Diabetes and Metabolic Syndrome

Fig. 23.1

Sympathetic activity measured by MSNA in normotensive controls (NT), diabetes mellitus type 2 (DM2), hypertension (HTN) and metabolic syndrome (HTN + DM2) (Modified from Huggett et al. [1])

There is also preclinical data pointing towards a potential beneficial effect of renal denervation in metabolic syndrome. Renal denervation has been investigated in a chronically instrumented, high-fat fed dog model, which is characterized by sodium retention and increased sympathetic nervous system activation. Whilst the high fat diet resulted in a 50 % increase in body mass in both control and denervated dogs, blood pressure increased significantly only in the control but not in the denervated dogs. Furthermore, sodium retention was reduced by 50 % in the denervated dogs.

The predominant mechanism linking sympathetic drive to insulin resistance is likely related to sympathetically mediated redistribution of blood flow from insulin sensitive striated muscle, towards insulin insensitive fat tissue [3]. As such, in the human forearm, increased noradrenaline release results in a substantial reduction in forearm blood flow [15]. It has been proposed that pressure induced restriction of the microcirculation limits nutritional flow, and thereby impairs glucose uptake in the skeletal muscle [16]. There is clinical and experimental data indicating that there is (i) a direct relationship between sympathetic nerve activity to the skeletal muscle tissue and insulin resistance and (ii) that insulin resistance is inversely related to the number of open capillaries [17]. In turn, increased levels of insulin exhibit sympathoexcitatory effects [18, 19], contributing to activation of the sympathetic nervous system with its pathophysiological consequences. There is a bidirectional relationship between sympathetic overactivity inducing insulin resistance and hyperinsulinemia producing sympathetic activation, thus initiating a vicious cycle (Fig. 23.2).

Fig. 23.2

Vicious circle initiated by increased sympathetic activity

The gold standard in diagnosing insulin resistance is the hyperinsulinemic-euglycemic clam method, but this approach is not suitable for routine clinical practice. Thus, less invasive methods for evaluation, like homeostasis model assessment (HOMA-IR = (Glucose × Insulin)/405)), were developed. HOMA-IR is an established parameter for evaluation of insulin resistance [20, 21], correlating to the results of hyperinsulinemic-euglycemic clamp [22]. There is a direct relationship between the central sympathetic activity, measured by muscle sympathetic nerve activity, and the HOMA-IR [13].

In line, inhibition of the sympathetic nervous system by moxonidine has been shown to improve glucose metabolism by decreasing glucagon secretion and increasing skeletal blood flow with less glycogenolysis and gluconeogenesis [23], which confirms the pathophysiological relation between central nervous system and insulin resistance [24]. However, the use of centrally acting sympatholytics is limited by adverse effects, leading to high non-adherence rates [25].

Effects of Renal Denervation on Glucose Metabolism

Since renal denervation has a favorable safety profile and results in marked reduction of the sympathetic activity measured by MSNA [26, 27], the benefits of the procedure may not be restricted to treat resistant hypertension. A recently published pilot study investigated the effect of renal denervation on glucose metabolism and insulin resistance in patients with resistant hypertension [28]. Fifty patients with resistant hypertension were included in the study (37 underwent renal denervation, 13 served as controls), 40 % were diabetics. Beside significant blood pressure reduction observed in the treatment group (−32/−12 mmHg; p < 0.001) after 3 months, fasting glucose (from 118 ± 3.4 mg/dl to 108 ± 3.8 mg/dl; p = 0.039), insulin levels (from 20.8 ± 3.0 to 9.3 ± 2.5 μIU/ml; p = 0.006), C-peptide levels (from 5.3 ± 0.6 ng/ml to 3.0 ± 0.9 ng/ml; p = 0.002) and the HOMA-IR improved significantly from 6.0 ± 0.9 to 2.4 ± 0.8 (p = 0.001) after 3 months (Fig. 23.3). Additionally, mean 2-h glucose levels during oral glucose tolerance test were reduced by 27 mg/dl (p = 0.012, Fig. 23.4) while there were no significant changes in blood pressure or any of the metabolic markers described above in the control group. Body mass index and antihypertensive background medication remained unchanged during the study period.

