Impact of nicotinamide nucleotide transhydrogenase inactivation on the glucose stimulation of insulin secretion by mouse pancreatic beta‐cells

Jonas, Jean-Christophe;Souza, Arnaldo H.;Santos, Laila R.B.;Takahashi, Hilton
(2014) EASD Islet Study Group 2014 “Pancreatic Islet Cels Plasticity in Health and Diabetes” — Location: Lausanne, Switzerland (12.September.2014)

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  • Jonas, Jean-Christopheorcid-logoUCLouvain
    Author
  • Souza, Arnaldo H.UCLouvain
    Author
  • Santos, Laila R.B.UCLouvain
    Author
  • Takahashi, HiltonUCLouvain
    Author
Abstract
Background and aim: Nicotinamide nucleotide transhydrogenase (NNT) contributes to NADPH production in the mitochondrial matrix of eukaryotic cells. Its inactivation in beta‐cells was previously shown to markedly reduce glucose‐induced rises in ATP, calcium and insulin secretion, but these effects vary between experimental models. We recently found that, in islets from C57BL/6J mice that express a truncated inactive NNT, glucose does not reduce the mitochondrial glutathione redox state measured using GRX1‐roGFP2, in contrast to its effect in islets from C57BL/6N mice that express wild‐type NNT (abstract by Laila RB Santos). Here, we re‐evaluated the role of NNT by simultaneously measuring key stimulus‐secretion coupling events in islets from C57BL/6J and C57BL/6N mice perifused in the presence of increasing glucose concentrations. Results: 1) The glucose‐induced rise in NAD(P)H autofluorescence was significantly larger in N vs. J islets (normalised to the fluorescence in 0.5 mM glucose or after addition of FCCP). 2) The glucose‐induced changes in mitochondrial membrane potential and cytosolic calcium concentration were similar in both types of islets (rhodamine 123 fluorescence normalised to that measured after addition of FCCP). 3) The insulin/DNA content ratio was similar in both types of islets, but the glucose stimulation of insulin secretion was 2 to 2.5 times higher in N vs. J islets (normalized to insulin or DNA content). 4) The stimulation of insulin secretion by high potassium was 2 to 2.5 times higher in N vs. J islets at any glucose concentration, so that the amplifying action of glucose was similar in both types of islets. Conclusion: The lack of functional NNT in J vs. N islets markedly reduced their glucose‐induced rise in NAD(P)H autofluorescence and insulin secretion without affecting mitochondrial membrane hyperpolarisation and rise in cytosolic calcium concentration. These results suggest that the insulin secretion defect of J vs. N islets lies at a step distal to calcium influx.
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Jonas, J.-C., Souza, A. H., Santos, L. R. B., & Takahashi, H. (2014). Impact of nicotinamide nucleotide transhydrogenase inactivation on the glucose stimulation of insulin secretion by mouse pancreatic beta‐cells. EASD Islet Study Group 2014 “Pancreatic Islet Cels Plasticity in Health and Diabetes”, Lausanne, Switzerland. https://hdl.handle.net/2078.5/47867