The integrative biology of type 2 diabetes


Weight problems and type 2 diabetes are the most frequent metabolic conditions, but their causes stay largely uncertain. Insulin resistance, the common underlying problem, arises from imbalance between energy consumption and expenditure favouring nutrient-storage pathways, which developed to make the most of energy utilization and preserve sufficient substrate supply to the brain. Initially, dysfunction of white fat and distributing metabolites modulate tissue interaction and insulin signalling. When the energy imbalance is persistent, mechanisms such as inflammatory pathways speed up these abnormalities. Here we summarize current studies providing insights into insulin resistance and increased hepatic gluconeogenesis associated with obesity and type 2 diabetes, concentrating on data from people and appropriate animal designs.

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    This research study is supported by grants from the German Federal Ministry of Health and Ministry of Culture and Science of the state North Rhine-Westphalia to DDZ, the German Federal Ministry of Education and Research Study to DZD, European Funds for Regional Development (EFRE-0400191), EUREKA Eurostars-2 (E! 113230 DIA-PEP) and the German Science Foundation (CRC/SFB 1116/ 2 B12) (to M.R.) and by grants from the United States Public Health Service (R01 DK-113984, R01 DK114793, R01 DK116774, R01 DK119968, P30 DK-045735) (to G.I.S.). The content is exclusively the obligation of the authors and does not necessarily represent the official views of the NIH.

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    1. Division of Endocrinology and Diabetology, Medical Professors, Heinrich-Heine University, Düsseldorf, Germany

      • Michael Roden
    2. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research Study at Heinrich-Heine University, Düsseldorf, Germany

      • Michael Roden
    3. German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany

      • Michael Roden
    4. Departments of Internal Medicine and Cellular and Molecular Physiology, Yale Diabetes Proving Ground, Yale School of Medicine, New Sanctuary, CT, USA

      • Gerald I. Shulman


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    M.R. and G.I.S. wrote the manuscript.

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    M.R. is on the clinical advisory boards of Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, NovoNordisk, Servier Laboratories, Target Pharmasolutions and Terra Firma and receives investigator-initiated support from Boehringer Ingelheim, Nutricia/Danone and Sanofi– Aventis. G.I.S. is on the scientific boards of advisers of Merck, NovoNordisk, Gilead Sciences, AstraZeneca, Aegerion, iMBP, Janssen Research study and Advancement and receives investigator-initiated assistance from Gilead Sciences, Merck and AstraZeneca.

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    Roden, M., Shulman, G.I. The integrative biology of type 2 diabetes.
    Nature576, 51–60(2019) doi: 10.1038/ s41586 -019-1797 -8

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