Evaluation of insulin sensitivity by hyperinsulinemic-euglycemic clamps using stable isotope-labeled glucose.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC5902507 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Evaluation of insulin sensitivity by hyperinsulinemic-euglycemic clamps using stable isotope-labeled glucose.
Zhang Yuanyuan Y Xu Lina L Liu Xiaohui X Wang Yiguo Y
Cell discovery 20180417
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Project description:ObjectiveThe euglycemic-hyperinsulinemic clamp is the gold standard to evaluate insulin resistance (IR), but there are only a few studies on the prevalence of IR in Chinese Han women with polycystic ovary syndrome (PCOS). This study investigated: (a) the prevalence of IR in Chinese Han women with PCOS by clamp, (b) the degree of reduction in insulin sensitivity (IS) and the contribution of body mass index (BMI).DesignRetrospective cross-sectional analysis.PatientsChinese Han women with PCOS (n = 448) visiting the Department of Endocrinology or the Department of Obstetrics and Gynaecology of the First Affiliated Hospital of Chongqing Medical University. Chinese Han women without PCOS (controls) from the same area (n = 40).MeasurementsClamp-measured IS, age, BMI, and total testosterone.ResultsThe prevalence of IR and reduction in IS were 56.3% and 30.3%, respectively, in Chinese Han women with PCOS (both P < 0.001). The inherent reduction in IS was 18.8% in lean women with PCOS and BMI independently reduced IS by 37.9% in obese women with PCOS. The prevalence of IR estimated by homeostatic model assessment (HOMA) was lower than that determined by clamp. The multivariable analysis showed that IR by clamp (R2 = 0.48, P < 0.001) was independently associated with BMI (β = -0.52, P < 0.001), waist-hip ratio (β = -0.23, P < 0.001), total testosterone (β = -0.07, P = 0.045) and age (β = 0.17, P < 0.001), while IR by HOMA was only associated with BMI (R2 = 0.25, β = 0.50, P < 0.001). There were no differences in BMI groups distribution, HOMA-IR and M values among the four PCOS subtypes (all P > 0.05).Conclusions56.3% of Chinese Han women with PCOS had IR and their reduction in IS was 30.3%. Obesity exacerbated the reduction in IS. When being evaluated by HOMA, the prevalence and the risk factors of IR in Chinese women with PCOS were underestimated.
| S-EPMC7380049 | biostudies-literature
Project description:d-Allulose, a C-3 epimer of d-fructose, is a rare sugar that has no calories. Although d-allulose has been reported to have several health benefits, such as anti-obesity and anti-diabetic effects, there have been no reports evaluating the effects of d-allulose on insulin resistance using a hyperinsulinemic-euglycemic clamp (HE-clamp). Therefore, we investigated the effects of d-allulose on a high-sucrose diet (HSD)-induced insulin resistance model. Wistar rats were randomly divided into three dietary groups: HSD containing 5% cellulose (HSC), 5% d-allulose (HSA), and a commercial diet. The insulin tolerance test (ITT) and HE-clamp were performed after administration of the diets for 4 and 7 weeks. After 7 weeks, the muscle and adipose tissues of rats were obtained to analyze Akt signaling via western blotting, and plasma adipocytokine levels were measured. ITT revealed that d-allulose ameliorated systemic insulin resistance. Furthermore, the results of the 2-step HE-clamp procedure indicated that d-allulose reversed systemic and muscular insulin resistance. d-Allulose reversed the insulin-induced suppression of Akt phosphorylation in the soleus muscle and epididymal fat tissues and reduced plasma TNF-α levels. This study is the first to show that d-allulose improves systemic and muscle insulin sensitivity in conscious rats.
| S-EPMC8461346 | biostudies-literature
Project description:BackgroundInsulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants.MethodsWe assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures.ResultsAfter low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e-4), among which glycerol (beta [Confidence Interval] = - 1.41 [- 1.54, - 1.27] s.d., p = 1.28e-95) and three-hydroxybutyrate (- 1.22 [- 1.36, - 1.07] s.d., p = 1.44e-61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, - 1.78 [- 1.88, - 1.69] s.d., P = 2.7e-295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters.ConclusionMetabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.
