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

Background. The risk genotype for the common variant rs7903146 of the transcription factor-7-like-2 gene (TCF7L2) 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 rs7903146 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. Methods Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m2) were genotyped for the rs7903146 of TCF7L2 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. The incretin effect was measured as 100*(AUC-SROGTT – AUC-SRiso-IVGTT)/AUC-SROGTT [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. Results The presence of T risk allele for TCF7L2 was associated with a markedly reduced 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. Conclusion A reduced incretin effect and its association with the TCF7L2 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.

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

10.2337/figshare.12665477.v2 ◽

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

Background. The risk genotype for the common variant rs7903146 of the transcription factor-7-like-2 gene (TCF7L2) 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 rs7903146 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. Methods Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m2) were genotyped for the rs7903146 of TCF7L2 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. The incretin effect was measured as 100*(AUC-SROGTT – AUC-SRiso-IVGTT)/AUC-SROGTT [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. Results The presence of T risk allele for TCF7L2 was associated with a markedly reduced 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. Conclusion A reduced incretin effect and its association with the TCF7L2 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.

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Effects of eccentric exercise on insulin secretion and action in humans

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.5.2151 ◽

1993 ◽

Vol 75 (5) ◽

pp. 2151-2156 ◽

Cited By ~ 19

Author(s):

D. S. King ◽

T. L. Feltmeyer ◽

P. J. Baldus ◽

R. L. Sharp ◽

J. Nespor

Keyword(s):

Insulin Secretion ◽

Eccentric Exercise ◽

Plasma Glucose ◽

Early Phase ◽

Pancreatic Beta Cell ◽

Late Phase ◽

Insulin Response ◽

Whole Body ◽

Glucose Disposal ◽

Hyperglycemic Clamp

The effects of an exhaustive bout of eccentric exercise on insulin secretion and action were determined using the hyperglycemic clamp technique. Clamps were performed on eight healthy men after 7 days of inactivity and approximately 36 h after a bout of eccentric exercise. Eccentric exercise consisted of 10 sets of 10 repetitions of combined knee extensions and flexions for each leg at a mean torque 84 +/- 5% of peak concentric torque. During the hyperglycemic clamp procedure, plasma glucose concentration was acutely raised to 10 mmol/l and was maintained near this level for 120 min. Arterialized blood samples were obtained from a heated hand vein to determine plasma glucose and insulin concentrations. Eccentric exercise appeared to produce marked muscle damage, as indicated by a 50-fold increase in plasma creatine phosphokinase (100 +/- 17 vs. 5,209 +/- 3,811 U/l, P < 0.001) and subjective reports of muscle soreness. Peak insulin response during the early phase (0–10 min) of the hyperglycemic clamp was higher after eccentric exercise (183 +/- 38 microU/ml) than after the control clamp (100 +/- 23 microU/ml, P < 0.005). Late-phase (10- to 120-min) insulin response was not altered after eccentric exercise. Peak plasma C-peptide concentrations were higher during the early phase (5.0 +/- 0.7 vs. 4.3 +/- 0.8 ng/ml, P < 0.05) and the late phase (7.5 +/- 0.9 vs. 5.4 +/- 0.6 ng/ml, P < 0.05). Prior eccentric exercise had no significant effect on whole body glucose disposal or glucose disposal rate adjusted for prevailing plasma insulin concentration. These data provide evidence that a single bout of eccentric exercise causes an increase in pancreatic beta-cell insulin secretion in response to hyperglycemia.

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PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.5.e834 ◽

1998 ◽

Vol 274 (5) ◽

pp. E834-E842 ◽

Cited By ~ 16

Author(s):

Karin Filipsson ◽

Giovanni Pacini ◽

Anton J. W. Scheurink ◽

Bo Ahrén

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Elimination Rate ◽

Insulin Response ◽

Area Under The Curve ◽

Glucose Disposal ◽

Sensitivity Index ◽

Maximal Effect ◽

Intravenous Glucose

Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1–5 min) insulin response was 3.8 ± 0.4 nmol/l (PACAP-27) and 3.3 ± 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 ± 0.1 nmol/l after glucose alone ( P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% ( P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 ± 0.04 10−4min−1/(pmol/l) for PACAP-27 and 0.29 ± 0.06 10−4min−1/(pmol/l) for PACAP-38 vs. 0.46 ± 0.02 10−4min−1/(pmol/l) for controls ( P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.

