glucagon-like-peptide-1 and Diabetes--Gestational

Gestational diabetes mellitus (GDM) is a metabolic disease affecting an increasing number of pregnant women around the world. It is not only associated with numerous perinatal complications but also has long-term consequences impacting maternal health and fetal development. To prevent them, it is important to keep glucose levels under control. As much as 15-30% of GDM patients will require treatment with insulin, metformin, or glyburide. With that in mind, it is crucial to keep searching for novel and improved pharmacotherapies. Nowadays, there are ongoing studies investigating the use of other groups of drugs that have proven successful in the treatment of T2DM. Glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor are among the drugs targeting the incretin system and are currently receiving significant attention. The aim of our review is to demonstrate the potential of these medications in treating GDM and preventing its later complications. It seems that both groups may be successful in the GDM management used alone or as an addition to better-known drugs, including metformin and glyburide. However, more clinical trials are needed to confirm their importance in GDM treatment and to demonstrate effective therapeutic strategies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glyburide; Humans; Hypoglycemic Agents; Incretins; Metformin; Pregnancy

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diabetic Retinopathy; Epigenesis, Genetic; Female; Fetal Development; Genetic Predisposition to Disease; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Life Style; Liver; Muscle, Skeletal; Myocardium; Obesity; Prediabetic State; Pregnancy

All forms of diabetes are increasing in prevalence, but with the advent of the obesity epidemic, we now face the prospect of an increasing number of women conceiving whilst taking traditional oral antidiabetic agents (OADs). This is also further complicated by the availability of new incretin-based therapies, the dipeptidylpeptidase-4 (DPP-IV) inhibitors and glucagon-like-1 receptor (GLP-1R) analogues. Original concerns regarding the use of such OADs have meant that diet control and insulin has been the mainstay of treatment for hyperglycaemia during pregnancy. However, recent NICE guidelines have suggested a role for oral antidiabetic agents. Safety is of paramount concern, especially in pregnancy, and this review will discuss the evidence to date.

Topics: Diabetes, Gestational; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Pregnancy; Thiazolidinediones

Diabetes can be classified as type 1, type 2, and gestational diabetes mellitus (GDM). It has been reported that children born from mothers with GDM present motor impairment, however, underlying mechanisms of GDM-induce fetal neurological diseases remain unknown. In this study, NOD (nonobese diabetic) mice were used to construct the GDM model; after 2 weeks of gestation, thalamocortical axon development of fetal was evaluated by immunofluorescence. PCR of LRRC4C was used to confirm axon development of the thalamus cortex. RNA array was used to predict possible targets affected by GDM during fetal neurodevelopment. Western blot was used to investigate the underlying mechanism, PI3K inhibitor, and MAPK inhibitor was used to determine key pathway involved in this model, in vitro axonal growth was evaluated using neural stem cells, tactile sensory behavior of offspring was assessed to confirm neurological influence further. The result shown that maternal diabetes significantly suppressed axonal development of fetal thalamus cortex, PCR array of GDM fetal brain indicated that upregulation of GLP-1R compared with normal fetal, ELISA confirmed that GLP-1 level was decreased in GDM maternal serum compared with that of wild type pregnant mice. In vitro study observed enhanced axonal elongation after supplements of GLP-1 analog, GLP-1 analog PI3K-dependently active ROCK1 activity, IP injection of GLP-1 analog could partly reverse GDM-induced suppression of fetal thalamocortical axon development and improve tactile sensory behavior of GDM offspring. Our study provided a novel mechanism of GDM induced-neurological diseases and predicted GLP-1 as possible prevention supplement during gestation.

Topics: Animals; Diabetes, Gestational; Female; Fetus; Glucagon-Like Peptide 1; Humans; Mice; Mice, Inbred NOD; Phosphatidylinositol 3-Kinases; Pregnancy; rho-Associated Kinases

