scholarly journals Targeted Lipidomics Reveals Associations Between Serum Sphingolipids and Insulin Sensitivity Measured by the Hyperinsulinemic-euglycemic Clamp

2020 ◽  
Author(s):  
Jingya Ye ◽  
Xuan Ye ◽  
Wanzi Jiang ◽  
Chenyan Lu ◽  
Xiaomei Geng ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Metabolic Diseases ◽  
Roc Curves ◽  
Diagnostic Value ◽  
Ionization Mass ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Obesity And Diabetes ◽  
Insight Into

Abstract BackgroundSPs are a group of ubiquitously produced lipids that are structurally involved in cell membranes and include SMs, ceramides, GM3s, etc. Sphingolipids and their substrates and constituents, FAs, are implicated in the pathogenesis of various metabolic diseases associated with obesity, diabetes, and atherosclerosis. Decreased insulin sensitivity or insulin secretion is a multifactorial condition related to obesity and diabetes. Therefore, it is likely that perturbations in serum SPs are associated with diseases. Identifying these associations may reveal useful predictors or give perceptive insight into disease processes. This study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes.MethodsWe conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp, and FPIR was measured to evaluate insulin secretion by the IVGTT. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity based on GIR30 derived from the glucose clamp, which is the standard method, and the cutoff point of GIR30 was set as 5.1 mg/(kg *min).ResultsDifferential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. We also found that higher concentrations of serum free FAs (FFA 22:6, FFA 22:5, FFA 18:2, FFA 18:1) were associated with a higher risk of decreased insulin secretion. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria. ConclusionsThese results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. This suggests that the balance of SMs metabolism, rather than ceramide is correlated with the pathology of insulin resistance, obesity and T2DM. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

scholarly journals Target lipidomics reveals associations between serum sphingolipids and insulin sensitivity by the glucose clamp

2020 ◽  
Author(s):  
Jingya Ye ◽  
Xuan Ye ◽  
Wanzi Jiang ◽  
Chenyan Lu ◽  
Xiaomei Geng ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Roc Curves ◽  
Diagnostic Value ◽  
Ionization Mass ◽  
Chinese Adults ◽  
Euglycemic Clamp ◽  
Differential Correlation ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Obesity And Diabetes

AbstractBackgroundThis study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes.MethodsWe conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity.ResultsDifferential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria.ConclusionsThese results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

scholarly journals The GLP-1 Analogue Exenatide Improves Hepatic and Muscle Insulin Sensitivity in Diabetic Rats: Tracer Studies in the Basal State and during Hyperinsulinemic-Euglycemic Clamp

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Hui Wu ◽  
Chunhua Sui ◽  
Hui Xu ◽  
Fangzhen Xia ◽  
Hualing Zhai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Production ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Peripheral Tissues ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Glucagon Like Peptide 1

Objective. Glucagon-like peptide-1 (GLP-1) analogues (e.g., exenatide) increase insulin secretion in diabetes but less is known about their effects on glucose production or insulin-stimulated glucose uptake in peripheral tissues.Methods. Four groups of Sprague-Dawley rats were studied: nondiabetic (control, C); nondiabetic + exenatide (C + E); diabetic (D); diabetic + exenatide (D + E) with diabetes induced by streptozotocin and high fat diet. Infusion of 3-3H-glucose and U-13C-glycerol was used to measure basal rates of appearance (Ra) of glucose and glycerol and gluconeogenesis from glycerol (GNG). During hyperinsulinemic-euglycemic clamp, glucose uptake into gastrocnemius muscles was measured with 2-deoxy-D-14C-glucose.Results. In the diabetic rats, exenatide reduced the basalRaof glucose (P<0.01) and glycerol (P<0.01) and GNG (P<0.001). During the clamp,Raof glucose was also reduced, whereas the rate of disappearance of glucose increased and there was increased glucose uptake into muscle (P<0.01) during the clamp. In the nondiabetic rats, exenatide had no effect.Conclusion. In addition to its known effects on insulin secretion, administration of the GLP-1 analogue, exenatide, is associated with increased inhibition of gluconeogenesis and improved glucose uptake into muscle in diabetic rats, implying improved hepatic and peripheral insulin sensitivity.

