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.

Effects of growth hormone releasing hormone on insulin action and insulin secretion in a hypopituitary patient evaluated by the clamp technique

1992 ◽  
Vol 127 (1) ◽  
pp. 93-96 ◽  
Author(s):  
Silva Arslanian ◽  
Satish Kalhan
Keyword(s):  
Growth Hormone ◽  
Insulin Secretion ◽  
Insulin Action ◽  
Glucose Disposal ◽  
Second Phase ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Euglycemic Clamp ◽  
Hyperglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

The effect of growth hormone releasing hormone (GHRH-44) therapy on insulin action and secretion was evaluated in a hypopituitary patient after one month and one year of treatment. Hepatic and peripheral insulin action was studied with the hyperinsulinemic-euglycemic clamp in combination with [6,6-2H2]glucose tracer infusion. First and second phase insulin secretion was assessed with the hyperglycemic clamp. Prior to GHRH-44 therapy the hypopituitary patient had higher insulin mediated glucose disposal rate and lower basal and stimulated insulin concentrations by more than two standard deviations from the mean of a control group. Following therapy there was no change in basal hepatic glucose production; however, there was evidence of diminished peripheral insulin action. This was manifested by decreased insulin mediated glucose disposal during the hyperinsulinemic-euglycemic clamp, and increased insulin secretion during the hyperglycemic clamp. We conclude that GHRH-44 therapy in this patient was associated with decreased peripheral insulin action which was compensated for by increased insulin secretion.

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 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 A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

2020 ◽  
Author(s):  
Alfonso Galderisi ◽  
Domenico Trico ◽  
Bridget Pierpont ◽  
Veronika Shabanova ◽  
Stephanie Samuels ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Plasma Glucose ◽  
Metabolic Phenotype ◽  
Glucose Disposal ◽  
Incretin Effect ◽  
Tcf7l2 Gene ◽  
Intravenous Glucose ◽  
Hyperglycemic Clamp

<b>Background.</b> The risk genotype for the common variant <i>rs7903146 </i>of the transcription factor-7-like-2 gene (<i>TCF7L2</i>) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the <i>rs7903146</i> variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. <p><b>Methods</b> Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m<sup>2</sup>) were genotyped for the <i>rs7903146 </i>of <i>TCF7L2</i> and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.</p> <p>The incretin effect was measured as 100*(AUC-SR<sub>OGTT </sub>– AUC-SR<sub>iso-IVGTT</sub>)/AUC-SR<sub>OGTT </sub>[AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.</p> <p><b>Results </b>The presence of T risk allele for <i>TCF7L2</i> was associated with a markedly reduced </p> <p>incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. </p> <p><b>Conclusion </b>A<b> </b> reduced incretin effect and its association with the <i>TCF7L2</i> variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal. </p>

scholarly journals OR26-07 Mild Physiologic Hyperglycemia Does Not Affect Glucose Mediated but Impairs Insulin-Mediated Suppression of Plasma Glucagon in Healthy Normal Glucose Tolerant Subjects

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Devjit Tripathy ◽  
Xi chen ◽  
aurora merovci ◽  
Jonathan Trejo ◽  
Ralph DeFronzo
Keyword(s):  
Plasma Glucose ◽  
Plasma Insulin ◽  
Glucose Infusion ◽  
Plasma Glucagon ◽  
Euglycemic Clamp ◽  
Hyperglycemic Clamp ◽  
Before And After ◽  
Normal Glucose ◽  
Glucose Tolerant ◽  
Plasma Insulin Levels

Abstract Plasma glucagon levels are regulated by plasma glucose concentrations as well as intra-islet and circulating insulin concentrations. Hyperglycemia adversely affects skeletal muscle and hepatic insulin sensitivity (glucotoxicity). However, the effect of physiologic hyperglycemia on glucose-mediated and insulin-mediated suppression of glucagon is not known. The aim of the present study was to evaluate effect of chronic (48 or 72 hours) physiologic increase (+45 mg/dl) in plasma glucose concentration on the suppression of plasma glucagon concentration in healthy NGT individuals: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 yrs, BMI = 27 ± 1 kg/m2) and 8 with FH of T2DM (FH+) (4M/4F, age = 48±2, BMI = 26±1 kg/m2). Subjects received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes) before and after 72 hour glucose infusion. On another occasion subjects participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2·min) euglycemic clamp before and after a 48 hour glucose infusion. Plasma insulin and C-peptide concentrations were obtained every 2-5 minutes during each hyperglycemic clamp step and plasma glucagon concentrations were measured every 10 minutes. The ratio of insulin/glucagon was measured and used as an index of insulin-medicated suppression of plasma glucagon. FPG concentration increased from 97±4 to 140±4 mg/dl during the 72 hour glucose infusion. Following chronic glucose infusion, plasma insulin levels were significantly higher during the basal state and during each hyperglycemic clamp step (by 59% and 78%). There was no difference in plasma glucagon levels following chronic glucose infusion and the degree of suppression of glucagon during 2-step hyperglycemic (+125 and +300 mg/dl) were similar. However, the plasma insulin/glucagon ratio was significantly higher during the fasting state (by 76%) and during the first (by 128%) and second (by 178%) hyperglycemic clamp steps. Similarly during the three step euglycemic clamp (10, 20, 40 mU/m2·min) studies following 48 hr glucose infusion, despite similar plasma glucose concentrations during each clamp step, plasma insulin and glucagon concentrations were higher following chronic glucose infusion. These results demonstrate that sustained physiologic hyperglycemia for 48 hrs or 72 hours (i.e. glucotoxicity) does not affect the glucose mediated suppression of glucagon, but impairs insulin-mediated suppression of glucagon, and could contribute to fasting and post-prandial hyperglycemia in T2DM patients.

