2. Academic Validation
  3. β Cell-specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responses

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

  • JCI Insight. 2022 May 23;7(10):e154198. doi: 10.1172/jci.insight.154198.
Christopher H Emfinger 1,  Eleonora de Klerk 2,  Kathryn L Schueler 1,  Mary E Rabaglia 1,  Donnie S Stapleton 1,  Shane P Simonett 1,  Kelly A Mitok 1,  Ziyue Wang 3 4,  Xinyue Liu 5,  Joao A Paulo 5,  Qing Yu 5,  Rebecca L Cardone 6,  Hannah R Foster 7,  Sophie L Lewandowski 7,  José C Perales 8,  Christina M Kendziorski 3,  Steven P Gygi 5,  Richard G Kibbey 6 9,  Mark P Keller 1,  Matthias Hebrok 2,  Matthew J Merrins 7 10,  Alan D Attie 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 2 UCSF Diabetes Center, UCSF, San Francisco, California, USA.
  • 3 Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 4 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.
  • 5 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • 6 Department of Internal Medicine (Endocrinology), Yale University, New Haven, Connecticut, USA.
  • 7 Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 8 Department of Physiological Sciences, School of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain.
  • 9 Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, USA.
  • 10 William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
PMID: 35603790 DOI: 10.1172/jci.insight.154198
Abstract

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.

Keywords

Beta cells; Calcium signaling; Endocrinology; Insulin; Metabolism.

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