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Background & Aims: Denervation of renal sympathetic nerves (RDN) is an invasive endovascular procedure introduced as an antihypertensive treatment with a potential beneficial effect on insulin resistance (IR). We have previously demonstrated a reduction in blood pressure (BP) six months after RDN, but severe hepatic and peripheral IR, assessed by glucose tracer and two step hyperinsulinemic-euglycemic clamp (HEC), did not improve. The aim of the current study was to evaluate IR and adipokines profiles in relation to BP and arterial stiffness changes two years after RDN., Methods: In 20 non-diabetic patients with true treatment-resistant hypertension, ambulatory and office BP were measured after witnessed intake of medications prior to, six and 24 months after RDN. Arterial stiffness index (AASI) was calculated from ambulatory BP. Insulin sensitivity (IS) was assessed using an oral glucose tolerance test (OGTT), the Homeostasis Model Assessment (HOMA-IR), HOMA-Adiponectin Model Assessment (HOMA-AD), the Quantitative Insulin Sensitivity Check Index (QUICKI), the Triglyceride and Glucose Index (TyG) and the Leptin-to-Adiponectin Ratio (LAR). These surrogate indices of IS were compared with tracer/HEC measurements to identify which best correlated in this group of patients., Results: All measured metabolic variables and IS surrogate indices remained essentially unchanged two years after RDN apart from a significant increase in HOMA-AD. OGTT peak at 30 min correlated best with reduction in endogenous glucose release (EGR) during low insulin HEC (r = -0.6, p = 0.01), whereas HOMA-IR correlated best with whole-body glucose disposal (WGD) (r = -0.6, p = 0.01) and glucose infusion rate (r = -0.6, p = 0.01) during high insulin HEC. BP response was unrelated to IS prior to RDN. Nocturnal systolic BP and arterial stiffness before RDN correlated positively with a progression in hepatic IR at six-month follow-up., Conclusion: IR, adiponectin and leptin did not improve two years after RDN. There was no correlation between baseline IS and BP response. Our study does not support the notion of a beneficial metabolic effect of RDN in patients with treatment resistant hypertension., Competing Interests: Conflict of interest No potential conflict of interest was reported by the authors., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Insulin resistance is an independent negative predictor of outcome after elective surgery and increases mortality among surgical patients in intensive care. The incretin hormone glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin release from the pancreas but may also increase insulin sensitivity in skeletal muscle and directly suppress hepatic glucose release. Here, we investigated whether a perioperative infusion of GLP-1 could counteract the development of insulin resistance after surgery. Pigs were randomly assigned to three groups; surgery/control, surgery/GLP-1, and sham/GLP-1. Both surgery groups underwent major abdominal surgery. Whole-body glucose disposal (WGD) and endogenous glucose release (EGR) were assessed preoperatively and postoperatively using D-[6,6-2H2]-glucose infusion in combination with hyperinsulinemic euglycemic step-clamping. In the surgery/control group, peripheral insulin sensitivity (i.e., WGD) was reduced by 44% relative to preoperative conditions, whereas the corresponding decline was only 9% for surgery/GLP-1 (P < 0.05). Hepatic insulin sensitivity (i.e., EGR) remained unchanged in the surgery/control group but was enhanced after GLP-1 infusion in both surgery and sham animals (40% and 104%, respectively, both P < 0.05). Intraoperative plasma glucose increased in surgery/control (∼20%) but remained unchanged in both groups receiving GLP-1 (P < 0.05). GLP-1 diminished an increase in postoperative glucagon levels but did not affect skeletal muscle glycogen or insulin signaling proteins after surgery. We show that GLP-1 improves intraoperative glycemic control, diminishes peripheral insulin resistance after surgery, and suppresses EGR. This study supports the use of GLP-1 to prevent development of postoperative insulin resistance., (Copyright © 2019 Endocrine Society.)

We assessed whether insulin sensitivity improved after renal denervation (RDN) for resistant hypertension. Twenty-three patients underwent a two-step hyperinsulinemic-euglycemic 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 ± 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., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities, and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by D-[6,6-²H₂]glucose infusion and hyperinsulinemic euglycemic step clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (∼34%, P<0.01), whereas hepatic insulin sensitivity remained unchanged. Intramyofibrillar (IFM) and subsarcolemma mitochondria (SSM) isolated from skeletal muscle showed a postoperative decline in ADP-stimulated respiration (V(ADP)) for pyruvate (∼61%, P<0.05, and ∼40%, P<0.001, respectively), whereas V(ADP) for glutamate and palmitoyl-L-carnitine (PC) was unchanged. Mitochondrial leak respiration with PC was increased in SSM (1.9-fold, P<0.05) and IFM (2.5-fold, P<0.05), indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (∼32%, P<0.01) and positively correlated to the decline in peripheral insulin sensitivity (r=0.748, P<0.05). All other mitochondrial enzyme activities were unchanged. No changes in mitochondrial function in liver were observed. Mitochondrial H₂O₂ and O₂·⁻ emission was measured spectrofluorometrically, and H₂O₂ was increased in SSM, IFM, and liver mitochondria (∼2.3-, ∼2.5-, and ∼2.3-fold, respectively, all P<0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arises in the postoperative phase along with increased ROS emission, suggesting a link between mitochondrial function and development of acute postoperative insulin resistance., (Copyright © 2015 the American Physiological Society.)

