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

Autor: Emfinger CH; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., de Klerk E; UCSF Diabetes Center, UCSF, San Francisco, California, USA., Schueler KL; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Rabaglia ME; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Stapleton DS; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Simonett SP; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Mitok KA; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Wang Z; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.; Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA., Liu X; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA., Paulo JA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA., Yu Q; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA., Cardone RL; Department of Internal Medicine (Endocrinology), Yale University, New Haven, Connecticut, USA., Foster HR; Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin, USA., Lewandowski SL; Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin, USA., Perales JC; Department of Physiological Sciences, School of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain., Kendziorski CM; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA., Kibbey RG; Department of Internal Medicine (Endocrinology), Yale University, New Haven, Connecticut, USA.; Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, USA., Keller MP; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Hebrok M; UCSF Diabetes Center, UCSF, San Francisco, California, USA., Merrins MJ; Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin, USA.; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA., Attie AD; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2022 May 23; Vol. 7 (10). Date of Electronic Publication: 2022 May 23.
DOI: 10.1172/jci.insight.154198
Abstrakt: 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 fed both a chow and a Western-style diet. β-Zfp148KO islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels. β-Zfp148KO 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 β-Zfp148KO 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, 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.
Databáze: MEDLINE