Program in Molecular Medicine; Department of Medicine, Division of Cardiovascular Medicine; Department of Medicine, Division of Endocrinology, Metabolism and Diabetes; UMass Metabolic Network
Biochemistry | Cellular and Molecular Physiology | Endocrinology | Enzymes and Coenzymes | Molecular Biology
Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced beta cell mass, fewer proliferating beta cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from beta cells in mice.
diabetes, insulin, mitogen-activated protein kinase (MAPK), pancreas, pancreatic islet
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Copyright © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license.
DOI of Published Version
J Biol Chem. 2016 Jul 29;291(31):16221-30. doi: 10.1074/jbc.M116.718932. Epub 2016 May 20. Link to article on publisher's site
The Journal of biological chemistry
Roth Flach, Rachel J.; Danai, Laura V.; DiStefano, Marina; Kelly, Mark; Menendez, Lorena Garcia; Jurczyk, Agata; Sharma, Rohit B.; Jung, Dae Young; Kim, Jong Hun; Kim, Jason K.; Bortell, Rita; Alonso, Laura C.; and Czech, Michael P., "Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia" (2016). Open Access Articles. 2780.
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