Fig. 23.3

Change in fasting glucose, insulin levels, C-peptide levels, and the HOMA-IR in patients undergoing renal denervation and in the control group (Modified from Mahfoud et al. [28])

Fig. 23.4

Change in 60- and 120-min glucose level (n = 37) after administration of glucose 3 months after renal denervation (Modified from Mahfoud et al. [28])

Polycystic Ovary Syndrome

These findings are supported by investigations of patients with polycystic ovary syndrome (PCOS) [29]. PCOS is characterized by obesity, insulin resistance and BP elevation related to sympathetic nervous activation. Using the hyperinsulinaemic-euglycaemic clamp methodology it was demonstrated that insulin sensitivity improved by 17.5 % in the absence of any weight change at 3 months following renal denervation. Beside the improvements in glucose metabolism authors also report a reduction in sympathetic activity measured by MSNA, urinary albumin excretion and glomerular hyperfiltration, indicating beneficial effects of renal denervation on renal structure and function. These findings are of interest as renal denervation has been shown to prevent the development of structural renal changes due to early diabetic nephropathy in an animal model [30]. Functional and anatomic studies performed 2 weeks after the onset of streptozotocin-induced diabetes in denervated rats revealed attenuation of physiologic and anatomic findings of early diabetic nephropathy. In line, studies in humans demonstrated that sympathoinhibition with the centrally acting drug moxonidine reduced microalbuminuria in normotensive patients with type 1 diabetes, in the absence of any significant blood pressure changes [31]. This is supported by recently published data, investigating the effects of renal denervation on urinary albumin excretion in 100 patients with resistant hypertension and preserved renal function. The study demonstrated a reduced number of patients with micro- and macroalbuminuria after renal denervation and improvements in renal hemodynamics [32].

Obstructive Sleep Apnea

Individuals with obstructive sleep apnea syndrome (OSAS) are usually obese and have high prevalence of the metabolic syndrome [3]. OSAS itself is characterized by an increased sympathetic activity [33]. A recently published pilot study investigated the effects of renal denervation on OSAS severity and glucose metabolism in patients with resistant hypertension [34]. This observational series has confirmed significant reduction in blood pressure (−34/−13 mmHg; p < 0.01) and improvement in the OSAS severity in eight of ten enrolled patients 6 months after renal denervation. Decreases were also observed in plasma glucose concentration 2 h after glucose administration (median: 7.0 versus 6.4 mmol/L; p = 0.05) and in hemoglobin A1C level (median: 6.1 % versus 5.6 %; p < 0.05) at 6 months (Table 23.1). A larger randomized controlled trial investigating the effect of renal denervation in patients with OSAS is currently ongoing (NCT01366625).

Table 23.1

Change in glucose metabolism and obstructive sleep apnea severity after renal denervation (n = 10)

	Baseline	3 months	6 months
AHI, events/h	30.7 ± 26.5	20.0 ± 25.3	16.1 ± 22.2
Epworth sleepiness scale score, points	9	6.5 (p = ns)	7 (p < 0.05)
120 min glucose level, OGTT, mmol/l	8.4 ± 3.3	6.8 ± 2.5 (p = 0.051)	6.8 ± 2.9 (p < 0.05)
HbA1C, %	6.4 ± 0.8	6.0 ± 0.7 (p < 0.05)	5.9 ± 0.7 (p < 0.05)

Created using data from Witkowski et al. [34]

Outlook

Since renal denervation in patients with resistant hypertension has been shown to reduce sympathetic activity and blood pressure [35–37], improve glucose metabolism and glucose tolerance, it may be speculated that this treatment prolongs or even prevents the progression of type 2 diabetes and associated cardiovascular complications. The estimated change in cardiovascular risk associated with blood pressure reduction and improvement in diabetic state appears to be more than additive. Preclinical observations on renal protection against diabetic glomerular sclerosis coupled with the human data on renal denervation resulting in reduced blood pressure with improved insulin sensitivity and urinary albumin excretion justify additional studies in this area. Substantial research is needed to (i) enhance the understanding on the potential retinal, renal and cardiovascular consequences of these findings and (ii) to document the durability of the results.

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