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 agreement with this, β-Zfp148KO islets displayed enhanced insulin
secretion in response to L-glutamine and activation of glutamate
dehydrogenase. Understanding pathways controlled by ZFP148 may provide
promising strategies for improving β-cell function that are robust to the
metabolic challenge imposed by a Western diet.