scholarly journals Ghrelin enhances glucose-induced insulin secretion in scheduled meal-fed sheep

2006 ◽  
Vol 189 (1) ◽  
pp. 67-75 ◽  
Author(s):  
H Takahashi ◽  
Y Kurose ◽  
S Kobayashi ◽  
T Sugino ◽  
M Kojima ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Infusion ◽  
Glucose Disposal ◽  
Euglycemic Clamp ◽  
Hyperglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Plasma Insulin Levels ◽  
Plasma Gh

The purpose of this study was to investigate the effects of physiologic levels of ghrelin on insulin secretion and insulin sensitivity (glucose disposal) in scheduled fed-sheep, using the hyperglycemic clamp and hyperinsulinemic euglycemic clamp respectively. Twelve castrated Suffolk rams (69.8 ± 0.6 kg) were conditioned to be fed alfalfa hay cubes (2% of body weight) once a day. Three hours after the feeding, synthetic ovine ghrelin was intravenously administered to the animals at a rate of 0.025 and 0.05 μg/kg body weight (BW) per min for 3 h. Concomitantly, the hyperglycemic clamp or the hyperinsulinemic euglycemic clamp was carried out. In the hyperglycemic clamp, a target glucose concentration was clamped at 100 mg/100 ml above the initial level. In the hyperinsulinemic euglycemic clamp, insulin was intravenously administered to the animals for 3 h at a rate of 2 mU/kg BW per min. Basal glucose concentrations (44± 1 mg/dl) were maintained by variably infusing 100 mg/dl glucose solution. In both clamps, plasma ghrelin concentrations were dose-dependently elevated and maintained at a constant level within the physiologic range. Ghrelin infusions induced a significant (ANOVA; P < 0.01) increase in plasma GH concentrations. In the hyperglycemic clamp, plasma insulin levels were increased by glucose infusion and were significantly (P < 0.05) greater in ghrelin-infused animals. In the hyperinsulinemic euglycemic clamp, glucose infusion rate, an index of insulin sensitivity, was not affected by ghrelin infusion. In conclusion, the present study has demonstrated for the first time that ghrelin enhances glucose-induced insulin secretion in the ruminant animal.

scholarly journals PWD/PhJ and WSB/EiJ Mice Are Resistant to Diet-Induced Obesity But Have Abnormal Insulin Secretion

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3005-3017 ◽  
Author(s):  
Katie T. Y. Lee ◽  
Subashini Karunakaran ◽  
Maggie M. Ho ◽  
Susanne M. Clee
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Large Scale ◽  
Mouse Strains ◽  
Second Phase ◽  
Fasting Insulin ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Obesity And Diabetes

Recently, novel inbred mouse strains that are genetically distinct from the commonly used models have been developed from wild-caught mice. These wild-derived inbred strains have been included in many of the large-scale genomic projects, but their potential as models of altered obesity and diabetes susceptibility has not been assessed. We examined obesity and diabetes-related traits in response to high-fat feeding in two of these strains, PWD/PhJ (PWD) and WSB/EiJ (WSB), in comparison with C57BL/6J (B6). Young PWD mice displayed high fasting insulin levels, although they had normal insulin sensitivity. PWD mice subsequently developed a much milder and delayed-onset obesity compared with B6 mice but became as insulin resistant. PWD mice had a robust first-phase and increased second-phase glucose-stimulated insulin secretion in vivo, rendering them more glucose tolerant. WSB mice were remarkably resistant to diet-induced obesity and maintained very low fasting insulin throughout the study. WSB mice exhibited more rapid glucose clearance in response to an insulin challenge compared with B6 mice, consistent with their low percent body fat. Interestingly, in the absence of a measurable in vivo insulin secretion, glucose tolerance of WSB mice was better than B6 mice, likely due to their enhanced insulin sensitivity. Thus PWD and WSB are two obesity-resistant strains with unique insulin secretion phenotypes. PWD mice are an interesting model that dissociates hyperinsulinemia from obesity and insulin resistance, whereas WSB mice are a model of extraordinary resistance to a high-fat diet.

