stimulated insulin secretion in human islets.ResultsWhile stimulation of beta-cells with the cytokines IL-1β, TNFα and IFN-γ or palmitate significantly decreased viability, Nampt and NMN showed no direct effect on viability in INS-1E cells or in human islets, neither alone nor in the presence of pro-diabetic conditions (elevated glucose concentrations and palmitate or cytokines). At chronic conditions over 3 days of culture, Nampt and its product NMN had no effects on insulin secretion. In contrast, both Nampt and NMN potentiated glucose stimulated insulin secretion acutely during 1 h incubation of human islets.Conclusion/InterpretationNampt and NMN neither influenced beta-cell viability nor apoptosis but acutely potentiated glucose stimulated insulin secretion.

Physiological and pathophysiological roles of NAMPT and NAD metabolism

“…21 In confirmation of this hypothesis, NAMPT and NMN were shown to induce increased insulin secretion compared with glucose alone in human islets after 1 h incubation with high glucose concentrations. 138 In HFD-induced obese mice, a direct effect of NAMPT not only on glucose metabolism but also on the pathogenesis of T2DM was found. 139 NAD biosynthesis mediated by NAMPT was impaired in HFD-fed mice with T2DM compared with that in regular chow-fed controls, whereas administration of NMN ameliorated glucose intolerance by restoring levels of NAD.…”

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“…JEG-3 cells and PMTs apoptosis were detected by Alexa Flour 488 Annexin V/Dead Cell Apoptosis Kit (Invitrogen) to detect early apoptotic cells (cells with intact membranes with externalized phosphatidylserine residues), late apoptotic cells (apoptotic cells showing compromised membrane integrity), and nonapoptotic cells at 24 h of culture (37). Cells were washed in ice-cold PBS (Sigma-Aldrich) and resuspended in 100 ml annexin V binding buffer (140 mmol/L NaCl, 2.5 mmol/L CaCl 2 , 1.5 mmol/L MgCl 2 , and 10 mmol/L HEPES, pH 7.4) containing annexin V-FITC and propidium iodide (PI; 1 mg/ml) for 15 min.…”