Petronel TULUC

Altered glucose-induced electrical activity and insulin release during pancreatic β-cell postnatal development

Tamara Theiner, Petronel Tuluc

Monogenic forms of diabetes indicate an early age incidence independent of the immune response. While many postnatal physiological changes could be the cause, we hypothesized that also age-dependent variations in pancreatic β-cell function and mass contribute.

In 1-day, 14-days and 3-month old mice the pancreatic islets are well formed but, adult islets show a higher β-cell count (~80%) compared to earlier developmental stages (~67-70%). Electrophysiological characterization demonstrates that β-cells of 1-day old mice have significantly smaller high voltage-gated calcium channel (HVCC) currents compared to 14-day or adult mice by ~41% and ~15% respectively. Additionally, HVCC calcium influx in 1-day old β-cells is conducted mostly by R-type (~33%) and P/Q-type (~42%) while L-type channels contribute only with ~25%. Conversely, 14-day old β-cells show the largest HVCC calcium influx compared to other ages. Nevertheless, the L-type channels contribution to whole-cell calcium influx is similar to adults (~44% vs 50%). The smaller L-type currents in β-cells of 1-day old mice causes a complete absence of β-cell specific glucose-induced electrical activity. Conversely, the higher HVCC currents in β-cells of 14-days old mice enhance the glucose sensitivity of the electrical activity (EC50 = 6.1 mM Glucose) compared to adults (EC50 = 8.9 mM Glucose). Nevertheless, despite the better glucose sensitivity and larger calcium influx, the islets of 14-days old mice show ~30% lower peak of glucose-induced insulin release compared to adults.

Cumulative our data show extensive variability in β-cell mass, glucose sensitivity, HVCC calcium currents, and electrical activity that cause reduced insulin release during postnatal development.