Discussion The present study reveals the effects of insulin on the HVR in individuals with non-insulin dependent diabetes mellitus. While HC showed that insulin increases the isocapnic HVR, no such effect was observed in individuals with T2DM. Additionally, under fasting conditions the effect of hyperoxia on ventilation was less in T2DM compared to HC, a sign of carotid body excitation. Finally, sympathetic excitation was noted in T2DM. These data indicate an impaired carotid body function in T2DM with signs of insulin resistance coupled with impaired autonomic function regulation of the carotid body. Previous studies, both in animal models and humans, exploring the effects of insulin on the CB and ventilation showed that insulin increases CB activation and increases ventilation.22,4,28 Ward et al. performed isocapnic HVR in healthy humans during hypoglycemia and hyperglycemia, and found increased hypoxic sensitivity during hyperglycemia and more so during hypoglycemia.29 Our study is the first, to our knowledge, to assess the effects of hypoxia under influence of hyperinsulinemic-euglycemia in humans. Our finding of an enhanced HVR in HC in a state of hyperinsulemic-euglycemia is a new finding, which agrees with earlier studies. Data on the effect of T2DM on the HVR, both in animal models and in man, is conflicting. Some studies indicate an increased response,3,4 while other found no difference,28 or diminished responses.30,31,32 The heterogeneity of these results could potentially be explained by the metabolic state of the control group (fasting or euglycemic hyperinsulinemia), a factor that is either not mentioned or considered in the aforementioned studies. Our study’s observation of an unaltered HVR during HEC (mimicking a postprandial state) in T2DM contributes to our understanding of these differences. Our observations point towards (1) carotid body insulin resistance in T2DM (no effect of insulin on the HVR) and (2) a hyperactive carotid body (reduced depression of ventilation during hyperoxia), coupled to a general state of sympathicoexcitation, as observed from the heart variability data and the enhanced cardiac index in T2DM. The latter was particularly observed for the parasympathetic tone, where the T2DM groups showed pronounced suppression, in contrast to the heightened activity in HC. Such autonomic shifts, as observed from the heart rate variability metrics may be instrumental in shaping the HVR.33 We argue that the heightened sympathetic tone in T2DM affects the HVR response to insulin. In agreement with this statement, we observed that HC exhibited a resilience in maintaining, or perhaps even enhancing, their autonomic 112
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