Abstract

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN

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Acknowledgements

The authors acknowledge grants from: the South Texas Veterans Healthcare System to R.A.D.; the National Institutes of Health (grants R01DK24092 to R.A.D.; DK58845 and P30 DK46200 to F.B.H.; R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659 and R24 DK085610 to G.I.S.; P30 DK036836 to C.R.K. Novo Nordisk Foundation for Basic Metabolic Research and the University of Copenhagen to G.I.S. and C.R.K.; DVA-Merit Review grant and VA San Diego Healthcare System to R.H.; National Institute for Diabetes and Digestive and Kidney Disease (grant P30DK092926) to W.H.; the Swedish Research Council (grants 2010–3490 and 2008–6589) and European Council (grants GA269045) to L.G.; Italian Ministry of University & Research (MIUR 2010329EKE) to E.F.; the Patient-Centered Outcomes Research Institute (PCORI) Program Award (CE1304-6756) to D.C.S. and M.A.T.; NovoNordisk Foundation to the NNF Center for Basic Metabolic Research to J.H. W.H. acknowledges the Michigan Center for Diabetes Translational Research and I.R. thanks R. Sprung for editorial assistance.

Author information

Affiliations

  1. Diabetes Division, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System and Texas Diabetes Institute, 701 S. Zarzamoro, San Antonio, Texas 78207, USA.

    • Ralph A. DeFronzo
  2. CNR Institute of Clinical Physiology, Pisa, Italy.

    • Ele Ferrannini
  3. Department of Clinical Science Malmoe, Diabetes & Endocrinology, Lund University Diabetes Centre, Lund, Sweden.

    • Leif Groop
  4. University of California, San Diego, Section of Diabetes, Endocrinology & Metabolism, Center for Metabolic Research, VA San Diego Healthcare System, San Diego, California, USA.

    • Robert R. Henry
  5. University of Michigan, Ann Arbor, Michigan, USA.

    • William H. Herman
  6. University of Copenhagen, Kobenhavn, Denmark.

    • Jens Juul Holst
  7. Department of Nutrition, Harvard T.H. Chan School of Public Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Frank B. Hu
  8. Harvard Medical School and Joslin Diabetes Center, Boston, Massachusetts, USA.

    • C. Ronald Kahn
  9. Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.

    • Itamar Raz
  10. Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Gerald I. Shulman
  11. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Donald C. Simonson
  12. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Marcia A. Testa
  13. Department of Human Metabolism and Nutrition, Braun School of Public Health, Hebrew University, Jerusalem, Israel.

    • Ram Weiss

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Contributions

Introduction (R.R.H.); Epidemiology (F.B.H.); Mechanisms/pathophysiology (L.C.G., C.R.K., E.F., G.I.S. and R.A.D.); Diagnosis, screening and prevention (W.H.H.); Management (R.A.D.); Quality of life (D.C.S. and M.A.T.); Outlook (I.R., J.J.H. and R.W.); overview of Primer (R.A.D.).

Competing interests

The authors declare the following potential COI: (1) R.A.D.: Research Grant Support - AstraZeneca, Bristol Myers Squibb, Janssen; Speaker's Bureau - AstraZeneca, Novo Nordisk, Advisory Board/Consultant - AstraZeneca, Janssen, Novo Nordisk, Boehringer Ingelheim, Lexicon, Intarcia; (2) E.F.: Research Grant Support - Boehringer Ingelheim, Eli Lilly; Consultant/Speaker Bureau-Boehringer Ingelheim, Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Takeda, Medtronic, Intarcia; (3) C.R.K. serves as a consultant for Medimmune, Merck, Five Prime Therapeutics, CohBar, Antriabio, and Catabasis; (4) L.G. has no conflict of interest; (5) R.H. has received grant support from Hitachi, Janssen, Eli Lilly, Sanofi-Aventis and Viacyte and is a consultant/advisory board member for Alere, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clin Met, Eisai, Elcelyx, Gilead, Intarcia, Isis, Janssen, Merck, Novo Nordisk, Sanofi-Aventis, and Vivus; (6) W.H.H. has no conflict of interest; (7) J.J.H. has received grant support from Novartis and Merck and is a consultant/advisory board member for Glaxo, Smith, Kline, Novo Nordisk, and Zealand Pharmaceuticals; (8) M.A.T. has no conflict of interest; (9) R.W. serves as a consultant for Medtronics and Kamada and is on the speaker's bureau for Medtronics and Novo Nordisk; (10) F.H. has received research support from California Walnut Commission and Metegenics; (11) G.I.S. serves on scientific advisory boards for Merck and Novartis and he has received research grant support from Gilead Pharmaceuticals; (12) D.C.S. has no conflict of interest; (13) I.R. – Advisory Board: Novo Nordisk, Astra Zeneca/BMS, MSD, Eli Lilly, Sanofi, Medscape Cardiology; Consultant: Astra Zeneca/BMS, Insuline; Speaker's Bureau: Eli Lilly, Novo Nordisk, Astra Zeneca/BMS, J&J, Sanofi, MSD, Novartis, Teva; Shareholder: Insuline, Labstyle.

Corresponding author

Correspondence to Ralph A. DeFronzo.

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DOI

https://doi.org/10.1038/nrdp.2015.19

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