scholarly journals Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice

1999 ◽  
Vol 277 (6) ◽  
pp. E996-E1004 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Elimination Rate ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Maximal Effect ◽  
Glucose Effectiveness ◽  
Plasma Insulin Levels ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance in anesthetized mice. GLP-1 dose dependently potentiated insulin secretion after glucose administration, with the half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area under the glucose curve (AUCglucose) and increased the glucose elimination rate (KG) but did not affect the glucose effectiveness (SG). Furthermore, the insulin sensitivity index (SI) was reduced after administration of GLP-1. Because insulin secretion was stimulated to a larger degree than SI was reduced, the peptide increased the global disposition index (GDI = AUCinsulin × SI). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced the influences of GLP-1 on AUCglucose, KG, SI, and GDI. Finally, the GLP-1 receptor antagonist exendin-3-(9—39) inhibited the actions of GLP-1. We conclude that GLP-1 increases glucose tolerance in the mouse mainly by potently stimulating insulin secretion.

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 Evaluation of Insulin Sensitivity in Healthy Volunteers Treated with Olanzapine, Risperidone, or Placebo: A Prospective, Randomized Study Using the Two-Step Hyperinsulinemic, Euglycemic Clamp

2003 ◽  
Vol 88 (12) ◽  
pp. 5875-5880 ◽  
Author(s):  
Margaret Sowell ◽  
Nitai Mukhopadhyay ◽  
Patrizia Cavazzoni ◽  
Christopher Carlson ◽  
Sunder Mudaliar ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Tolerance Test ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Mixed Meal ◽  
Meal Tolerance Test ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Mixed Meal Tolerance Test

Abstract The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

scholarly journals A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

2020 ◽  
Author(s):  
Alfonso Galderisi ◽  
Domenico Trico ◽  
Bridget Pierpont ◽  
Veronika Shabanova ◽  
Stephanie Samuels ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Plasma Glucose ◽  
Metabolic Phenotype ◽  
Glucose Disposal ◽  
Incretin Effect ◽  
Tcf7l2 Gene ◽  
Intravenous Glucose ◽  
Hyperglycemic Clamp

<b>Background.</b> The risk genotype for the common variant <i>rs7903146 </i>of the transcription factor-7-like-2 gene (<i>TCF7L2</i>) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the <i>rs7903146</i> variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. <p><b>Methods</b> Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m<sup>2</sup>) were genotyped for the <i>rs7903146 </i>of <i>TCF7L2</i> and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.</p> <p>The incretin effect was measured as 100*(AUC-SR<sub>OGTT </sub>– AUC-SR<sub>iso-IVGTT</sub>)/AUC-SR<sub>OGTT </sub>[AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.</p> <p><b>Results </b>The presence of T risk allele for <i>TCF7L2</i> was associated with a markedly reduced </p> <p>incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. </p> <p><b>Conclusion </b>A<b> </b> reduced incretin effect and its association with the <i>TCF7L2</i> variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal. </p>

scholarly journals A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

2020 ◽  
Author(s):  
Alfonso Galderisi ◽  
Domenico Trico ◽  
Bridget Pierpont ◽  
Veronika Shabanova ◽  
Stephanie Samuels ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Plasma Glucose ◽  
Metabolic Phenotype ◽  
Glucose Disposal ◽  
Incretin Effect ◽  
Tcf7l2 Gene ◽  
Intravenous Glucose ◽  
Hyperglycemic Clamp

<b>Background.</b> The risk genotype for the common variant <i>rs7903146 </i>of the transcription factor-7-like-2 gene (<i>TCF7L2</i>) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the <i>rs7903146</i> variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. <p><b>Methods</b> Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m<sup>2</sup>) were genotyped for the <i>rs7903146 </i>of <i>TCF7L2</i> and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.</p> <p>The incretin effect was measured as 100*(AUC-SR<sub>OGTT </sub>– AUC-SR<sub>iso-IVGTT</sub>)/AUC-SR<sub>OGTT </sub>[AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.</p> <p><b>Results </b>The presence of T risk allele for <i>TCF7L2</i> was associated with a markedly reduced </p> <p>incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. </p> <p><b>Conclusion </b>A<b> </b> reduced incretin effect and its association with the <i>TCF7L2</i> variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal. </p>

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