Insulin Feedback Alters Mitochondrial Activity Through an ATP-sensitive K+ Channel–Dependent Pathway in Mouse Islets and β-Cells

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 7; pp. 1765 - 1772
• Main Authors: Nunemaker, Craig S, Zhang, Min, Satin, Leslie S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2004
• Subjects: Adenosine Triphosphate - metabolism; Animals; Associated diseases and complications; Biological and medical sciences; Calcium Channels - physiology; Culture Techniques; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Feedback, Physiological; Fluorescent Dyes; Insulin - metabolism; Insulin - pharmacology; Insulin Secretion; Intracellular Membranes - physiology; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Medical sciences; Membrane Potentials - drug effects; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - physiology; Oscillometry; Potassium Channels - physiology; Rhodamine 123; Time Factors; Endocrinopathy; Pancreatic hormone; Diabetes mellitus; Rodentia; Langerhans islet; Ionic channel; Inorganic element; Insulin; Vertebrata; Mitochondria; Mammalia; Mouse; Feedback; Animal; β Cell; ATP; Potassium; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.7.1765

Insulin Feedback Alters Mitochondrial Activity Through an ATP-sensitive K + Channel–Dependent Pathway in Mouse Islets and β-Cells Craig S. Nunemaker , Min Zhang and Leslie S. Satin From the Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia Address correspondence and reprint requests to Dr. Leslie S. Satin, Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980524, Richmond, VA 23298. E-mail: lsatin{at}hsc.vcu.edu Abstract Recent work suggests that insulin may exert both positive and negative feedback directly on pancreatic β-cells. To investigate the hypothesis that insulin modulates β-cell metabolism, mouse islets and β-cell clusters were loaded with rhodamine 123 to dynamically monitor mitochondrial membrane potential (ΔΨ m ). Spontaneous oscillations in ΔΨ m (period: 218 ± 26 s) were observed in 17 of 30 islets exposed to 11.1 mmol/l glucose. Acute insulin application (100 nmol/l) hyperpolarized ΔΨ m , indicating a change in mitochondrial activity. The ATP-sensitive K + (K ATP ) channel opener diazoxide or the l -type calcium channel blocker nifedipine mimicked the effect of insulin, suggesting that insulin activates K ATP channels to hyperpolarize ΔΨ m by inhibiting calcium influx. Treatment with forskolin, which increases endogenous insulin secretion, also mimicked the effect of exogenous insulin, suggesting physiological feedback. Pretreatment with nifedipine or the K ATP inhibitor glyburide prevented insulin action, further implicating a K ATP channel pathway. Together, these data suggest a feedback mechanism whereby insulin receptor activation opens K ATP channels to inhibit further secretion. The resulting reduction in β-cell calcium increases the energy stored in the mitochondrial gradient that drives ATP production. Insulin feedback onto mitochondria may thus help to calibrate the energy needs of the β-cell on a minute-to-minute basis. ΔΨm, mitochondrial membrane potential FCCP, fluoro-carbonyl cyanide phenylhydrazone KATP channel, ATP-sensitive K+ channel PI, phosphatidylinositol Rh123, rhodamine 123 ROI, region of interest Footnotes Accepted April 13, 2004. Received March 10, 2004. DIABETES