Insulin is secreted from the pancreatic β-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 β-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 β-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 Ca(2+) imaging and 
static islet incubations. Light stimulation of islets from transgenic ChR2 mice 
triggered prompt increases in intracellular Ca(2+). 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 Ca(2+) 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 
Ca(2+) response in β-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.