Pregnant women with obesity are more likely to deliver infants who are large for gestational age (LGA). LGA is associated with increased perinatal morbidity and risk of developing metabolic disease later in life. However, the mechanisms underpinning fetal overgrowth remain to be fully established. Here, we identified maternal, placental, and fetal factors that are associated with fetal overgrowth in pregnant women with obesity. Maternal and umbilical cord plasma and placentas were collected from women with obesity delivering infants who were LGA (n=30) or appropriate for gestational age (AGA, n=21) at term. Maternal and umbilical cord plasma analytes were measured using multiplex sandwich assay and ELISA. Insulin/mechanistic target of rapamycin (mTOR) signaling activity was determined in placental homogenates. Amino acid transporter activity was measured in isolated syncytiotrophoblast microvillous membrane (MVM) and basal membrane (BM). Glucagon-like peptide-1 receptor (GLP-1R) protein expression and signaling were measured in cultured primary human trophoblast (PHT) cells. Maternal plasma glucagon-like peptide-1 (GLP-1) was higher in LGA pregnancies and positively correlated to birthweight. Umbilical cord plasma insulin, C-peptide, and GLP-1 were increased in obese-large for gestational age (OB-LGA) infants. LGA placentas were larger but showed no change in insulin/mTOR signaling or amino acid transport activity. GLP-1R protein was expressed in the MVM isolated from human placenta. GLP-1R activation stimulated protein kinase alpha (PKA), extracellular signal-regulated kinase-1 and-2 (ERK1/2), and mTOR pathways in PHT cells. Our results suggest elevated maternal GLP-1 may drive fetal overgrowth in obese pregnant women. We speculate that maternal GLP-1 acts as a novel regulator of fetal growth by promoting placental growth and function.

Topics: Diabetes, Gestational; Female; Fetal Development; Fetal Macrosomia; Glucagon-Like Peptide 1; Humans; Insulin; Obesity; Placenta; Pregnancy; TOR Serine-Threonine Kinases

Incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) cause increased insulin secretion in non-pregnant adults, but their role in pregnancy, where there are additional metabolically-active hormones from the placenta, is less clear. The aim of the present study was to assess if fasting and post-load incretin concentrations were predictive of pregnancy insulin and glucose concentrations.. Pregnant women (n = 394) with one or more risk factors for gestational diabetes were recruited at 28 weeks for a 75 g oral glucose tolerance test (OGTT). Glucose, insulin, GLP-1 and GIP were measured in the fasting state and 120 min after glucose ingestion.. Fasting plasma GLP-1 concentrations were associated with plasma insulin (standardised β' 0.393 (0.289-0.498), p = 1.3 × 10. These results suggest that the relationship between insulin and incretins is preserved in pregnancy, but that other factors, such as placental hormones or counter-regulatory hormones, may be more important determinants of glycaemia and gestational diabetes aetiology.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Placenta; Pregnancy

Incretins are crucial stimulators of insulin secretion following food intake. Data on incretin secretion and action during pregnancy are sparse.. The aim of the study was to investigate the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes mellitus (GDM).. We analyzed data from the ongoing observational PREG study (NCT04270578).. The study was conducted at the University Hospital Tübingen.. We examined 167 women (33 with GDM) during gestational week 27 ± 2.2.. Subjects underwent 5-point OGTT with a 75-g glucose load.. We assessed insulin secretion and levels of total glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), glicentin, and glucagon during OGTT. Linear regression was used to analyze the relation of GLP-1 and glucose with insulin secretion and the association of incretin levels on birth outcome.. Insulin secretion was significantly lower in women with GDM (P < 0.001). Postload GLP-1 and GIP were ~20% higher in women with GDM (all P < 0.05) independent of age, body mass index, and gestational age. GLP-1 increase was associated with insulin secretion only in GDM, but not in normal glucose tolerance. Postprandial GLP-1 levels were negatively associated with birth weight.. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. Higher GLP-1 levels might be protective against fetal overgrowth.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Macrosomia; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Pregnancy

Intrauterine exposure to gestational diabetes mellitus (GDM) increases risk for type 2 diabetes (T2D). Ghrelin and GLP-1 have opposite functions in nutritional homeostasis and are associated with insulin secretion, but it is not known if individuals exposed to GDM exhibit dysregulation in these associations.. Test the hypothesis that children exposed to GDM in utero will exhibit dysregulation among ghrelin, GLP-1, and C-peptide (reflecting insulin secretion).. Data from N = 43 children aged 5 to 10 years were included in this secondary analysis of ghrelin, GLP-1, and C-peptide response to a liquid meal test. Repeated measures mixed model analyses were used to measure associations among hormones.. The association of ghrelin and GLP-1 was moderated by GDM group (P < .01), such that ghrelin was inversely associated with GLP-1 in children without GDM exposure, but not for those exposed to GDM. GLP-1 was positively associated with C-peptide in both groups, but the association was stronger in those exposed to GDM (estimate = 1.06 vs 1.01).. Differences in the associations among ghrelin, GLP-1, and C-peptide displayed here suggest novel lines of research about whether the regulation of gut hormones and insulin secretion contribute to obesity and risk for T2D in children exposed to GDM.

