Therapeutic Effect of Vagus Nerve Stimulation on Depressive-Like Behavior, Hyperglycemia and Insulin Receptor Expression in Zucker Fatty Rats

Abstract

Depression and type 2 diabetes (T2D) are common comorbid diseases and highly prevalent in the clinical setting with an unclarified mechanism. Zucker diabetic fatty (ZDF, fa/fa) rats natively develop T2D with hyperglycemia and hyperinsulinemia. Here we studied whether ZDF rats also innately develop depression, what a correlation is between depression and T2D, whether insulin receptor (IR) expression is involved in, and whether transcutaneous auricular vagus nerve stimulation (taVNS) would be beneficial in amelioration of the comorbidity. Six week old male ZDF and Zucker lean (ZL, fa/+) littermates were randomly divided into naïve (ZDF, n = 6; ZL, n = 7) and taVNS (ZDF-taVNS, n = 8; ZL-taVNS, n = 6) groups. Once daily 30 min-taVNS sessions were administrated under anesthesia for 34 consecutive days in taVNS groups. Blood glucose levels were tested weekly, and plasma glycosylated hemoglobin (HbAlc) level and immobility time in forced swimming test were determined on day 35 in all groups. The expression of insulin receptor (IR) in various tissues was also detected by immunostaining and Western blot. We found that naïve ZDF rats developed hyperglycemia steadily. These ZDF rats showed a strong positive correlation between longer immobility time and higher plasma HbAlC level. Long term taVNS treatment simultaneously prevented the development of depression-like behavior and progression of hyperglycemia in ZDF rats. The expression of IR in various tissues of naïve ZDF rats is lower than in naïve ZL and long-term taVNS treated ZDF rats. Collectively, our results indicate that in ZDF rats, i) depression and T2D develop simultaneously, ii) immobility time and HbAlc concentrations are highly and positively correlated, iii) a low expression of IR may be involved in the comorbidity of depression and T2D, and iv) taVNS is antidiabetic and antidepressive possibly through IR expression upregulation.

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

“…When compared to control heterozygotes or wild-types, only ZDF rats homozygous for the fatty (fa/fa) leptin receptor mutation develop cardinal symptoms of glucose-intolerant diabetes 13 including hyperphagia 69,83 , hyperinsulinemia 51, 65, 92 , obesity 69 , hyperglycemia 69, 73, 101 , elevated HbA1c 51, 92 , and increased MG-AGE 89 . In the first experiment we characterized the progression of hyperglycemia and pain-like behavior in diabetic ZDF and control ZL rats.…”

Cervical vagal nerve stimulation impairs glucose tolerance and suppresses insulin release in conscious rats

“…However, in the majority of the patients treated with VNS, stimulation occurs at the site of the cervical vagus nerve and both, efferent and afferent nerve fibers are activated. Thus, despite the reports from animal studies suggesting beneficial metabolic effects of VNS at more peripheral sites than the cervical vagus nerve (Li et al 2014;Malbert et al 2017) or with selective efferent cervical VNS (Peitl et al 2005;Meyers et al 2016), the question if nonselective (combined efferent and afferent) VNS at the site of the cervical vagus nerve may deteriorate glucose tolerance and place patients at risk for type 2 diabetes is highly relevant and important because our previous study demonstrated inhibition of insulin release despite marked increases in blood glucose levels during non-selective (intact nerve) and selective afferent (dissected nerve) cervical VNS. To further explore this question, we hypothesized that chronic cervical VNS of the intact vagus nerve inhibits glucose-induced insulin release and, thus, impairs glucose tolerance in conscious rats.…”

“…Indeed, studies in animals suggest that chronic stimulation of vagal nerve branches other than the cervical vagus nerve may have beneficial effects on glucose metabolism. For example, chronic bilateral stimulation of the subdiaphragmatic vagal nerves improved insulin sensitivity in diet-induced obesity in mini-pigs (Malbert et al 2017) and transcutaneous auricular vagus nerve stimulation prevented the increase in blood glucose levels and glycosylated HbA1c in Zucker diabetic fatty rats (Li et al 2014). Thus, it is possible that stimulation of more peripheral branches of the vagus nerve (e.g., subdiaphragmatic) improves glucose metabolism through efferent signaling to metabolic end-organs, such as the pancreas or the liver.…”

Effect of vagus nerve stimulation on blood glucose concentration in epilepsy patients – Importance of stimulation parameters

“…Other potential clinical indications for VNS, such as heart failure (Premchand et al, 2014;Zannad et al, 2015;Gold et al, 2016), Crohn's disease (Bonaz et al, 2016), chronic pain management (Chakravarthy et al, 2015), and obesity (Bodenlos et al, 2007;Pardo et al, 2007;Bodenlos et al, 2014) are emerging. There have also been promising reports in rats (Li et al, 2014) and humans (Huang et al, 2014;Huang et al, 2016), suggesting a potential beneficial role of noninvasive transcutaneous auricular VNS in diabetes. In contrast to these studies utilizing noninvasive transcutaneous auricular VNS, studies on the effects of invasive cervical VNS on glucose homeostasis are less promising.…”