A Novel Use of the Hyperinsulinemic-Euglycemic Clamp Technique to Estimate Insulin Sensitivity of Systemic Lipolysis

2001 ◽  
Vol 33 (2) ◽  
pp. 89-95 ◽  
Author(s):  
M Stumvoll ◽  
H G Wahl ◽  
K Löblein ◽  
R Becker ◽  
A Volk ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Euglycemic Clamp ◽  
Clamp Technique ◽  
Hyperinsulinemic Euglycemic Clamp

scholarly journals Chronic kidney disease and obesity bias surrogate estimates of insulin sensitivity compared with the hyperinsulinemic euglycemic clamp

2017 ◽  
Vol 312 (3) ◽  
pp. E175-E182 ◽  
Author(s):  
Iram Ahmad ◽  
Leila R. Zelnick ◽  
Nicole R. Robinson ◽  
Adriana M. Hung ◽  
Bryan Kestenbaum ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Insulin Sensitivity ◽  
Kidney Disease ◽  
Oral Glucose ◽  
Cross Sectional ◽  
Euglycemic Clamp ◽  
Insulin Kinetics ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Sensitivity Indices ◽  
Organ Specific

Insulin sensitivity can be measured by procedures such as the hyperinsulinemic euglycemic clamp or by using surrogate indices. Chronic kidney disease (CKD) and obesity may differentially affect these measurements because of changes in insulin kinetics and organ-specific effects on insulin sensitivity. In a cross-sectional study of 59 subjects with nondiabetic CKD [estimated glomerular filtration rate: (GFR) <60 ml·min−1·1.73 m2] and 39 matched healthy controls, we quantified insulin sensitivity by clamp (SIclamp), oral glucose tolerance test, and fasting glucose and insulin. We compared surrogate insulin sensitivity indices to SIclamp using descriptive statistics, graphical analyses, correlation coefficients, and linear regression. Mean age was 62.6 yr; 48% of the participants were female, and 77% were Caucasian. Insulin sensitivity indices were 8–38% lower in participants with vs. without CKD and 13–59% lower in obese compared with nonobese participants. Correlations of surrogate indices with SIclamp did not differ significantly by CKD or obesity status. Adjusting for SIclamp in addition to demographic factors, Matsuda index was 15% lower in participants with vs. without CKD ( P = 0.09) and 36% lower in participants with vs. without obesity ( P = 0.0001), whereas 1/HOMA-IR was 23% lower in participants with vs. without CKD ( P = 0.02) and 46% lower in participants with vs. without obesity ( P < 0.0001). We conclude that CKD and obesity do not significantly alter correlations of surrogate insulin sensitivity indices with SIclamp, but they do bias surrogate measurements of insulin sensitivity toward lower values. This bias may be due to differences in insulin kinetics or organ-specific responses to insulin.

scholarly journals Superimposition of Postnatal Calorie Restriction Protects the Aging Male Intrauterine Growth- Restricted Offspring from Metabolic Maladaptations

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4216-4226 ◽  
Author(s):  
Yun Dai ◽  
Shanthie Thamotharan ◽  
Meena Garg ◽  
Bo-Chul Shin ◽  
Sherin U. Devaskar
Keyword(s):  
Physical Activity ◽  
Insulin Sensitivity ◽  
Postnatal Growth ◽  
Growth Restriction ◽  
Fine Tuning ◽  
Whole Body ◽  
Aging Male ◽  
Intrauterine Growth ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