Topics: Child; Child, Preschool; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Pregnancy; Prenatal Exposure Delayed Effects

Defects in incretin have been shown to be related to the pathogenesis of type 2 diabetes. Whether such a deficiency happens in gestational diabetes mellitus (GDM) remains to be confirmed. We assessed the association of fasting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) with GDM. We also studied the longitudinal circulation of these peptides during pregnancy and afterwards.. 53 women with GDM (30 managed with diet only (GDM-diet) and 23 treated with insulin (GDM-insulin)) and 43 pregnant women with normal glucose tolerance (NGDM) were studied, with GIP and GLP-1 levels measured at 24-28 weeks (E1), prior (E2) and after (E3) delivery, and postpuerperium (E4).. Basal GIP was shown to be low in GDM groups compared to NGDM in E1, and in E4 for GDM-diet. GLP-1 was low in GDM groups during pregnancy and afterwards. At E1, serum GIP and GLP-1 were inversely associated with GDM and participants with lower levels of GIP (<0.23 ng/mL) and GLP-1 (<0.38 ng/mL) had a 6 (95% CI 2.5-14.5)- and 7.6 (95% CI 3.0-19.1)-fold higher risk of developing GDM compared with the higher level, respectively. In the postpuerperium, when there is a drop in. There is an independent, inverse association between fasting incretins and higher risk of GDM. Furthermore, lowered levels of these peptides may play an important role in the abnormality of glucose regulation following pregnancy.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes, Gestational; Diet Therapy; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Logistic Models; Longitudinal Studies; Postpartum Period; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies

The influential role of incretin hormones on glucose metabolism in patients with a history of Roux-en-Y gastric bypass (RYGB) has been investigated thoroughly, but there has been little examination of the effect of incretins and ectopic lipids on altered glucose profiles, especially severe hypoglycemia in pregnant women with RYGB.. In this prospective clinical study, an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and continuous glucose monitoring (CGM) were conducted in 25 women with RYGB during pregnancy, 19 of normal weight (NW) and 19 with obesity (OB) between the 24th and the 28th weeks of pregnancy, and 3 to 6 months post-partum. Post-partum, the ectopic lipid content in the liver, heart, and skeletal muscle was analyzed using. RYGB patients presented with major fluctuations in glucose profiles, including a high occurrence of postprandial hyperglycemic spikes and hypoglycemic events during the day, as well as a high risk of hypoglycemic periods during the night (2.9 ± 1.1% vs. 0.1 ± 0.2% in the OB and vs. 0.8 ± 0.6% in the NW groups, p < 0.001). During the extended OGTT, RYGB patients presented with exaggerated expression of GLP-1, which was the main driver of the exaggerated risk of postprandial hypoglycemia in a time-lagged correlation analysis. Basal and dynamic GLP-1 levels were not related to insulin sensitivity, insulin secretion, or beta cell function and did not differ between pregnant women with and without GDM. A lower amount of liver fat (2.34 ± 5.22% vs.5.68 ± 4.42%, p = 0.015), which was positively related to insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR: rho = 0.61, p = 0.002) and beta-cell function (insulinogenic index: rho = 0.65, p = 0.001), was observed in the RYGB group after delivery in comparison to the OB group.. GLP-1 is mainly involved in the regulation of postprandial glucose metabolism and therefore especially in the development of postprandial hypoglycemia in pregnant RYGB patients, who are characterized by major alterations in glucose profiles, and thus in long-term regulation, multiple organ-related mechanisms, such as the lipid content in the liver, must be involved.

Topics: Adult; Anastomosis, Roux-en-Y; Blood Glucose; Diabetes, Gestational; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Lipids; Obesity; Pregnancy

Glucagon-like peptide 1 (GLP-1) levels may be reduced in type 2 diabetes, but whether a similar impairment exists in gestational diabetes mellitus (GDM) has not been established. We studied this in a prospective cohort study of pregnant women (

Topics: Adult; Blood Glucose; Diabetes, Gestational; Female; Gestational Age; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Pregnancy; Prospective Studies; Young Adult

