OBJECTIVE: The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). RESEARCH DESIGN AND METHODS: We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. RESULTS: Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. CONCLUSIONS: We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

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