Relationship between autonomic function and parameters of beta cell secretion across the entire spectrum of glucose homeostasis

Background: type 2 diabetes is determined by a reduction of β cell mass and function besides a defect in insulin sensitivity. It was demonstrated that pancreatic islets are innervated by sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) fibers and autonomic function contributes to the regulation of glucose homeostasis. An alteration in neuronal control of β cell function could be involved in the pathogenesis of the type 2 diabetes. Aim: we focused on finding a possible association between autonomic function and the different parameters that describe β cell function in The Maastricht Study, a population-based cohort. We sought this association also in the population of Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), a study of patients with newly diagnosed type 2 diabetes. Research design and Methods: in the Maastricht study population from 24-h electrocardiogram we derived Heart Rate Variability (HRV) time and frequency domains (individual z-scores, based upon seven and six variables, respectively). From a standard 2-hour 75 g OGTT we estimated different aspects of β cell function, i.e. C-peptidogenic index t0-30, overall insulin secretion, β cell glucose sensitivity, β cell potentiation factor, and β cell rate sensitivity, using formula-based methods and mathematical modeling. In the VNDS study cardiovascular autonomic function was assessed by a computerized system which analyzed heart rate and blood pressure variations during lying to standing (LS), deep breathing (DB), and Valsalva maneuver (VM), following the criteria presented by Ewing and Clarke. From a 5-hour 75g OGTT we estimated through mathematical modelling two main parameters of beta cell glucose sensitivity: derivative (first phase) and proportional control (second phase) of insulin secretion. Results: in the Maastricht study we analyzed 2007 individuals with a mean  standard deviation (SD) age of 59.8  8.2 years, of whom 52% were men and 24% with type 2 diabetes (oversampled by design). After adjustment for age, sex, educational level and Matsuda index, time and frequency domain HRV were significantly and directly associated with C-peptidogenic index, β cell glucose sensitivity and β cell potentiation factor, but not with overall insulin secretion. Then, further adjustment for cardiovascular risk factors (model 4) did not materially alter these associations, though only the association of HRV with C-peptidogenic remained statistically significant (standardized β [95%CI] per 1-SD increment in HRV TIME domain, for respectively C-peptidogenic index, overall insulin secretion, β cell glucose sensitivity, and β cell potentiation, 0.05 [0.00; 0.09]; 0.04 [-0.00; 0.08]; 0.04 [0.00; 0.08] ; and 0.04 [-0.00; 0.08]; standardized β [95%CI] per 1-SD increment in HRV FREQUENCY domain, for respectively C-peptidogenic index, overall insulin secretion, β cell glucose sensitivity, and β cell potentiation, 0.05 [0.00; 0.09]; 0.04 [-0.00; 0.08]; 0.04 [0.00; 0.08] ; and 0.04 [-0.00; 0.08]). HRV time and frequency domain weren’t significantly associated with rate sensitivity. Furthermore, we evaluated data of 537 patients with newly diagnosed type 2 diabetes with a mean ± SD age of 58.3 ± 9.6 of whom 66.3% were male. 91 subjects (16.9%) showed at least one abnormal test used to evaluate cardiovascular autonomic function (CAN). We found a worse derivative control of beta cell function in people with signs of cardio autonomic neuropathy as compared to the other group. This difference however did not reach statistical significance (p=0.063). Conclusion: In summary, in the present research we analyzed a possible association between autonomic function and β cell secretion, estimated from OGTT. We found that autonomic dysregulation could contribute to β-cell dysfunction, in particular affecting the first phase of insulin secretion. This mechanism could add to the other factors that lead to the impairment of glucose homeostasis.