| S-EPMC8190027 | biostudies-literature
Project description:ObjectiveMeasurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose-to-(2)H(2)O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown.Research design and methodsTen nondiabetic and 10 diabetic subjects ingested (2)H(2)O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU . kg(-1) . min(-1) and glucose was clamped at approximately 5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and (2)H(2)O enrichments were measured hourly from 2 h onward.ResultsPlasma C2 glucose and plasma (2)H(2)O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma (2)H(2)O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose-to-(2)H(2)O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose-to-(2)H(2)O ratio overestimated (P < 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.ConclusionsPlasma C5 glucose-to-(2)H(2)O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2-3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated.
| S-EPMC2453627 | biostudies-literature
Project description:Metabolic pathways that are corrupted at early stages of insulin resistance (IR) remain elusive. This study investigates changes in body metabolism in clinically healthy and otherwise asymptomatic subjects that may become apparent already under compromised insulin sensitivity (IS) and prior to IR. 47 clinically healthy Arab male subjects with a broad range of IS, determined by hyperinsulinemic-euglycemic clamp (HIEC), were investigated. Untargeted metabolomics and complex lipidomics were conducted on serum samples collected under fasting and HIEC conditions. Linear models were used to identify associations between metabolites concentrations and IS levels. Among 1896 identified metabolites, 551 showed significant differences between fasting and HIEC, reflecting the metabolic switch in energy utilization. At fasting, 336 metabolites, predominantly di- and tri-acylglycerols, showed significant differences between subjects with low and high levels of IS. Changes in amino acid, carbohydrate and fatty acid metabolism in response to insulin were impaired in subjects with low IS. Association of altered mannose and amino acids with IS was also replicated in an independent cohort of T2D patients. We identified metabolic phenotypes that characterize clinically healthy Arab subjects with low levels of IS at their fasting state. Our study is providing further insights into the metabolic pathways that precede IR.
| S-EPMC7555540 | biostudies-literature
Project description:Insulin aspart is a short-acting insulin analogue that is used to control postprandial glycemia levels in diabetic patients. The aim of this clinical trial was to compare the pharmacokinetics and pharmacodynamics of GP40071 (GP-Asp) and NovoRapid Penfill (Novo-Asp) in a hyperinsulinemic euglycemic clamp (HEC). This trial was conducted as a part of a GP40071 biosimilar clinical development program. This was a phase I randomized, double-blind, two-period crossover study. Twenty-six healthy male volunteers aged 18 to 45 years who met the inclusion criteria underwent the procedure of an HEC following a single subcutaneous injection of 0.3 IU/kg of either GP-Asp or Novo-Asp into the abdomen. After doses, plasma glucose levels were monitored every 5 minutes for 8 hours. The adjustment of the glucose infusion rate (GIR) was based on the blood glucose measurements. The GIR values were used to evaluate the PD profiles of the studied drugs. Regular blood sampling was performed during the study to obtain sufficient pharmacokinetic data. The 90% confidence intervals for the geometric mean ratios of the pharmacokinetic (AUCins.0-t , Cins.max ) and pharmacodynamic (GIRmax , AUCGIR0-t ) parameters of GP-Asp were within the 80%-125% comparability limits. The safety profiles of the drugs were also comparable. Bioequivalence, similar PD, and safety of GP-Asp and Novo-Asp were demonstrated.
| S-EPMC9541865 | biostudies-literature
Project description:Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Muscle is mainly responsible for insulin-stimulated glucose clearance from the bloodstream. Thus, regulation of gene expression in muscle tissue may be involved in the pathogenesis of insulin resistance. The objective was to investigate gene expression and metabolic pathways alterations in skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in obese insulin-resistant subjects. We carried out a transcriptome comparison of skeletal muscle tissue before and after a 3-h euglycemic-hyperinsulinemic clamp following 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) (1.8 g/day) with or without a supplement of fish gelatin (FG) (25 % of daily protein intake) in 16 obese insulin-resistant subjects. Results indicate that approximately 5 % (1932) of expressed transcripts were significantly changed after the clamp in both n-3 PUFA and n-3 PUFA + FG supplementation periods. Of these differentially expressed transcripts, 1394 genes associated with enzymes, transcription and translation regulators, transporters, G protein-coupled receptors, cytokines, and ligand-dependent nuclear receptors were modified. Metabolic pathways that were significantly modified included liver X receptor/retinoid X receptors (RXR) activation, vitamin D receptor/RXR activation, interleukin (IL)-8, acute phase response, IL10, triggering receptor expressed on myeloid cells 1, peroxisome proliferator-activated receptor, G-beta/gamma and hepatocyte growth factor and IL6 signaling. Taken together, results suggest that mainly inflammatory and transcription factors are modified following clamp in obese insulin-resistant subjects. Overall, understanding the changes in metabolic pathways due to insulin may be a potential target for the management of insulin resistance.