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The Incretin Effect in Female Mice With Double Deletion of GLP-1 and GIP Receptors

Journal of the Endocrine Society ◽

10.1210/jendso/bvz036 ◽

2019 ◽

Vol 4 (2) ◽

Author(s):

Bo Ahrén ◽

Yuichiro Yamada ◽

Yutaka Seino

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Insulin Response ◽

Oral Glucose ◽

Incretin Effect ◽

Intravenous Glucose ◽

C Peptide ◽

Female Mice

Abstract To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide (AUCC-peptide) correlated linearly with suprabasal AUCglucose both in WT (r = 0.942, P = .017) and DIRKO mice (r = 0.972, P = .006). The slope of this regression was lower in DIRKO than in WT mice (0.012 ± 0.006 vs 0.031 ± 0.006 nmol C-peptide/mmol glucose, P = .042). In contrast, there was no difference in the insulin response to intravenous glucose between WT and DIRKO mice. Furthermore, oral and intravenous glucose administration at matching glucose levels showed that the augmentation of insulin secretion after oral glucose (the incretin effect) in WT mice (11.8 ± 2.3 nmol/L min) was entirely absent in DIRKO mice (3.3 ± 1.2 nmol/L min). We conclude that GIP and GLP-1 are required for normal glucose tolerance and beta-cell function after oral glucose in mice, that they are the sole incretin hormones after oral glucose at higher dose levels, and that they contribute by 65% to insulin secretion after oral glucose.

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Postnatal insulin secretion and sensitivity after manipulation of fetal growth by embryo transfer in the horse

Journal of Endocrinology ◽

10.1677/joe.0.1810459 ◽

2004 ◽

Vol 181 (3) ◽

pp. 459-467 ◽

Cited By ~ 29

Author(s):

AJ Forhead ◽

JC Ousey ◽

WR Allen ◽

AL Fowden

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Beta Cell ◽

Embryo Transfer ◽

Plasma Glucose ◽

Cell Function ◽

The Other ◽

Intrauterine Growth ◽

Cell Responses ◽

The Relationship

This study examined the effects of intrauterine growth on insulin secretion and resistance in newborn foals. Embryo transfer between small pony and large Thoroughbred mares was used to produce four groups of foals with different birth weights (pony in pony n=7; pony in Thoroughbred n=7; Thoroughbred in Thoroughbred n=8; Thoroughbred in pony n=8). On day 2 after birth, glucose (0.5 g/kg) was administered intravenously to the foal and blood samples were taken for 2 h to determine plasma glucose and insulin concentrations. On day 3, insulin sensitivity was assessed by giving insulin (0.75 U/kg i.v.) and measuring the decrement in plasma glucose in the foals. There were no significant differences in insulin secretion, insulin sensitivity or glucose tolerance between the control and growth-retarded Thoroughbred foals. Overgrown pony foals delivered by Thoroughbred mares had higher basal insulin levels and greater beta cell responses to glucose than the other groups of foals. The relationship between plasma glucose and insulin was also significantly steeper in overgrown pony foals than in the other groups. Variations in intrauterine growth rate, therefore, affect postnatal insulin secretion in the horse. More specifically, it is overgrowth, not growth retardation in utero that alters equine beta cell function in the immediate neonatal period.

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Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.6.e1055 ◽

1999 ◽

Vol 276 (6) ◽

pp. E1055-E1066 ◽

Cited By ~ 43

Author(s):

André Carpentier ◽

Steven D. Mittelman ◽

Benoǐt Lamarche ◽

Richard N. Bergman ◽

Adria Giacca ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Cell Function ◽

Peak Plasma ◽

Sensitivity Index ◽

Β Cell ◽

Intravenous Glucose ◽

Hyperglycemic Clamp

The in vivo effect of elevated free fatty acids (FFA) on β-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, ∼10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (SI) was lower, and disposition index (DI = insulin sensitivity × insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 ± 1.4 × 10−3l2 ⋅ kg−1 ⋅ min−2in control vs. 10.0 ± 1.9 × 10−3l2 ⋅ kg−1 ⋅ min−2with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 ± 1.2 × 10−3l2 ⋅ kg−1 ⋅ min−2in control vs. 6.1 ± 0.7 × 10−3l2 ⋅ kg−1 ⋅ min−2with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this β-cell compensation.

