Sympathetic nerve activity in type 2 diabetes mellitus; a promising potential therapeutic target

Abstract

Augmented sympathetic nerve activity (SNA) has an important effect on various diseases. SNA is significantly related to glucose metabolism in type 2 diabetes mellitus (DM). Type 2 DM causes cardiovascular complications such as heart failure, arrhythmia, and myocardial infarction. These complications are reported to be associated with increasing SNA. Previous studies have not shown a beneficial effect of insulin and conventional sulfonylurea therapy on cardiovascular mortality and morbidity. In previous studies, the principal therapeutic target in type 2 DM is recognized as lowering glycemic control. However, there is a lack of evidence for improvement of SNA and glycemic control in type 2 DM. Therefore, additional therapeutic strategy is required to prevent major cardiovascular complications in type 2 DM. In this review, we reconsidered effect of conventional anti-diabetic drugs on SNA and also discuss the risk and benefit of using beta blockade in the treatment of type 2 DM patients.

Introduction

Augmented sympathetic nerve activity (SNA) has an important effect on various diseases such as heart failure [1,2], hypertension [3], metabolic syndrome [4], and type 2 diabetes mellitus (DM) [5]. In heart failure patients, the sympathetic activation initially plays a compensatory role in acute decompensate state but increased SNA in chronic state is associated with adverse consequences at both cardiac and vascular levels which may aggravate the clinical status and negatively affect prognosis [6]. Sympathoexcitation induces also fatal arrhythmia [2,7]. It is well known that reducing SNA with beta blockade improve prognosis in heart failure. Beneficial effects of beta blockade have been reported. In CIBIS–II trial, bisoprolol showed 44 percent risk reduction of death [8]. In COPERNICUS trial, 35 percent decrease in the risk of death with carvedilol compared with placebo [9]. Likewise in type 2 DM, it is considered to be crucial to improve augmented SNA, which might contribute to better prognosis.

Type 2 DM causes cardiovascular complications that are related to mortality and morbidity. Previous studies have not shown a beneficial effect of insulin and conventional sulfonylurea therapy on cardiovascular mortality and morbidity [10,11]. Therefore, additional therapeutic strategy is required to prevent major cardiovascular events in type 2 DM, and one of the targets might be sympathetic nerve activity.

In this review, we reconsidered effect of conventional antidiabetic drugs on SNA and also discuss the risk and benefit of using beta blockade in the treatment of type 2 DM patients.

Insulin Activates Sympathetic Nerve Activity

In type 2 DM patients sympathetic nerve activity is higher than normal subjects [12]. Anderson et al. reported that acute increase of plasma insulin elevated muscle sympathetic nerve activity (MSNA) in healthy young control [13]. There are three pathways by which insulin activates sympathetic nerve activity; one is a direct effect oncentral nervous system [14], the others is hypoglycemia by insulin [15], and finally, feedback mechanism against vasodilatation induced by insulin [13]. Increased insulin resistance observed in the patient, such as obese, requires more insulin which activates sympathetic nerve activity.

Many types of anti–diabetic drugs are available to lower blood glucose. However, little is known about anti–diabetic drugs affect sympathetic nerve activity for treatment of type 2 DM patients.

Relationship Anti–Diabetic Drugs With Sympathetic Nerve Activity

Sulfonylurea

It was shown that sulfonylurea stimulate beta cell in pancreas, leading to lowering blood glucose. Sulfonylurea developed positive inotropic effect and increasing blood pressure without the mediation of glucagon, insulin, or adrenaline in dogs [16]. In human study, glibenclamide therapy is associated with greater responses of blood pressure and higher nocturnal blood pressures [17]. In the study, plasma insulin levels were significantly higher during glibenclamide treatment. The relationship blood pressure and plasma insulin was unclear, but hypoglycemia might induce the response. There is no report about the direct effect on central nervous system. However, sulfonylurea might increase the secretion of insulin, which might contribute to sympathoexcitation.

Biguanide

Metformin significantly increased insulin–stimulated glucose transport by 2.6 fold in rats, resulting in improvement in insulin resistance [18]. Intravenous administration of metformin decreased arterial pressure and sympathetic nerve activity [19]. With improvement in insulin resistance, metformin decreased blood pressure in diabetic hypertension patients [20]. Resting MSNA, total body and right renal norepinephrine spillover did not differ significantly after placebo and metformin treatment [21]. Inmeta–analysis, metformin reduced systolic and diastolic pressure. Metformin treatment was associated with a significant improvement in cardiac sympathovagal balance [22].

Its effectiveness was seen especially in type 2DM patients with obesity. UKPDS study was performed in obese type 2 DM, cardiovascular event decreased in metformin group [11]. These results suggest that metformin affect not only diabetic profiles but also improvement in sympathetic activity, which contribute to favorable outcomes

Alpha–glucosidase inhibitor

STOP–NIDDM trial showed that acarbose treatment in patients with impaired glucose tolerance (IGT) is associated with a significant reduction in the risk of developing diabetes, hypertension, and cardiovascular complications [23]. Acarbose acts as an alphaglucosidase inhibitor (GI) and slows the digestion of starch in the small intestine without reducing insulin release [24] or insulin sensitivity [25]. This study was performed in IGT subjects, so early intervention is associated with preventing progression of macro vascular disease. From our previous study, MSNA was significant higher in type 2 DM patient even treated with alpha–GI group compared to healthy control (Figure) [5].

Figure 1: Comparison of the burst frequency and burst incidence between DM treated with before and after pioglitazone, and healthy subjects. Both the burst frequency and burst incidence in DM patients treated with pioglitazone were significantly lower than those in alpha–GI. In addition, both MSNA in pioglitazone were similar to those in healthy subjects. The results are expressed as means ± SD. # p < 0.01 compared between alpha–GI and pioglitazone. ∗ p < 0.01 compared between alpha–GI and healthy subjects [3].