ArticleThe Journal of biological chemistry2016
Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.The Journal of pharmacology and experimental therapeutics · 2024Review
- Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity.JCI insight · 2023Article
- Molecular Genetics of Abnormal Redox Homeostasis in Type 2 Diabetes Mellitus.International journal of molecular sciences · 2023Review
- Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?Annual review of pharmacology and toxicology · 2022Review
- The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition.Diabetes · 2020Article
- Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents.Cell chemical biology · 2019Article
- Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents.JCI insight · 2018Observational
- Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium.Microcirculation (New York, N.Y. : 1994) · 2018Article
- RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis.International journal of molecular sciences · 2018Article
- Map4k4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity.American journal of physiology. Endocrinology and metabolism · 2017Article
- Insulin action and resistance in obesity and type 2 diabetes.Nature medicine · 2017Review
- Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance.Molecular and cellular biochemistry · 2017Review
- Molecular docking performance evaluated on the D3R Grand Challenge 2015 drug-like ligand datasets.Journal of computer-aided molecular design · 2016Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
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