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

<p>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 <em>Zfp148</em> (β-<em>Zfp148</em>^KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca²⁺ imaging of islets from β‑<em>Zfp148</em>^KO and control mice on both a chow and a Western-style diet. β-<em>Zfp148</em>^KO islets demonstrate improved sensitivity and sustained Ca²⁺ oscillations in response to elevated glucose. β-<em>Zfp148</em>^KO 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-<em>Zfp148</em>^KO 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-<em>Zfp148</em>^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 β-cell function that are robust to the metabolic challenge imposed by a Western diet.</p>