Elsevier

Metabolism

Volume 62, Issue 5, May 2013, Pages 717-724
Metabolism

Clinical Science
Reduced capacity of heart rate regulation in response to mild hypoglycemia induced by glibenclamide and physical exercise in type 2 diabetes

https://doi.org/10.1016/j.metabol.2012.12.003Get rights and content

Abstract

Objective

Decreased heart rate variability (HRV) is associated with enhanced mortality due to abnormal cardiac rhythm. While hypoglycemic events are increasingly common in the treatment of type 2 diabetes, HRV is part of the counter-regulation against low blood glucose levels. We hypothesized that HRV was impaired in mild hypoglycemia in diabetic individuals.

Materials/Methods

Hyperinsulinemic–hypoglycemic clamps were performed in twelve type 2 diabetic patients without cardiovascular disease and in non-diabetic subjects matched for age, sex, and weight. In an additional study, hypoglycemic events, induced by either a single morning dose of glibenclamide or physical exercise, were recorded for the subsequent 24 h. Blood glucose concentrations and electrocardiograms were continuously monitored. Serum hormone levels, hypoglycemic symptoms, and forearm blood flow were measured at defined time points.

Results

Occurrence of a symptomatic hypoglycemic episode (mean blood glucose 3.1 ± 0.4 mmol/l) attenuated most of the time and frequency domain measurements in both healthy and diabetic individuals. The magnitude of reduction of HRV parameters was significantly lower in diabetic compared to healthy subjects. Glibenclamide taken in the morning enhanced the daily number of mild hypoglycemic events compared with placebo or moderate exercise. Concordantly, 24-h mean HRV measurements were decreased.

Conclusion

HRV response to hypoglycemia is impaired in type 2 diabetic subjects resulting in a higher than expected risk for sudden arrhythmia following mild hypoglycemic episodes.

Introduction

Compared to type 1 diabetes the risk of symptomatic hypoglycemia in type 2 diabetic patients is low, but increases with targeting intensive glycemic control [1]. Any hypoglycemic event is considered mild when the patient reacts without third-party assistance; whereas it is referred to as severe, if assistance is required for recovery. In recent clinical trials, prevalence of severe hypoglycemia was reported to depend on the mode of anti-diabetic therapy and on the presence of vascular co-morbidities [2], [3]. However, little is known about the frequency of mild hypoglycemia because symptoms are often self-reported by the patient without confirmation of blood glucose measurement, and if blood glucose levels are documented they are frequently within the normal range. Repeated hypoglycemic events could compromise both the patient's self-care routine and the communication between patient and health care provider [4]. Thresholds for symptom recognition were diminished with the effect that especially older patients were unaware of low blood glucose concentrations [5].

Acute fluctuations of blood glucose levels were observed in diabetic patients exercising after a meal [6]. Such glucose changes had a powerful impact on heart rate variability (HRV) and induced signs of cardiac ischemia [7], [8]. Elevation of epinephrine and norepinephrine release, enhancement of sympathetic neural activity [9], and decrease in cardiac vagal outflow [10], [11], [12] characterize the physiological regulation of low blood glucose levels. Reduction of HRV was associated with sudden cardiac death in patients with coronary heart disease [13], [14], [15], and was used to confirm autonomic neuropathy in diabetes patients [16], [17].

On the basis of known associations between HRV, blood glucose, and cardiac mortality the present study investigated the association of mild hypoglycemic episodes in type 2 diabetic patients with specific patterns of HRV compared to non-diabetic persons. Only well-controlled patients without a history of cardiovascular disease or autonomic neuropathy were included in the study. Under these conditions changes in HRV during drug- or exercise-induced hypoglycemia were investigated.

Section snippets

Type 2 diabetic patients

Patients, either on an anti-diabetic diet or taking metformin, and non-diabetic subjects were admitted to pre-study visits for acquisition of informed consent and screening measurements. The maximal rate of oxygen consumption (VO2max) was determined by indirect calorimetry (Deltatrac II, Datex, Freiburg, Germany) using an incremental protocol of 12.5 W/min performed on an electromagnetically braked cycle ergometer until the participant was unable to maintain a pedal cadence of 60 rpm. A

Reduction of HRV in diabetic patients

Both time and frequency domain parameters were significantly reduced in diabetic compared with non-diabetic participants (Table 2). Induction of hypoglycemia resulted in a further decrease of SDNN in diabetic patients, whereas pNN50 responded with pronounced reduction in healthy subjects. Low blood glucose decreased RMSSD compared to the euglycemic stage in both diabetic (25 ± 13 ms vs. 16 ± 8.7 ms, p = 0.01) and healthy participants (71 ± 25 ms vs. 30 ± 6.5 ms, p = 0.01).

Fig. 1 shows representative power

Effects of a single hypoglycemic episode on heart rate variability

A major aim of this study was to investigate autonomic cardiac function during a single hypoglycemic episode in subjects with and without type 2 diabetes. We used a hyperinsulinemic single-day study protocol and assessed each HRV parameter exactly at the time of the induced hypoglycemic event. Overall, we found a pattern of heart rate variability characteristic of pathological cardiac vagal action in type 1 diabetes [12], [18], [19].

Effect of glibenclamide and exercise on the frequency of hypoglycemic events

The combination of glibenclamide and exercise increased the

Authors contributions

All authors participated in various aspects of the study analysis and interpretation of the data, and to the development of the manuscript. The final version was seen and approved by all authors. TL as a principal investigator generated the study concept together with RGB and contributed to the interpretation of the data. NS was the main contributor in the drafting and development of the report. BF was involved in performance of the hypoglycemic clamps and drafting of data. FW and AP

Funding

This work was supported by grants from Behring-Roentgen-Stiftung (56/0019 to TL), Deutsche Forschungsgemeinschaft (LI 353/17-1 to TL), MSD Germany (to RGB), and Research Ministry of the Federal State of Hessia, LOEWE-MIBIE program (to AP, FW, and TL).

Conflict of interest

None. All authors declare that they have no conflicts of interest.

Acknowledgment

We want to thank Sina Streichert for taking care of the patients day and night. Petra Saar and Barbara Büttner provided expert technical assistance with the hypoglycemic clamps.

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