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Effect of 7 days of bed rest on dose-response relation between plasma glucose and insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.257.1.e43 ◽

1989 ◽

Vol 257 (1) ◽

pp. E43-E48 ◽

Cited By ~ 5

Author(s):

K. J. Mikines ◽

F. Dela ◽

B. Tronier ◽

H. Galbo

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Insulin Response ◽

Bed Rest ◽

Glucose Disposal ◽

Cell Secretion ◽

Hyperglycemic Clamp ◽

Peripheral Insulin Resistance ◽

Glucose Stimulated Insulin Secretion ◽

Beta Cell Secretion

Physical training decreases glucose-stimulated insulin secretion. To further explore the influence of the level of daily physical activity on beta-cell secretion, the effect of 7 days of bed rest was studied in six young, healthy men by sequential hyperglycemic clamp technique (7, 11, and 20 mM glucose, each step lasting 90 min). At 11 and 20 mM glucose, insulin concentrations in plasma were higher after (87 +/- 11 and 303 +/- 63 microU/ml) than before (63 +/- 5 and 251 +/- 50 microU/ml, P less than 0.05) bed rest. Also C-peptide levels were higher after bed rest than before during glucose stimulation. The responses of other hormones, metabolites, or electrolytes influencing beta-cell secretion were not influenced by bed rest. In spite of increased insulin levels after bed rest, glucose disposal at 20 mM of glucose was significantly lower after bed rest than before. It is concluded that bed rest for 7 days increases the glucose-stimulated insulin response, at least partly due to a beta-cell adaptation increasing glucose-stimulated insulin secretion. However, the insulin secretion does not increase adequately compared with the peripheral insulin resistance induced by bed rest.

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Increased β-Cell Responsivity Independent of Insulin Sensitivity in Healthy African American Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa234 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2429-e2438

Author(s):

Latif Armiyaw ◽

Camila Sarcone ◽

Andin Fosam ◽

Ranganath Muniyappa

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Fat Free Mass ◽

Glucose Disposal ◽

Second Phase ◽

Β Cell ◽

Intravenous Glucose ◽

C Peptide ◽

Glucose Clamp Technique ◽

Cell Glucose

Abstract Background Primary insulin hypersecretion predicts type 2 diabetes (T2DM) independent of insulin resistance. Enhanced β-cell glucose responsivity contributes to insulin hypersecretion. African Americans (AAs) are at a higher risk for T2DM than non-Hispanic Whites (NHWs). Whether AAs manifest primary insulin hypersecretion is an important topic that has not been examined systematically. Objective To examine if nondiabetic AA adults have a higher β-cell glucose responsivity compared with NHWs. Methods Healthy nondiabetic AA (n = 18) and NHW (n=18) subjects were prospectively recruited. Indices of β-cell function, acute C-peptide secretion (X0); basal (Φ B), first-phase (Φ 1), second-phase (Φ 2), and total β-cell responsivity to glucose (Φ TOT), were derived from modeling of insulin, C-peptide, and glucose concentrations during an intravenous glucose tolerance test. Insulin sensitivity was assessed by the hyperinsulinemic–euglycemic glucose clamp technique. Results Glucose disposal rate (GDR) during clamp was similar in AAs and NHWs (GDR: [AA] 12.6 ± 3.2 vs [NHW] 12.6 ± 4.2 mg/kg fat free mass +17.7/min, P = .49). Basal insulin secretion rates were similar between the groups. AA had significantly higher X0 (4423 ± 593 vs 1807 ± 176 pmol/L, P = .007), Φ 1 [377.5 ± 59.0 vs 194.5 ± 26.6 (109) P = 0.03], and Φ TOT [76.7 ± 18.3 vs 29.6 ± 4.7 (109/min), P = 0.03], with no significant ethnic differences in Φ B and Φ 2. Conclusions Independent of insulin sensitivity, AAs showed significantly higher first-phase and total β-cell responsivity than NHWs. We propose that this difference reflects increased β-cell responsivity specifically to first-phase readily releasable insulin secretion. Future studies are warranted to identify mechanisms leading to primary β-cell hypersensitivity in AAs.

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

Journal of Endocrinology ◽

10.1677/joe.1.06310 ◽

2006 ◽

Vol 189 (1) ◽

pp. 67-75 ◽

Cited By ~ 30

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.

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