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1 The Institute for Diabetes, Obesity and Metabolism and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, United States
2 The Institute for Diabetes, Obesity and Metabolism and Department of Genetics, University of Pennsylvania, Philadelphia, United States
3 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
4 Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
5 Pharmacological Research 1, Novo Nordisk, Bagsvaerd, Denmark
6 University of Pennsylvania School of Medicine, The Institute for Diabetes, Obesity and Metabolism and Department of Biochemistry, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: nicolai{at}mail.med.upenn.edu.
Neural and endocrine factors (i.e. acetylcholine (Ach) and GLP-1) restore defective glucose-stimulated insulin release in pancreatic islets lacking sulfonylurea type 1 receptors (SUR1-/-) (Am J Physiol 286: E834-843, 2004). The goal of the present study is to assess the fuel-induced respiration in SUR1-/- islets and to correlate it with changes in intracellular Ca2+, insulin and glucagon secretion. Using a method based on O2 quenching of phosphorescence, the O2 consumption rate (OCR) of isolated islets was measured on-line in a perifusion system. Basal insulin release (IR) was 7-10 times higher in SUR1-/- compared to control (CON) islets but the OCR was comparable. The effect of high glucose (16.7 mM) on IR and OCR was markedly reduced in SUR1-/- islets compared to CON. Ach (0.5 µM) in the presence of 16.7 mM glucose caused a large burst of IR in CON and SUR1-/- islets with minor changes in OCR in both groups of islets. In SUR1-/- islets high glucose failed to inhibit glucagon secretion during stimulation with AAM or Ach. Conclusions: 1) Reduced glucose responsiveness of SUR1-/- islets may be in part due to impaired energetics as evidenced by significant decrease in glucose-stimulated OCR. 2) Elevated intracellular Ca2+ levels may contribute to altered insulin and glucagon secretion in SUR1-/- islets. 3) The amplitudes of the changes in OCR during glucose and Ach stimulation do not correlate with IR in normal and SUR1-/- islets suggesting that the energy requirements for exocytosis are minor compared to other ATP consuming reactions.
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