Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion in the early postnatal period
Objective: Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We hypothesized that this transitional hyperinsulinism is due to the persistence of a fetal lower glucose threshold for insulin release from β-cells into the first postnatal days. Methods: We tested dynamic insulin secretion from freshly isolated rat islets between late gestation and adult age and from rat islets kept in culture for 1 or 2 days. We used single-cell transcriptomic and electrophysiology approaches to investigate the mechanism for insulin secretion at low glucose concentrations. Results: We found that a lower threshold for glucose-stimulated insulin secretion (GSIS) is present in embryonic day (E)22 islets and persists into the first postnatal days. The glucose threshold increases in the postnatal period and reaches the adult level by postnatal day (P)14. We also demonstrated that culturing P14 islets for 24-48 hrs can also decrease the glucose threshold. Insulin release in response to BCH, a non-metabolizable leucine analog activating glutamate dehydrogenase, had a similar lower threshold in P1 compared to P14 islets. This showed that the low threshold for GSIS is determined at a step downstream of the glycolytic pathway. P1 islets had lower insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels, compared to P14 islets, suggesting that decreased KATP channel expression and/or function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal differences in transcripts between E22 and P14 β-cells supporting the lower glucose threshold. The investigation of electrophysiological characteristics of dispersed β cells showed that early neonatal cells and cultured islet cells had fewer functional KATP channels per unit membrane area. Conclusion: These findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.