Background: Diabetes mellitus is a metabolic disorder associated with several complications. Among the microvascular complications, cardiac autonomic neuropathy (CAN) is the most important autonomic neuropathy due to its potential life threatening outcome, especially in poorly controlled patients. Its treatment lies in the early diagnosis, life style management of associated risk factors and optimization of glycemic control. Heart rate variability (HRV) defined as the beat to beat alteration in heart rate, provides a non-invasive tool for exploring the autonomic nervous system. Diabetes mellitus tends to affect the vagal nerve first with consequence being a reduced heart rate variability associated with poor cardiovascular prognosis.  Intensive glycemic control prevents the development of CAN in patients with type 1 diabetes. There is little information on whether the intensification of glycemic control using insulin will improve cardiac autonomic functions in patients with type 2 diabetes mellitus. 
Aim: Our main objective was to determine the effect of optimizing glycemic control using insulin on the heart rate variability in type 2 diabetes mellitus patients.
Method: We conducted a single arm clinical trial at the National Obesity Centre of the Yaoundé Central Hospital. Participants were poorly controlled type 2 diabetes mellitus patients (glycated hemoglobin ≥ 7%) which constituted the intervention group and well controlled patients (glycated hemoglobin < 7%). The intervention lasted 60 days and consisted in the intensification of blood glucose control through the initiation of a basal plus insulin regimen with the titration of insulin to defined blood glucose targets which were; fasting blood glucose: 70-130mg/dl and post prandial blood glucose < 180mg/dl. The primary outcome measure was a change in HRV parameters and the secondary outcome measures a change in glycated hemoglobin, glycemia and weight. Results were analyzed as treated.
Results: A total of 54 consenting type 2 diabetes mellitus patients without clinical signs of CAN were recruited (26 males and 28 females). The median age was 56[43-62] years, and duration of diabetes 3[1-7] years. The intervention was carried out on 29 poorly controlled patients, compared at baseline to 25 well controlled patients who had been matched for age sex and body mass index. Markers of sympathetic tone were lower and thus altered in the poorly controlled group (SDNN: 102.01[90.45-111.05]ms vs 112.30[104.40-131.15]ms, p=0.014 and SDANN 88.01[72.95-99.70]ms vs 97.80[91.80-114.50]ms, p= 0.012). The intervention induced a change in HbA1c from 10.1[9.1-11.9]% to 6.7[5.9-6.9]% (p<0.001). Concerning HRV analysis, there was a significant increase in markers of the parasympathetic (PNN50: 5.70[3.55-10.25]% to 8.12[3.05-16.90]%, p=0.008) and sympathetic activities (SDNN: 102.01[90.45-111.05]ms to 122.40[91.70-135.95]ms, p=0.01). Two out of 29 participants reported having symptomatic confirmed hypoglycemia less than 70mg/dl. However there was no severe hypoglycemic episode. Weight increased from 75[69-84]kg to 77[71-86]kg, p<0.001.
Discussion: Our results show that HRV parameters (SDNN and SDANN) were lower in poorly controlled patients when compared to well-controlled patients. This is consistent with some findings from previous studies. This is because hyper-glycemia is considered a permissive pathogenesis factor activating various biochemical pathways leading to the development of CAN through neuronal ischemia and cellular death. The intervention led to an improvement in SDNN a marker of sympathetic activity and PNN50 a marker of parasympathetic activity. This is because, bringing exogenous insulin put the β- cells of the islets of Langerhans to rest thereby improving the activities of the parasympathetic branch which is responsible for insulin secretion. 
In conclusion, the optimization of glycemic control using a basal plus insulin regimen while inducing a significant reduction in glycated hemoglobin, significantly improves HRV parameters representing the sympathetic and parasympathetic activities. This suggests that tight glycemic control using insulin may improve cardiac autonomic functions in type 2 diabetes mellitus patients.

Effect of optimizing glycemic control using insulin on the heart rate variability in type 2 diabetes mellitus patients