Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes.
OBJECTIVE
To determine the effects of glycemic control on the counterregulatory responses to hypoglycemia in type 2 diabetes.


METHODS
Seven poorly controlled type 2 diabetes patients (mean HbA1c, 11.3 +/- 1.1%) were studied by stepped hyperinsulinemic hypoglycemic clamp (nadir, 2.4 mmol/l) before and after improving glycemic control with insulin treatment. Counterregulatory hormones, symptoms, and four-choice reaction time were measured at each glucose plateau.


RESULTS
In patients with poorly controlled type 2 diabetes, counterregulatory hormone responses began at higher plasma glucose levels than did those in healthy subjects (epinephrine, 4.4 +/- 0.2 vs. 3.7 +/- 0.2 mmol/l, P = 0.011). After significant improvement in glycemic control (mean HbA1c, 8.1 +/- 0.9%, P < 0.001) was achieved without severe hypoglycemia, hormonal responses started at much lower plasma glucose levels (e.g., epinephrine, 3.5 +/- 0.3 mmol/l, P = 0.005) and were significantly reduced in magnitude (e.g., area under epinephrine response curve, 306 +/- 93 vs. 690 +/- 107 nmol.min-1.l-1, P = 0.012). This was accompanied by a change in the plasma glucose threshold at which hypoglycemic symptoms first developed from 3.6 +/- 0.2 to 3.0 +/- 0.2 mmol/l (P = 0.019). In contrast, the plasma glucose threshold at which four-choice reaction time deteriorated did not change significantly (3.1 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l, P = 0.125).


CONCLUSIONS
Counterregulatory responses begin at normoglycemia in poorly controlled type 2 diabetes. Improving glycemic control with insulin therapy normalizes hormonal responses but lowers the plasma glucose levels at which hypoglycemic symptoms develop to levels associated with impairment of four-choice reaction time, a marker of cognitive function. This process potentially increases the risk of severe hypoglycemia, but to a lesser extent than occurs in type 1 disease.
Korzon-Burakowska
A
A
Department of Medicine, King's College School of Medicine and Dentistry, London, UK.
Hopkins
D
D
Matyka
K
K
Lomas
J
J
Pernet
A
A
Macdonald
I
I
Amiel
S
S
D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D013006:Growth Hormone / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007003:Hypoglycemia / Q000139:chemically induced* / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D011597:Psychomotor Performance; D011930:Reaction Time
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013006:Growth Hormone; D005934:Glucagon; D005947:Glucose; D009638:Norepinephrine; D004837:Epinephrine