PKA enhances the acute insulin response leading to the restoration of glucose control

Kelly A. Kaihara, Lorna M. Dickson, Johanne H. Ellenbroek, Caitlin M D Orr, Brian T. Layden, Barton Wicksteed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Diabetes arises from insufficient insulin secretion and failure of the β-cell mass to persist and expand. These deficits can be treated with ligands to Gs-coupled G-protein-coupled receptors that raise β-cell cAMP. Here we studied the therapeutic potential of β-cell cAMP-dependent protein kinase (PKA) activity in restoring glucose control usingβ-caPKA mice. PKA activity enhanced the acute insulin response (AIR) to glucose, which is a primary determinant of the efficacy of glucose clearance. Enhanced AIR improved peripheral insulin action, leading to more rapid muscle glucose uptake. In the setting of pre-established glucose intolerance caused by diet-induced insulin resistance or streptozotocinmediated β-cell mass depletion, PKA activation enhanced β-cell secretory function to restore glucose control, primarily through augmentation of the AIR. Enhanced AIR and improved glucose control were maintained through 16 weeks of a high-fat diet and aging to 1 year. Importantly, improved glucose tolerance did not increase the risk for hypoglycemia, nor did it rely upon hyperinsulinemia or β-cell hyperplasia, although PKA activity was protective forβ-cell mass. These data highlight that improving β-cell function through the activation of PKA has a large and underappreciated capacity to restore glucose control with minimal risk for adverse side effects.

Original languageEnglish (US)
Pages (from-to)1688-1697
Number of pages10
JournalDiabetes
Volume64
Issue number5
DOIs
StatePublished - May 2015

Funding

This study was supported by an American Diabetes Association Junior Faculty Award (1-08-JF-58), by a grant from the National Institutes of Health (NIH) (DK-085129) to B.W., and by University of Chicago Diabetes Research and Training Center funding from the NIH (DK-020595) to B.W. K.A.K. and C.M.D.O. were supported by a T32 NIH training grant (DK-087703). K.A.K. was also supported by an NIH F31 grant (AG-035620). J.H.E. was supported by a Junior Diabetes Fonds Fellowship from Diabetes Fonds (2013.81.1675). B.T.L. was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Career Development (grant number 1IK2-BX-001587-01). Acknowledgments. Glucose uptake experiments were performed at the Mouse Metabolic Phenotyping Center at Yale University. Funding. This study was supported by an American Diabetes Association Junior Faculty Award (1-08-JF-58), by a grant from the National Institutes of Health (NIH) (DK-085129) to B.W., and by University of Chicago Diabetes Research and Training Center funding from the NIH (DK-020595) to B.W. K.A.K. and C.M.D.O. were supported by a T32 NIH training grant (DK-087703). K.A.K. was also supported by an NIH F31 grant (AG-035620). J.H.E. was supported by a Junior Diabetes Fonds Fellowship from Diabetes Fonds (2013.81.1675). B.T.L. was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Career Development (grant number 1IK2-BX-001587-01). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. K.A.K., L.M.D., and B.W. conceived and conducted this study, interpreted these data, and prepared the manuscript. J.H.E. and C.M.D.O. assisted with technical aspects of experiments. B.T.L. interpreted these data and prepared the manuscript. B.W. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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