We assessed whether insulin sensitivity improved after renal denervation (RDN) for resistant hypertension. Twentythree patients underwent a two-step hyperinsulinemiceuglycemic clamp (HEC) with glucose tracer and labeled glucose infusion and oral glucose tolerance test (OGTT) before and 6 months after RDN. Eighteen patients had metabolic syndrome at baseline. Blood pressure declined significantly after RDN, whereas mean (SD) fasting plasma glucose concentration (5.9 6 0.7 mmol/L), median (minimum-maximum) insulin concentration (254 pmol/L [88-797 pmol/L]), and median C-peptide concentration (2.4 nmol/L [0.9-5.7 nmol/L]) remained unchanged. Endogenous glucose release during HEC was less suppressed after RDN, suggesting a slight decrease in hepatic insulin sensitivity. During high-dose insulin infusion, whole-body glucose disposal was low and remained unchanged after RDN, indicating persistent peripheral insulin resistance (IR). Area under the curve for 0-120 min for glucose and insulin during OGTT, Quantitative Insulin Sensitivity Check Index, Simple Index Assessing Insulin Sensitivity Oral Glucose Tolerance, and HOMA-IR were high, and did not improve after RDN. Despite a significant decrease in blood pressure, neither peripheral nor hepatic insulin sensitivity improved 6 months after RDN treatment in this group of insulin-resistant patients without diabetes and with resistant hypertension, as measured with gold standard methods.More than 50% of patients with essential hypertension are considered to have insulin resistance (IR) (1). The link between these two disorders is partly unknown, but it has been hypothesized that increased sympathetic nerve activity (SNA) plays an important role (2). Sympathetic activation results in peripheral vasoconstriction through the release of norepinephrine, which acts upon vascular muscle adrenoreceptors. A subsequent reduction in skeletal muscle blood flow leads to reduced whole-body glucose utilization (3). Consequently, increased SNA may reduce insulin sensitivity (IS) through direct effects on the regulation of glucose uptake by skeletal muscle (4,5).Targeting both sympathetic tone and IR might be of relevance to reduce the cardiovascular risk associated with hypertension. Renal denervation (RDN) has been shown to lower SNA by the ablation of both afferent and efferent nerves (6). The first study showing improved IS after RDN used only surrogate indexes of whole-body IR (7). To investigate the possible effects of RDN on IR in more detail, we applied a two-step hyperinsulinemiceuglycemic clamp (HEC) with glucose tracer infusion and labeled glucose infusate to separately assess glucose turnover, as well as hepatic and peripheral IS before and after RDN. Patients were also subjected to an oral glucose tolerance test (OGTT).