| S-EPMC3534998 | biostudies-literature
Project description:BackgroundGlucose values of continuous glucose monitoring (CGM) have time delays compared with plasma glucose (PG) values. The artificial pancreas (STG-55, Nikkiso, Japan) (AP), which measures venous blood glucose directly, also has a time delay because of the long tubing lines from sampling vessel to the glucose sensor. We investigate accuracy and time delay of CGM and AP in comparison with PG values during 2-step glucose clamp study.MethodsSeven patients with type 2 diabetes and 2 healthy volunteers were included in this study. CGM (Enlite sensor, Medtronic, Northridge, CA, USA) was attached on the day before the experiment. Hyperglycemic (200 mg/dL) clamp was performed for 90 minutes, followed by euglycemic (100 mg/dL) hyperinsulinemic (100 ?U/mL) clamp for 90-120 minutes using AP. CGM sensor glucose was calibrated just before and after the clamp study. AP and CGM values were compared with PG values.ResultsAP values were significantly lower than PG values at 5, 30 minute during hyperglycemic clamp. In comparison, CGM value at 0 minute was significantly higher, and its following values were almost significantly lower than PG values. The time delay of AP and CGM values to reach maximum glucose levels were 5.0 ± 22.3 (NS) and 28.6 ± 32.5 ( P < .05) min, respectively. Mean absolute rate difference of CGM was significantly higher than AP (24.0 ± 7.6 vs 15.3 ± 4.6, P < .05) during glucose rising period (0-45 min); however, there were no significant differences during other periods.ConclusionsBoth CGM and AP failed to follow plasma glucose values during nonphysiologically rapid glucose rising, but indicated accurate values during physiological glucose change.
| S-EPMC5951059 | biostudies-literature
Project description:6 lean humans were submitted to a 3 hours hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were taken before and after the clamp. Set of arrays that are part of repeated experiments
2010-06-04 | GSE11868 | GEO
Project description:The therapeutic effect of basal insulin analogs will be sustained at a rather low insulin level. When employing healthy volunteers to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of long-acting insulin preparations by euglycemic clamp techniques, endogenous insulin cannot be ignored and sufficient endogenous insulin inhibition is crucial for the PD and/or PK assessment. This study aimed to explore a way to sufficiently inhibit endogenous insulin secretion. Healthy Chinese male and female volunteers were enrolled. After a subcutaneous injection of insulin glargine (IGlar) (LY2963016 or Lantus) (0.5 IU/kg), they underwent a manual euglycemic clamp for up to 24 h where the target blood glucose (BG) was set as 0.28 mmol/L below the individual's baseline. Blood samples were collected for analysis of PK/PD and C-peptide. The subjects fell into two groups according to the reduction extent of postdose C-peptide from baseline. After matching for the dosage proportion of Lantus, there were 52 subjects in group A (C-peptide reduction<50%) and 26 in group B (C-peptide reduction≥50%), respectively. No significant difference was detected in age, body mass index, the proportion of Latus treatment and female participants. A lower basal BG was observed in group B compared to group A (4.35 ± 0.26 vs. 4.59 ± 0.22 mmol/L, p < 0.05). The clamp studies were all conducted with high quality (where BG was consistently maintained around the target and exhibited a low variety). The binary logistic regression analysis indicated low basal BG as an independent factor for the success of sufficient endogenous insulin suppression. In conclusion, setting a lower sub-baseline target BG (e.g., 10% instead of 5% below baseline) might be an approach to help achieve sufficient endogenous insulin suppression in euglycemic clamps with higher basal BG levels (e.g., beyond 4.60 mmol/L).
| S-EPMC9354408 | biostudies-literature