Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia*
| Autor: | Michael P. Czech, Laura V. Danai, Rita Bortell, Lorena Garcia Menendez, Marina T. DiStefano, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Rachel J. Roth Flach, Mark J. S. Kelly, Agata Jurczyk, Rohit Sharma, Laura C. Alonso |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty insulin medicine.medical_treatment Mitogen-activated protein kinase kinase Protein Serine-Threonine Kinases Biochemistry 03 medical and health sciences Mice Insulin resistance Internal medicine Insulin-Secreting Cells Insulin Secretion medicine Hyperinsulinemia Animals mitogen-activated protein kinase (MAPK) pancreas Obesity Protein kinase A Molecular Biology Protein kinase B Mice Knockout biology diabetes Insulin Molecular Bases of Disease Cell Biology pancreatic islet medicine.disease Dietary Fats IRS2 Insulin receptor 030104 developmental biology Endocrinology biology.protein Insulin Resistance Peptides |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | 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 β cell mass, fewer proliferating β 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 β cells in mice. |
| Databáze: | OpenAIRE |
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