Hypoglycemic conditions enhance neonatal β-cell glucose responsiveness via AMPK/mTOR-increased KATP channel density

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Abstract
At birth, blood glucose levels drop sharply before rising to normoglycemic adult levels. This is accompanied by functional maturation of pancreatic β-cells and the acquisition of glucose-responsive insulin secretion. Although transcriptional programs have been well characterized, the metabolic adjustments that enhance insulin secretion in neonatal β-cells remain poorly understood. Neonatal islets exhibit a high rate of basal insulin secretion, and elevating glucose to high concentrations produces little additional stimulation (unlike adult islets). This study aimed to elucidate how neonatal pancreatic β-cells become glucose-responsive, using an in vitro protocol involving culture of neonatal islets at low glucose to emulate systemic hypoglycemia. Low-glucose exposure markedly improved glucose responsiveness of neonatal islets by selectively lowering insulin secretion at low glucose concentrations. Unlike adult β-cells, neonatal β-cells were depolarized and generated spontaneous action potentials at low glucose, resulting in elevated [Ca2+]i and a blunted response to high glucose. These changes were reversed by brief (1-2 hours) low-glucose culture, which was accompanied by increased KATP channel surface expression and activity. The effects of low-glucose incubation were mimicked by the AMPK agonist AICAR. These insights may inform strategies to restore glucose-regulated insulin secretion in type 2 diabetes.
Funding Information
  • Juvenile Diabetes Foundation International—Israel Science Foundation (#1541/21)
  • Vetenskapsrådet
  • Insamlingsstiftelsen Diabetes Wellness Network Sverige
  • Diabetes Wellness Sweden
  • Svenska Sällskapet för Medicinsk Forskning
  • Svenska Sällskapet för Medicinsk Forskning
  • Medical Research Council Canada
  • Leona M. and Harry B. Helmsley Charitable Trust

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