Pathogenesis of Type 2 Diabetes Mellitus

  • Ralph A. DeFronzoEmail author
Reference work entry
Part of the Endocrinology book series (ENDOCR)


  • Type 2 diabetes is characterized by multiple pathophysiologic abnormalities which collectively have been referred to as the Ominous Octet:
    • Muscle insulin resistance → reduced glucose uptake

    • Hepatic insulin resistance → excessive glucose production

    • Adipocyte insulin resistance → accelerated lipolysis and elevated circulating levels of FFA and insulin-resistance provoking adipocytokines

    • Progressive β-cell failure and apoptosis

    • Increased alpha cell secretion of glucagon and increased hepatic sensitivity to glucagon

    • Reduced incretin effect due to beta cell resistance to GLP-1 and GIP

    • Increased renal glucose production

    • Elevated renal tubular glucose reabsorption

    • Brain insulin resistance and altered neurotransmitter dysfunction leading to impaired appetite suppression and weight gain.

  • Insulin resistance in muscle and liver are the earliest detectable abnormalities in the natural history of type 2 diabetes.

  • With time, progressive β-cell failure ensues and, in the presence of insulin resistance, individuals progress from normal glucose tolerance to impaired glucose tolerance to overt type 2 diabetes.


Pathophysiology of T2DM Insulin resistance Beta cell failure Liver, muscle, adipocyte Ominous octet 


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Diabetes Division, Diabetes Research UnitUniversity of Texas Health Science CenterSan AntonioUSA

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