Diminished fraction of blockable ATP-sensitive K+ channels in islets transplanted into diabetic mice.
The reasons for the poor outcome of islet transplantation in diabetic patients are not well known; a better understanding of the pathophysiology of transplanted islets is needed. To study the mechanism coupling secretagogue stimuli with insulin release in transplanted islets, we determined the effects of glucose, tolbutamide, and carbamylcholine on the beta-cell membrane potential and cytosolic calcium concentrations ([Ca2+]i) of islets syngeneically transplanted into normal and streptozocin-induced diabetic mice. In both groups, normoglycemia was maintained after transplantation. Islets transplanted into normal recipients showed similar changes in beta-cell membrane potential and [Ca2+]i oscillations to those in control islets. In contrast, when islets were transplanted into diabetic mice, bursts of electrical activity were triggered at lower glucose concentrations (5.6 mmol/l) than in control islets (11 mmol/l), and maximal electrical activity was achieved at lower glucose concentrations (11 mmol/l) than in control islets (22 mmol/l). When membrane potential was plotted as a function of glucose concentration, the dose-response curve was shifted to the left. Compared with control islets, glucose-induced [Ca2+]i oscillations were broader in duration (22.3 +/- 0.6 s vs. 118.1 +/- 12.6 s; P < 0.01) and higher in amplitude (135 +/- 36 nmol/l vs. 352 +/- 36 nmol/l; P < 0.01). Glucose supersensitivity was attributed to a resting decrease in the fraction of blockable ATP-sensitive K+ (K+(ATP)) channels in transplanted islets that maintained normoglycemia with a limited beta-cell mass.
Soria
B
B
Department of Physiology, School of Medicine, University of Alicante, Spain. Bernat.Soria@ua.es.
Martín
F
F
Andreu
E
E
Sanchez-Andrés
J V
JV
Nacher
V
V
Montana
E
E
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology* / Q000648:ultrastructure; D016381:Islets of Langerhans Transplantation; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D014044:Tolbutamide / Q000494:pharmacology
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D002217:Carbachol; D014044:Tolbutamide; D005947:Glucose; D002118:Calcium