Abstract
Glucose-stimulated insulin secretion from the pancreatic β-cells is driven by calcium (Ca2+) uptake. In mice Ca2+ is disproportionally controlled by functional subpopulations of β-cells, identified in affecting 2nd phase oscillatory Ca2+ response. Yet, the “1st-responder” cells that lead the 1st Ca2+phase disrupted in early diabetes were overlooked. It is unknown whether 1st responders are a distinct subpopulation, and if so, which factors underlie this distinction, and what is their role. We hypothesized that 1st responder metabolic and electrical parameters are distinct from the known β-cell subpopulations, and they play an important role in the 1st Ca2+phase of the islet response. We simultaneously measured Ca2+ dynamics and electrical coupling in intact islets using β-cells specific expression of the Ca2+ sensor GCaMP6s. We performed repeated glucose and Kapt channel blocker stimulation of the islet. We used femtosecond laser ablation of specific cells. This was complimented by multicellular islet electrophysiology model where we could remove specific cells from the islet and evaluate glucokinase rate, Katp and coupling conductance of the cells. We found no overlap of 1st responder with either “wave-initiator”, leading Ca2+ wave, or highly connected “hub” cell subpopulations, based on the oscillatory 2nd phase Ca2+ wave coordination. Interestingly 1st responders were less electrically coupled (p=0.0157), supported by simulations. 1st responders were consistent under repeatable glucose stimulation and remained 1st responders under the Katp channel blocker, supported by computational results of lower than average Katp channel conductance (p<0.0001). Removing 1st responder from the islet resulted in delayed 1st phase islet response compared to the random cell removal, both in experiment and simulation (p=.0428). In conclusion, 1st responders are distinct β-cell sub-population, which influences the islet 1st phase Ca2+response. Disclosure V. Kravets: None. J.M. Dwulet: None. W. Schleicher: None. R.K. Benninger: None. Funding JDRF (63012150); National Institutes of Health (R0163012150)
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