Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus

N Engl J Med. 1985 Jul 25;313(4):232-41. doi: 10.1056/NEJM198507253130405.


The prevention or correction of hypoglycemia is the result of both dissipation of insulin and activation of counterregulatory systems. In the models studied to date, glucagon and epinephrine have been shown to be the key counterregulatory factors; the potential roles of other hormones, neural factors, or substrate mechanisms in other models and during more gradual recovery from hypoglycemia remain to be defined. Deficient glucagon responses to decrements in plasma glucose, which are common in patients with IDDM and occur in some patients with NIDDM, result in altered counterregulation. But counterregulation is generally adequate, because epinephrine compensates for it. Defective glucose counterregulation due to combined deficiencies of glucagon and epinephrine secretory responses occurs in many patients, typically those with longstanding diabetes, and must be added to the list of factors known to increase the risk of hypoglycemia, at least during intensive therapy. From the material reviewed, it should be apparent that much has been learned about glucose counterregulation. It should be equally clear that much remains to be learned. Among the many possibilities, we consider four worthy of emphasis. First of all, we need to examine the physiology and pathophysiology of glucose counterregulation in additional models (e.g., during exercise) and over longer periods. Secondly, we need to determine whether central nervous system adaptation to antecedent glycemia occurs and, if so, identify its mechanisms. Thirdly, we need to develop better methods of insulin delivery or learn to correct or compensate for defective counterregulatory systems, if we are to achieve euglycemia safely in diabetic patients with defective glucose counterregulation. Finally, we need to know whether effective control of diabetes mellitus prevents development of defective glucose counterregulation.

Publication types

  • Review

MeSH terms

  • Blood Glucose / metabolism
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / physiopathology
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Epinephrine / metabolism
  • Epinephrine / physiology
  • Glucagon / metabolism
  • Glucagon / physiology
  • Glucose / metabolism*
  • Growth Hormone / metabolism
  • Growth Hormone / physiology
  • Humans
  • Hydrocortisone / metabolism
  • Hydrocortisone / physiology
  • Hyperglycemia / etiology
  • Hypoglycemia / metabolism*
  • Insulin / administration & dosage
  • Insulin / physiology
  • Insulin / therapeutic use*
  • Islets of Langerhans / metabolism
  • Liver / metabolism
  • Neurotransmitter Agents / physiology


  • Blood Glucose
  • Insulin
  • Neurotransmitter Agents
  • Growth Hormone
  • Glucagon
  • Glucose
  • Hydrocortisone
  • Epinephrine