Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

2007 ◽  
Vol 293 (1) ◽  
pp. E75-E82 ◽  
Author(s):  
M. J. De Blasio ◽  
M. Dodic ◽  
A. J. Jefferies ◽  
K. M. Moritz ◽  
E. M. Wintour ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Adult Male ◽  
Early Pregnancy ◽  
Male Offspring ◽  
Second Phase ◽  
Intravenous Glucose ◽  
Pregnant Sheep

An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life “programming”. Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, α-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.

scholarly journals Prenatal exposure to diesel exhaust PM2.5 causes offspring β cell dysfunction in adulthood

2018 ◽  
Vol 315 (1) ◽  
pp. E72-E80 ◽  
Author(s):  
Minjie Chen ◽  
Shuai Liang ◽  
Xiaobo Qin ◽  
Li Zhang ◽  
Lianglin Qiu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Adult Male ◽  
Diesel Exhaust ◽  
Maternal Exposure ◽  
Male Offspring ◽  
Β Cells ◽  
Β Cell

Environmental stressors that encounter in early-life and cause abnormal fetal and/or neonatal development may increase susceptibility to non-communicable diseases such as diabetes. Maternal exposure to ambient fine particulate matter (PM2.5) is associated with various fetal abnormalities, suggesting that it may program offspring’s susceptibility to diabetes. In the present study, we therefore examined whether maternal exposure to diesel exhaust PM2.5 (DEP), one of the major sources of ambient PM2.5 in urban areas, programs adult offspring’s glucose metabolism. Female C57Bl/6J mice were intratracheally instilled with DEP or vehicle throughout a 7-wk preconceptional period, gestation, and lactation, and the glucose homeostasis of their adult male offspring was assessed. Intraperitoneal glucose tolerance test (IPGTT) revealed that the maternal exposure to DEP significantly impaired adult male offspring’s glucose tolerance. Unexpectedly, it did not influence their insulin sensitivity, whereas it significantly decreased their glucose-induced insulin secretion (GIIS). This deficit in insulin secretion was corroborated by their significant decrease in arginine-induced insulin secretion. Histological analysis demonstrated that the deficit in insulin secretion was accompanied by the decrease in pancreatic islet and β cell sizes. To differentiate the effects of maternal exposure to DEP before birth and during lactation, some offspring were cross-fostered once born. We did not observe any significant effect of cross-fostering on the glucose homeostasis of adult male offspring and the function and morphology of their β cells. Prenatal exposure to DEP programs the morphology and function of β cells and thus homeostatic regulation of glucose metabolism in adult male offspring.

scholarly journals Impaired adaptation of first-phase insulin secretion in postmenopausal women with glucose intolerance

1997 ◽  
Vol 273 (4) ◽  
pp. E701-E707 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
B Cell ◽  
Postmenopausal Women ◽  
Second Phase ◽  
Hepatic Extraction ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
First Phase Insulin Secretion

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness, and hepatic extraction of insulin are altered in subjects with impaired glucose tolerance (IGT). The frequently sampled intravenous glucose tolerance test was performed in postmenopausal women (age 63 yr, body mass index range 21.6–28.9 kg/m2) with IGT ( n = 10) or normal glucose tolerance (NGT; n = 10). Insulin sensitivity (SI) was significantly lower in IGT than in NGT ( P = 0.030). In contrast, insulin secretion was not significantly different between the two groups as determined by area under the curve for insulin and C-peptide, acute insulin response to glucose (AIRG), and glucose sensitivity of first-phase (φ1) or of second-phase (φ2) insulin secretion. In NGT ( r = −0.68, P = 0.029) but not in IGT ( r = −0.05, not significant), SIcorrelated negatively with φ1. The B-cell “adaptation index” (SI × φ1) was lower in IGT than in NGT [83 ± 25 vs. 171 ± 29 min−2/(mmol/l), P = 0.042]. Also, the B-cell “disposition index” (SItimes AIRG) was lower in IGT (83 ± 25 10−4min−1) than in NGT (196 ± 30 10−4min−1, P = 0.011). In contrast, glucose effectiveness or hepatic extraction of insulin was not different between IGT and NGT. We conclude that postmenopausal women with IGT fail to adequately adapt to lowered SI by increasing first-phase insulin secretion.

Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort

2021 ◽  
pp. 153537022110094
Author(s):  
Ibiye Owei ◽  
Nkiru Umekwe ◽  
Frankie Stentz ◽  
Jim Wan ◽  
Sam Dagogo-Jack
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Intravenous Glucose Tolerance Test ◽  
Cross Sectional ◽  
Parental History ◽  
Intravenous Glucose

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

scholarly journals Postnatal ontogeny of glucose homeostasis and insulin action in sheep

2004 ◽  
Vol 286 (6) ◽  
pp. E1050-E1059 ◽  
Author(s):  
K. L. Gatford ◽  
M. J. De Blasio ◽  
P. Thavaneswaran ◽  
J. S. Robinson ◽  
I. C. McMillen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Early Adulthood ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Postnatal Ontogeny ◽  
Intravenous Glucose ◽  
Female Sheep

Glucose tolerance declines with maturation and aging in several species, but the time of onset and extent of changes in insulin sensitivity and insulin secretion and their contribution to changes in glucose tolerance are unclear. We therefore determined the effect of maturation on glucose tolerance, insulin secretion, and insulin sensitivity in a longitudinal study of male and female sheep from preweaning to adulthood, and whether these measures were related across age. Glucose tolerance was assessed by intravenous glucose tolerance test (IVGTT, 0.25 g glucose/kg), insulin secretion as the integrated insulin concentration during IVGTT, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (2 mU insulin·kg−1·min−1). Glucose tolerance, relative insulin secretion, and insulin sensitivity each decreased with age ( P < 0.001). The disposition index, the product of insulin sensitivity, and various measures of insulin secretion during fasting or IVGTT also decreased with age ( P < 0.001). Glucose tolerance in young adult sheep was independently predicted by insulin sensitivity ( P = 0.012) and by insulin secretion relative to integrated glucose during IVGTT ( P = 0.005). Relative insulin secretion before weaning was correlated positively with that in the adult ( P = 0.023), whereas glucose tolerance, insulin sensitivity, and disposition indexes in the adult did not correlate with those at earlier ages. We conclude that glucose tolerance declines between the first month of life and early adulthood in the sheep, reflecting decreasing insulin sensitivity and absence of compensatory insulin secretion. Nevertheless, the capacity for insulin secretion in the adult reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment.

scholarly journals Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

2020 ◽  
Author(s):  
Marine L. Croze ◽  
Arthur Guillaume ◽  
Mélanie Ethier ◽  
Grace Fergusson ◽  
Caroline Tremblay ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Free Fatty Acid ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Dependent Manner ◽  
High Fat ◽  
Normal Chow ◽  
Free Fatty Acid Receptors

ABSTRACTThe free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

scholarly journals Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity

2012 ◽  
Vol 303 (5) ◽  
pp. E587-E596 ◽  
Author(s):  
Lara Bonomi ◽  
Melissa Brown ◽  
Nathan Ungerleider ◽  
Meghan Muse ◽  
Martin M. Matzuk ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Activin A ◽  
Whole Body ◽  
Null Mouse ◽  
Islet Function ◽  
Islet Mass ◽  
Glucose Stimulated Insulin Secretion

Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets.

