Insulin feedback alters mitochondrial activity through an ATP-sensitive K+ channel-dependent pathway in mouse islets and beta-cells.
Recent work suggests that insulin may exert both positive and negative feedback directly on pancreatic beta-cells. To investigate the hypothesis that insulin modulates beta-cell metabolism, mouse islets and beta-cell clusters were loaded with rhodamine 123 to dynamically monitor mitochondrial membrane potential (DeltaPsi(m)). Spontaneous oscillations in DeltaPsi(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 DeltaPsi(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 DeltaPsi(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 beta-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 beta-cell on a minute-to-minute basis.
Nunemaker
Craig S
CS
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, USA.
Zhang
Min
M
Satin
Leslie S
LS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D046508:Culture Techniques; D025461:Feedback, Physiological; D005456:Fluorescent Dyes; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007425:Intracellular Membranes / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009991:Oscillometry; D015221:Potassium Channels / Q000502:physiology*; D020112:Rhodamine 123; D013997:Time Factors
D015220:Calcium Channels; D005456:Fluorescent Dyes; D007328:Insulin; D015221:Potassium Channels; D020112:Rhodamine 123; D000255:Adenosine Triphosphate