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

From the Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia

Recent work suggests that insulin may exert both positive and negative feedback directly on pancreatic ß-cells. To investigate the hypothesis that insulin modulates ß-cell metabolism, mouse islets and ß-cell clusters were loaded with rhodamine 123 to dynamically monitor mitochondrial membrane potential (_m). Spontaneous oscillations in _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 _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 _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 ß-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 ß-cell on a minute-to-minute basis.

Abbreviations: _m, mitochondrial membrane potential; FCCP, fluoro-carbonyl cyanide phenylhydrazone; K_ATP channel, ATP-sensitive K⁺ channel; PI, phosphatidylinositol; Rh123, rhodamine 123; ROI, region of interest

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