Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus

N Engl J Med. 1995 Dec 28;333(26):1726-31. doi: 10.1056/NEJM199512283332602.


Background: In patients with insulin-dependent diabetes mellitus (IDDM) whose treatment results in nearly normal mean plasma glucose concentrations, an unawareness of hypoglycemia can develop, and such patients are at increased risk for seizures and coma. We tested the hypothesis that during hypoglycemia, these patients would have normal glucose uptake in the brain and that consequently no sympathoadrenal activation would begin, resulting in an unawareness of hypoglycemia.

Methods: We measured glucose uptake in the brain at plasma glucose concentrations of 105 and 54 mg per deciliter (5.8 and 3.0 mmol per liter) in 24 patients with IDDM, stratified into three groups according to their glycosylated hemoglobin values (mean [+/- SD] values, 7.2 +/- 0.5, 8.5 +/- 0.4, and 10.2 +/- 1.3 percent) and compared the values for brain glucose uptake with those measured in 15 normal subjects at plasma glucose concentrations of 85 and 55 mg per deciliter (4.2 and 3.1 mmol per liter). We also recorded the subjects' hypoglycemic-symptom scores and measured their plasma concentrations of counterregulatory hormones.

Results: There was no significant change in the uptake of glucose in the brain (calculated as the uptake during hypoglycemia minus the uptake during normoglycemia) among the patients with IDDM who had the lowest glycosylated hemoglobin values (+0.6 +/- 2.0 mg [3.3 +/- 11.1 mumol] per 100 g of brain tissue per minute, P = 0.39). Conversely, glucose uptake in the brain fell in both the group with intermediate values (a decrease of 1.3 +/- 1.0 mg [7.2 +/- 5.6 mumol] per 100 g per minute, P = 0.009) and the group with the highest values (a decrease of 1.8 +/- 1.6 mg [10.0 +/- 9.0 mumol] per 100 g per minute, P = 0.01), as it did in the normal subjects (a decrease of 1.6 +/- 1.8 mg [9.0 +/- 10.1 mumol] per 100 g per minute, P = 0.003). The responses of plasma epinephrine and pancreatic polypeptide and the frequency of symptoms of hypoglycemia were lowest in the group with the lowest glycosylated hemoglobin values.

Conclusions: During hypoglycemia, patients with IDDM who have nearly normal glycosylated hemoglobin values have normal glucose uptake in the brain, which preserves cerebral metabolism, reduces the responses of counterregulatory hormones, and causes an unawareness of hypoglycemia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Blood Glucose / analysis
  • Brain / metabolism*
  • Cerebrovascular Circulation
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / metabolism*
  • Epinephrine / blood
  • Female
  • Glucose / metabolism*
  • Glycated Hemoglobin A / analysis
  • Humans
  • Hypoglycemia / blood
  • Hypoglycemia / etiology
  • Hypoglycemia / metabolism*
  • Male
  • Pancreatic Polypeptide / blood


  • Blood Glucose
  • Glycated Hemoglobin A
  • Pancreatic Polypeptide
  • Glucose
  • Epinephrine