β-cell-specific deletion of Zfp148 improves nutrient-stimulated β-cell Ca2+ responses

Insulin secretion from pancreatic β-cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that β-cell-specific deletion of Zfp148 (β-Zfp148KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from β‑Zfp148KO and control mice on both a chow and a Western-style diet. β-Zfp148KO islets demonstrate improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose. β-Zfp148KO islets also exhibit elevated sensitivity to amino acid-induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate (PEP)-dependent KATP channel closure, independent of glycolysis. RNA sequencing and proteomics of β-Zfp148KO islets revealed altered levels of enzymes involved in amino acid metabolism (SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, PSAT1) and intermediary metabolism (GOT1, PCK2), consistent with altered PEP cycling. In ...