Background & Aims: Preoperative oral carbohydrate (CHO) treatment is known to reduce postoperative insulin resistance, but the necessity of a preoperative evening dose is uncertain. We investigated the effect of single-dose CHO treatment two hours before surgery on postoperative insulin sensitivity., Methods: Thirty two pigs (∼ 30 kg) were randomized to 4 groups (n = 8) followed by D-[6,6-(2)H2] glucose infusion and hyperinsulinemic-euglycemic step clamping. Two groups received a morning drink of 25 g carbohydrate (CHO/surgery and CHO/control). Animals in the other two groups were fasted overnight (fasting/surgery and fasting/control). Counter-regulatory hormones, free fatty acids (FFA) and liver and muscle glycogen content were measured serially., Results: Glucose infusion rates needed to maintain euglycemia were higher after CHO/surgery than fasting/surgery during low (8.54 ± 0.82 vs. 6.15 ± 0.27 mg/kg/min, P < 0.05), medium (17.26 ± 1.08 vs. 14.02 ± 0.56 mg/kg/min, P < 0.02) and high insulin clamping (19.83 ± 0.95 vs. 17.16 ± 0.58 mg/kg/min, P < 0.05). The control groups exhibited identical insulin sensitivity. Compared to their respective controls, insulin-stimulated whole-body glucose disposal was significantly reduced after fasting/surgery (-41%, P < 0.001), but not after CHO/surgery (-16%, P = 0.180). CHO reduced FFA perioperatively (P < 0.05) and during the clamp procedures (P < 0.02), but did not affect hepatic insulin sensitivity, liver and muscle glycogen content or counter-regulatory hormone profiles. A strong negative correlation between peripheral insulin sensitivity and mean cortisol levels was seen in fasted (R = -0.692, P = 0.003), but not in CHO loaded pigs., Conclusions: Single-dose preoperative CHO treatment is sufficient to reduce postoperative insulin resistance, possibly due to the antilipolytic effects and antagonist properties of preoperative hyperinsulinemia on the suppressant actions of cortisol on carbohydrate oxidation., (Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Estimated glomerular filtration rate (eGFR) based on either cystatin C or creatinine performs similarly in estimating measured GFR, but associate differently with cardiovascular disease (CVD) and mortality. This could be due to confounding by non-GFR-related traits associated with cystatin C and creatinine levels. We investigated non-GFR-related associations between eGFR and two types of nontraditional risk factors for CVD and death: L-arginine/dimethylarginine metabolism and insulin resistance., Methods: GFR was measured via iohexol clearance in a cross-sectional study of 1,624 middle-aged persons from the general population without CVD, diabetes or chronic kidney disease. The dimethylarginines were measured using liquid chromatography tandem mass spectrometry (LC-MSMS). Insulin resistance was determined by the homeostasis model assessment (HOMA-IR)., Results: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), the L-arginine/ADMA ratio and insulin resistance were associated with creatinine-based eGFR after accounting for measured GFR in multivariable adjusted analyses. The cystatin C-based eGFR showed a similar residual association with SDMA; an oppositely directed, borderline significant association with ADMA; and a stronger residual association with insulin resistance compared with eGFR based on creatinine., Conclusion: Both creatinine- and cystatin C-based eGFR are influenced by nontraditional risk factors, which may bias risk prediction by eGFR in longitudinal studies., (© 2015 S. Karger AG, Basel.)

The present study aimed to establish hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate (step hot-GINF HEC) for assessment of acute insulin resistance in anesthetized pigs and to arrange for combination with invasive investigative methods. Tracer enrichment was measured during D-[6,6-(2)H(2)]glucose infusion before and after surgical instrumentation (n = 8). Insulin dose-response characteristics were determined by two step hot-GINF HEC procedures, with accordingly labeled glucose infusates performed at a total of six insulin infusion rates ranging from 0.2 to 2.0 mU kg(-1) min(-1) (n = 8). Finally, three-step hot-GINF HEC (0.4, 1.2, and 2.0 mU kg(-1) min(-1)) was performed subsequent to major surgical trauma (n = 8). Tracer enrichment, basal glucose kinetics, and circulating levels of C-peptide, cortisol, glucagon, and catecholamines were not influenced by surgical instrumentation. Mean intraindividual coefficient of variance levels for glucose infusion rates and repeatedly measured insulin, glucose, and tracer enrichment indicated stable clamping conditions. Basal and maximal insulin-stimulated glucose utilization was twice as high as in humans at approximately 5.5 and 21 mg kg(-1) min(-1). Surgical trauma elicited pronounced peripheral and moderate hepatic insulin unresponsiveness (45% lower whole body glucose disposal and 19% less suppressed endogenous glucose release) and apparently diminished metabolic insulin clearance. Step hot-GINF HEC seems suitable for assessment of acute insulin resistance in anesthetized pigs, and combination with invasive investigative methods requiring surgical instrumentation can be accomplished without the premises for utilization of the technique being altered, but attention must be paid to alterations in metabolic insulin clearance.