Insulin Therapy and Hypoglycemia in Type 2 Diabetes Mellitus

Philip E. Cryer, Irene E., Michael M. Karl

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background: Iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes mellitus (DM), is the result of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations. Objective: The goal of this article was to review the available evidence on insulin therapy and hypoglycemia, with a focus on type 2 DM. Methods: This review was based on the author's clinical experience, his >3 decades of translational research in the area of hypoglycemia, and his knowledge of the relevant preclinical and clinical literature. Results: Glycemic defenses become compromised rapidly in type 1 DM but slowly in type 2 DM. As a result, the frequency of hypoglycemia increases progressively as patients approach the insulin-deficient end of the spectrum of type 2 DM. Indeed, it appears that most episodes of hypoglycemia, including those of severe hypoglycemia, occur in individuals with type 2 DM. The conventional risk factors for hypoglycemia are based on relative or absolute insulin excess. It is clear that the pathogenesis of hypoglycemia-associated autonomic failure, and thus an increased risk for iatrogenic hypoglycemia, stems fundamentally from insulin deficiency. Relevant additional risk factors include the degree of insulin deficiency, a history of severe hypoglycemia, hypoglycemia unawareness, or both, as well as recent antecedent hypoglycemia, prior exercise and sleep, and aggressive glycemic therapy per se in advanced type 2 DM, just as in type 1 DM. The prevention of hypoglycemia involves the practice of hypoglycemia risk reductionU{double grave}discussion of the issue, application of the principles of aggressive therapy, and consideration of both the conventional risk factors and those relevant to compromised glycemic defensesU{double grave}in advanced type 2 DM, just as in type 1 DM. With this approach, it is possible to improve glycemic control and reduce the frequency of hypoglycemia in many people with DM. Conclusions: Pending the prevention and cure of DM, people with this disease need safe and effective therapies. Ultimately, that will require glucose-regulated insulin replacement or secretion. In the meantime, insight into the mechanisms of hypoglycemia-associated autonomic failure may lead to interventions that will further improve the lives of people affected by DM by reducing the frequency of hypoglycemia without compromising glycemic control.(Insulin. 2007;2:127-133).

Original languageEnglish
Pages (from-to)127-133
Number of pages7
Issue number3
StatePublished - Jul 2007


  • hypoglycemia
  • insulin
  • pathophysiology
  • type 1 diabetes mellitus
  • type 2 diabetes mellitus

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