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

Insulin secretion from pancreatic beta cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that beta cell-specific deletion of Zfp148 (beta-Zfp148(ko)) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from beta-Zfp148(ko) and control mice fed both a chow and a Westernstyle diet. beta-Zfp148(ko) islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels.beta-Zfri748(ko) islets also exhibited elevated sensitivity to amino acid-induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate-dependent (PEP-dependent), ATP-sensitive K+ channel closure, independent of glycolysis. RNA-Seq and proteomics of beta-Zfp748(ko) islets revealed altered levels of enzymes involved in amino acid metabolism (specifically, SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, and PSAT1) and intermediary metabolism (namely, GOT1 and PCK2), consistent with altered PEP cycling. In agreement with this, beta-Zfp148(ko) 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 beta cell function that are robust to the metabolic challenge imposed by a Western diet.