Intrauterine growth restriction (IUGR) results in dysregulated glucose homeostasis and adiposity in the adult. We hypothesized that with aging, these perturbations will wane, and superimposition of postnatal growth restriction (PNGR) on IUGR [intrauterine and postnatal growth restriction (IPGR)] will reverse the residual IUGR phenotype. We therefore undertook hyperinsulinemic-euglycemic clamp, energy balance, and physical activity studies during fed, fasted, and refed states, in light and dark cycles, on postweaned chow diet-fed more than 17-month aging male IUGR, PNGR, and IPGR vs. control (CON) rat offspring. Hyperinsulinemic-euglycemic clamp revealed similar whole-body insulin sensitivity and physical activity in the nonobese IUGR vs. CON, despite reduced heat production and energy expenditure. Compared with CON and IUGR, IPGR mimicking PNGR was lean and growth restricted with increased physical activity, O2 consumption (VO2), energy intake, and expenditure. Although insulin sensitivity was no different in IPGR and PNGR, skeletal muscle insulin-induced glucose uptake was enhanced. This presentation proved protective against the chronologically earlier (5.5 months) development of obesity and dysregulated energy homeostasis after 19 wk on a postweaned high-fat diet. This protective role of PNGR on the metabolic IUGR phenotype needs future fine tuning aimed at minimizing unintended consequences.

scholarly journals The antagonist of CXCR1 and CXCR2 protects db/db mice from metabolic diseases through modulating inflammation

2019 ◽  
Vol 317 (6) ◽  
pp. E1205-E1217 ◽  
Author(s):  
Siyuan Cui ◽  
Lu Qiao ◽  
Shanshan Yu ◽  
Lili Men ◽  
Yu Li ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Immune Cell ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Signal Pathways ◽  
Therapeutic Effects ◽  
Obesity And Diabetes ◽  
Phosphorylated Akt

Interleukin-8 (IL-8, also named CXCL8) binds to its receptors (CXCR1 and CXCR2) with subsequent recruitment of neutrophils and enhancement of their infiltration into inflamed sites, which exaggerates inflammation in many diseases. Recent studies have proposed that metabolic disorders can be attenuated by counteracting certain inflammatory signal pathways. In this study, we examined whether intervention with G31P, an antagonist of CXCL8, could attenuate tissue inflammation and development of metabolic disorders in db/db mice. The db/m and db/db mice were subcutaneously injected with G31P or equivalent normal saline once a day for 6 wk. The physical and metabolic parameters, glucose tolerance, insulin sensitivity, hepatic lipid accumulation, and inflammation markers were measured. G31P improved hepatic insulin sensitivity by modulating expression of genes related to gluconeogenesis and phosphorylated Akt levels. The expressions of several genes encoding proteins involved in de novo lipogenesis were decreased in G31P-treated db/db mice. Meanwhile, immune cell infiltration and cytokine release were attenuated in db/db mice with G31P treatment. G31P also improved the ratio of proinflammatory M1 and anti-inflammatory M2 macrophages. Furthermore, G31P ameliorates metabolic disturbances via inhibition of CXCR1 and CXCR2 pathways in db/db mice. These data suggest that the selective inhibition of CXC chemokines may have therapeutic effects on symptoms associated with obesity and diabetes.

scholarly journals Ghrelin- and GH-induced insulin resistance: no association with retinol-binding protein-4

2013 ◽  
Vol 2 (2) ◽  
pp. 96-103 ◽  
Author(s):  
Esben Thyssen Vestergaard ◽  
Morten B Krag ◽  
Morten M Poulsen ◽  
Steen B Pedersen ◽  
Niels Moller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Binding Protein ◽  
Human Subjects ◽  
Retinol Binding Protein ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Retinol Binding Protein 4 ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

ObjectiveSupraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.Materials and methodsTo study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic–euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic–euglycemic clamp technique.ResultsGhrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance.Conclusionsi) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.

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