Gαz negatively regulates insulin secretion and glucose clearance

Michelle E. Kimple, Jamie W. Joseph, Candice L. Bailey, Patrick T. Fueger, Ian A. Hendry, Christopher B. Newgard, Patrick J. Casey

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Relatively little is known about the in vivo functions of the α subunit of the heterotrimeric G protein Gz (Gαz). Clues to one potential function recently emerged with the finding that activation of Gαz inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. (2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a Gαz knock-out mouse model was utilized to determine whether Gαz function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets or in the islet DNA, protein, or insulin content between Gαz-null and wild-type mice. There was also no difference between the insulin sensitivity of Gαz-null mice and wild-type controls, as measured by insulin tolerance tests. Gαz-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in Gαz-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from Gαz-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in Gαz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Gαz-null islets in the absence of exogenous stimulation. These findings indicate that Gαz may be a potential new target for therapeutics aimed at ameliorating β-cell dysfunction in Type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)4560-4567
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number8
DOIs
StatePublished - Feb 22 2008
Externally publishedYes

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Insulin
Glucose
Islets of Langerhans
Heterotrimeric GTP-Binding Proteins
Insulinoma
Plasmas
Adenylyl Cyclases
Knockout Mice
Medical problems
Type 2 Diabetes Mellitus
Insulin Resistance
Chemical activation
Display devices
Cells
Cell Line
DNA
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Kimple, M. E., Joseph, J. W., Bailey, C. L., Fueger, P. T., Hendry, I. A., Newgard, C. B., & Casey, P. J. (2008). Gαz negatively regulates insulin secretion and glucose clearance. Journal of Biological Chemistry, 283(8), 4560-4567. https://doi.org/10.1074/jbc.M706481200

Gαz negatively regulates insulin secretion and glucose clearance. / Kimple, Michelle E.; Joseph, Jamie W.; Bailey, Candice L.; Fueger, Patrick T.; Hendry, Ian A.; Newgard, Christopher B.; Casey, Patrick J.

In: Journal of Biological Chemistry, Vol. 283, No. 8, 22.02.2008, p. 4560-4567.

Research output: Contribution to journalArticle

Kimple, ME, Joseph, JW, Bailey, CL, Fueger, PT, Hendry, IA, Newgard, CB & Casey, PJ 2008, 'Gαz negatively regulates insulin secretion and glucose clearance', Journal of Biological Chemistry, vol. 283, no. 8, pp. 4560-4567. https://doi.org/10.1074/jbc.M706481200
Kimple ME, Joseph JW, Bailey CL, Fueger PT, Hendry IA, Newgard CB et al. Gαz negatively regulates insulin secretion and glucose clearance. Journal of Biological Chemistry. 2008 Feb 22;283(8):4560-4567. https://doi.org/10.1074/jbc.M706481200
Kimple, Michelle E. ; Joseph, Jamie W. ; Bailey, Candice L. ; Fueger, Patrick T. ; Hendry, Ian A. ; Newgard, Christopher B. ; Casey, Patrick J. / Gαz negatively regulates insulin secretion and glucose clearance. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 8. pp. 4560-4567.
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