Journal
ISLETS
Volume 6, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/isl.28095
Keywords
optogenetics; Channelrhodopsin-2; islets; beta-cells; insulin secretion; diabetes
Categories
Funding
- NovoNordisk Foundation
- Magnus Bergvall Foundation
- Royal Physiographic Society
- Swedish Diabetes Association
- Swedish Research Council
- Novo Nordisk Fonden [NNF10OC1013350] Funding Source: researchfish
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Insulin is secreted from the pancreatic beta-cells in response to elevated glucose. In intact islets the capacity for insulin release is determined by a complex interplay between different cell types. This has made it difficult to specifically assess the role of beta-cell defects to the insulin secretory impairment in type 2 diabetes. Here we describe a new approach, based on optogenetics, that enables specific investigation of beta-cells in intact islets. We used transgenic mice expressing the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under control of the insulin promoter. Glucose tolerance in vivo was assessed using intraperitoneal glucose tolerance tests, and glucose-induced insulin release was measured from static batch incubations. ChR2 localization was determined by fluorescence confocal microscopy. The effect of ChR2 stimulation with blue LED light was assessed using Ca2+ imaging and static islet incubations. Light stimulation of islets from transgenic ChR2 mice triggered prompt increases in intracellular Ca2+. Moreover, light stimulation enhanced insulin secretion in batch-incubated islets at low and intermediate but not at high glucose concentrations. Glucagon release was not affected. Beta-cells from mice rendered diabetic on a high-fat diet exhibited a 3.5-fold increase in light-induced Ca2+ influx compared with mice on a control diet. Furthermore, light enhanced insulin release also at high glucose in these mice, suggesting that high-fat feeding leads to a compensatory potentiation of the Ca2+ response in beta-cells. The results demonstrate the usefulness and versatility of optogenetics for studying mechanisms of perturbed hormone secretion in diabetes with high time-resolution and cell-specificity.
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