Related Experiment Videos
Diminished fraction of blockable ATP-sensitive K+ channels in islets transplanted into diabetic mice
1Department of Physiology, School of Medicine, University of Alicante, Spain. Bernat.Soria@ua.es.
Abstract:
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.
Insights
Transplanted islets in diabetic mice show enhanced glucose sensitivity due to altered ATP-sensitive potassium channels. This explains improved glucose regulation despite limited beta-cell mass after islet transplantation.
Area of Science:
- Endocrinology
- Cellular Physiology
- Transplantation Biology
Background:
- The pathophysiology of transplanted islets and reasons for poor outcomes in diabetic patients require further investigation.
- Understanding the mechanisms of insulin release in transplanted islets is crucial for improving therapeutic success.
Purpose of the Study:
- To investigate the effects of glucose, tolbutamide, and carbamylcholine on beta-cell membrane potential and cytosolic calcium concentrations ([Ca2+]i) in islets transplanted into normal and diabetic mice.
- To elucidate the mechanism coupling secretagogue stimuli with insulin release in transplanted islets.
Main Methods:
- Syngeneic islet transplantation into normal and streptozocin-induced diabetic mice.
- Measurement of beta-cell membrane potential and cytosolic calcium concentrations ([Ca2+]i) in response to secretagogues.
- Analysis of ATP-sensitive K+ (K+(ATP)) channel function.
Main Results:
- Transplanted islets in diabetic mice exhibited increased electrical activity and calcium oscillations at lower glucose concentrations compared to controls.
- A leftward shift in the glucose dose-response curve for membrane potential was observed in transplanted islets from diabetic mice.
- Glucose-induced cytosolic calcium oscillations were broader and higher in amplitude in transplanted islets from diabetic mice.
Conclusions:
- Transplanted islets in diabetic mice display enhanced glucose sensitivity, a phenomenon attributed to a reduced fraction of functional ATP-sensitive K+ (K+(ATP)) channels.
- This glucose supersensitivity allows for normoglycemia maintenance with a limited beta-cell mass in transplanted islets.
- Findings provide insights into the pathophysiology of transplanted islets and potential strategies for improving islet transplantation outcomes.