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Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness
M T Korytkowski1, M Mokan, T F Veneman
1University of Pittsburgh School of Medicine, Pennsylvania, USA. korytkowski@med1.dept-med.pitt.edu
Objective:
We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes.
Research Design And Methods:
A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects.
Results:
Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg).
Conclusions:
We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.
Insights
Reduced beta-adrenergic sensitivity in type 1 diabetes may cause impaired hypoglycemia awareness. This study found lower adrenergic symptoms and hormone responses in unaware individuals, suggesting a link to reduced sensitivity.
Area of Science:
- Endocrinology
- Metabolic Disorders
- Neuroscience
Background:
- Hypoglycemia unawareness is a significant complication in type 1 diabetes.
- Impaired recognition of low blood glucose levels increases the risk of severe hypoglycemia.
- The role of tissue sensitivity to catecholamines in this phenomenon requires further investigation.
Purpose of the Study:
- To test the hypothesis that reduced tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in individuals with type 1 diabetes.
- To investigate the relationship between adrenergic symptoms, counterregulatory hormone responses, and beta-adrenergic sensitivity during induced hypoglycemia.
Main Methods:
- A cohort of 21 individuals with type 1 diabetes underwent a standardized insulin infusion protocol to induce stepwise hypoglycemia.
- Glycemic thresholds for adrenergic and neuroglycopenic symptoms, and counterregulatory hormone release were assessed.
- Beta-adrenergic sensitivity was quantified using the isoproterenol dose-response curve (I25).
Main Results:
- Individuals with type 1 diabetes and hypoglycemia unawareness exhibited adrenergic symptoms at significantly lower plasma glucose levels compared to those with awareness.
- Counterregulatory hormone secretion (epinephrine, norepinephrine, cortisol) and maximal responses were diminished in the unaware group.
- Reduced beta-adrenergic sensitivity, indicated by a higher isoproterenol dose (I25), was observed in subjects with hypoglycemia unawareness.
Conclusions:
- Reduced beta-adrenergic sensitivity is a key factor in hypoglycemia unawareness among individuals with type 1 diabetes.
- Impaired adrenergic warning symptoms during hypoglycemia are likely linked to this reduced sensitivity.
- These findings highlight the importance of assessing adrenergic function in managing hypoglycemia in type 1 diabetes.