Control of insulin secretion by cytochrome C and calcium signaling in islets with impaired metabolism.
The aim of the study was to assess the relative control of insulin secretion rate (ISR) by calcium influx and signaling from cytochrome c in islets where, as in diabetes, the metabolic pathways are impaired. This was achieved either by culturing isolated islets at low (3 mm) glucose or by fasting rats prior to the isolation of the islets. Culture in low glucose greatly reduced the glucose response of cytochrome c reduction and translocation and ISR, but did not affect the response to the mitochondrial fuel α-ketoisocaproate. Unexpectedly, glucose-stimulated calcium influx was only slightly reduced in low glucose-cultured islets and was not responsible for the impairment in glucose-stimulated ISR. A glucokinase activator acutely restored cytochrome c reduction and translocation and ISR, independent of effects on calcium influx. Islets from fasted rats had reduced ISR and cytochrome c reduction in response to both glucose and α-ketoisocaproate despite normal responses of calcium. Our data are consistent with the scenario where cytochrome c reduction and translocation are essential signals in the stimulation of ISR, the loss of which can result in impaired ISR even when calcium response is normal.
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Austin M
AM
Rountree
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Adam S
AS
Neal
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Mark
M
Lisowski
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Norma
N
Rizzo
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Jared
J
Radtke
the Department of Surgery, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Sarah
S
White
the Department of Surgery, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Dan S
DS
Luciani
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Francis
F
Kim
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and.
Christiane S
CS
Hampe
From the Diabetes and Obesity Center, Department of Medicine, University of Washington, Seattle, Washington 98195 and isweet@u.washington.edu.
Ian R
IR
Sweet
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005215:Fasting; D005947:Glucose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007651:Keto Acids / Q000494:pharmacology; D008659:Metabolic Diseases / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D007651:Keto Acids; C013082:alpha-ketoisocaproic acid; D045304:Cytochromes c; D005947:Glucose; D010100:Oxygen
Calcium; Calcium Signaling; Cytochrome c; Cytochrome c Translocation; Insulin Secretion; Mitochondrial Metabolism; Oxygen Consumption; Pancreatic Islet