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Objective: Previous research points to a role of the brain in the regulation of glucose and pathogenesis of type 2 diabetes (T2D) via modulation of counter-regulatory hormone secretion and activity in the autonomic nervous system (ANS). The aim of this study was to investigate glucose-dependent responses of catecholamines and ANS activity in individuals with T2D, prediabetes (PD), and normoglycemia (NG).

Design: Cross-sectional.

Methods: Individuals with T2D (n = 19, 7 men, HbA1c 49 mmol/mol), PD (n = 18, 8 men), and NG (n = 17, 3 men) underwent 1 stepwise hyperinsulinemic-euglycemic-hypoglycemic and 1 hyperglycemic clamp with repeated measurements of catecholamines, symptoms, heart rate variability (HRV), and hemodynamics.

Results: The hypoglycemic response of adrenaline was augmented in T2D and PD vs NG (both P <. 05), and there was a strong association with insulin resistance (P <. 05 for M-value). In relation to achieved glucose levels in both clamps, noradrenaline exhibited a steeper rise during hypoglycemia in T2D vs NG and PD (both P <. 05). There were trends toward more marked autonomic hypoglycemic symptoms in T2D vs PD and NG. By contrast, insulin resistance was associated with attenuated responses of heart rate and HRV indices P_LF and P_HF at the target glucose plateau of 2.7 mmol/L (P <. 05), independent of BMI and HbA1c.

Conclusion: Alterations in glucose-dependent responses of counter-regulatory hormones and the ANS appear before, and probably contribute to, the onset of T2D. Together with other reported alterations in neuroendocrine pathways, the findings suggest that a maladaptation of the brain's responses to glucose fluctuations is important in T2D progression.