Population-based modeling to demonstrate extrapancreatic effects of tolbutamide

1998 ◽  
Vol 274 (4) ◽  
pp. E758-E771 ◽  
Author(s):  
A. Rostami-Hodjegan ◽  
S. R. Peacey ◽  
E. George ◽  
S. R. Heller ◽  
G. T. Tucker
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Population Based ◽  
Hypoglycemic Effect ◽  
Sensitivity Index ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Intravenous Glucose Tolerance ◽  
Extrapancreatic Effects

Tolbutamide is used increasingly as an investigative tool in in vivo studies of the physiology of glucose tolerance. Its hypoglycemic effect in nondiabetic subjects is widely variable, reflecting possible variability in its pharmacokinetics, an insulinergic response, an extrapancreatic effect of the drug, or the hypoglycemic effect of insulin itself. Using population-based modeling, we have investigated the kinetics and dynamics of tolbutamide and assessed covariates in two groups of healthy subjects. The results indicate a high variability in insulinergic effect, measured by the area under of the curve of insulin (0–60 min), in response to tolbutamide injection (coefficient of variation = 29–96%). However, it appears that impaired insulin sensitivity is compensated by higher insulin secretion in response to tolbutamide. Thus the hypoglycemic effect of high insulin secretion is minimal in insulin-resistant subjects. Application of the model indicated that tolbutamide has appreciable extrapancreatic effects mediated by prolongation of the residence time of insulin in a remote effect and by enhancement of glucose effectiveness. An effect in increasing the insulin sensitivity index is also possible but could not be confirmed statistically for all groups of subjects studied. These observations may explain inconsistencies between the results of tolbutamide and insulin injection in the frequently sampled intravenous glucose tolerance test and call for further study of insulin- vs. tolbutamide-modified frequently sampled intravenous glucose tolerance tests in the assessment of the insulin sensitivity and glucose effectiveness indexes.

scholarly journals Betamethasone-exposed preterm birth does not impair insulin action in adult sheep

2017 ◽  
Vol 232 (2) ◽  
pp. 175-187 ◽  
Author(s):  
R De Matteo ◽  
D J Hodgson ◽  
T Bianco-Miotto ◽  
V Nguyen ◽  
J A Owens ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Preterm Birth ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Whole Body ◽  
Intravenous Glucose ◽  
Adult Sheep ◽  
Insulin Signalling Pathway ◽  
Increased Risk

Preterm birth is associated with increased risk of type 2 diabetes (T2D) in adulthood; however, the underlying mechanisms are poorly understood. We therefore investigated the effect of preterm birth at ~0.9 of term after antenatal maternal betamethasone on insulin sensitivity, secretion and key determinants in adulthood, in a clinically relevant animal model. Glucose tolerance and insulin secretion (intravenous glucose tolerance test) and whole-body insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were measured and tissue collected in young adult sheep (14 months old) after epostane-induced preterm (9M, 7F) or term delivery (11M, 6F). Glucose tolerance and disposition, insulin secretion, β-cell mass and insulin sensitivity did not differ between term and preterm sheep. Hepatic PRKAG2 expression was greater in preterm than in term males (P = 0.028), but did not differ between preterm and term females. In skeletal muscle, SLC2A4 (P = 0.019), PRKAA2 (P = 0.021) and PRKAG2 (P = 0.049) expression was greater in preterm than in term overall and in males, while INSR (P = 0.047) and AKT2 (P = 0.043) expression was greater in preterm than in term males only. Hepatic PRKAG2 expression correlated positively with whole-body insulin sensitivity in males only. Thus, preterm birth at 0.9 of term after betamethasone does not impair insulin sensitivity or secretion in adult sheep, and has sex-specific effects on gene expression of the insulin signalling pathway. Hence, the increased risk of T2D in preterm humans may be due to factors that initiate preterm delivery or in early neonatal exposures, rather than preterm birth per se.

scholarly journals PPARGC1A Gene Promoter Methylation as a Biomarker of Insulin Secretion and Sensitivity in Response to Glucose Challenges

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2790
Author(s):  
José L. Santos ◽  
Bernardo J. Krause ◽  
Luis Rodrigo Cataldo ◽  
Javier Vega ◽  
Francisca Salas-Pérez ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Gene Promoter ◽  
Tolerance Test ◽  
Proximal Promoter ◽  
Oral Glucose ◽  
Intravenous Glucose ◽  
Cpg Sites

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.

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