Quantification of changes in glucose and lipid concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and uncomplicated pregnancy and study of their influence on fetal growth.. A prospective study comparing metabolic outcomes in cholestastic and uncomplicated singleton pregnancies was undertaken at two university hospitals in the U.K. and U.S. from 2011-2014. A total of 26 women with ICP and 27 control pregnancies with no prior history of gestational diabetes mellitus were recruited from outpatient antenatal services and followed until delivery. Alterations in glucose, incretins, cholesterol, and triglycerides were studied using a continuous glucose monitoring (CGM) system and/or a standard glucose tolerance test (GTT) in conjunction with GLP-1 and a fasting lipid profile. Fetal growth was quantified using adjusted birth centiles.. Maternal blood glucose concentrations were significantly increased in ICP during ambulatory CGM (P < 0.005) and following a GTT (P < 0.005). ICP is characterized by increased fasting triglycerides (P < 0.005) and reduced HDL cholesterol (P < 0.005), similar to changes observed in metabolic syndrome. The offspring of mothers with ICP had significantly larger customized birth weight centiles, adjusted for ethnicity, sex, and gestational age (P < 0.005).. ICP is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. These findings may have implications regarding the future health of affected offspring.

Topics: Adult; Birth Weight; Blood Glucose; Cholestasis, Intrahepatic; Cholesterol; Diabetes, Gestational; Dyslipidemias; Female; Fetal Development; Fetal Macrosomia; Gestational Age; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Lipids; Male; Metabolic Syndrome; Metabolome; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Triglycerides

Tissue-specific dipeptidyl-peptidase 4 (DPP4) dysregulation has been described in adults with diabetes mellitus. The DPP4 -incretin system has not been studied in foetal life. In this study, DPP4 activity and glucagon-like peptide-1 (GLP-1) levels were assessed in cord blood of neonates born to women with gestational diabetes mellitus (GDM) and nondiabetic controls.. This study has been conducted in two Hungarian and one Austrian centres.. A total of 568 pregnant women were enrolled in the study after their OGTT between the 24th and 28th gestational week. Cord blood samplings with DPP4 activity and GLP-1 level measurements were possible in 270 (DPP4: 159 control, 111 GDM) and 112 (GLP-1: 72 control, 40 GDM) cases. OGTT (24-28th gestational week) and cord blood sampling at delivery were performed. Cord serum DPP4 activity was determined in a continuous monitoring microplate-based kinetic assay, and cord plasma GLP-1 was measured using a fluorescence ELISA method.. Cord serum DPP4 activity was lower in GDM [mean (95% CI): 28.07 U/L (26.32-29.82 U/L)] than in controls [31.61 U/L (29.93-33.29 U/L), MWU P = 0.0015]. Cord plasma active GLP-1 levels were close to the lower detection limit and were not altered in GDM (control: mean = 3.43 pM, 95% CI: 3.04-3.82 pM, GDM: mean = 3.61 pM, 95% CI: 2.96-4.28 pM - MWU test P = 0.6).. Decreased cord serum DPP4 activity in gestational diabetes mellitus might be the result of an adaptive foetal response or an early dysregulation in the entero-insular axis with consequences beyond the incretin system. Cord plasma GLP-1 levels may reflect the missing oral intake with a limited glucose sensing of L cells via the circulation in foetal life.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes, Gestational; Dipeptidyl Peptidase 4; Female; Fetal Blood; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulins; Pregnancy; Pregnancy Outcome

Fetal exposure to maternal diabetes is associated with increased risk of type 2 diabetes mellitus (T2DM) later in life. The pathogenesis of T2DM involves dysfunction of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as hyperglucagonemia.. Our aim was to investigate circulating plasma levels of GLP-1, GIP, and glucagon during the oral glucose tolerance test (OGTT) in adult offspring of women with diabetes in pregnancy.. We conducted a follow-up study of 567 offspring, aged 18-27 years. We included two groups exposed to maternal diabetes in utero: offspring of women with diet-treated gestational diabetes mellitus (O-GDM; n = 163) or type 1 diabetes (O-T1DM; n = 146). Two reference groups were included: offspring of women with risk factors for GDM, but normoglycemia during pregnancy (O-NoGDM; n = 133) and offspring from the background population (O-BP; n = 125). The subjects underwent a 75-g OGTT with venous samples at 0, 30, and 120 minutes.. Fasting plasma levels of GLP-1 were lower in the two diabetes-exposed groups compared to O-BP (O-GDM, P = .040; O-T1DM, P = .008). Increasing maternal blood glucose during OGTT in pregnancy was associated with reduced postprandial suppression of glucagon in the offspring. Lower levels of GLP-1 and higher levels of glucagon during the OGTT were present in offspring characterized by overweight or prediabetes/T2DM at follow-up, irrespective of exposure status.. Lower levels of fasting GLP-1 and impaired glucagon suppression in adult offspring exposed to maternal diabetes during pregnancy are diabetogenic traits that may contribute to glucose intolerance in these persons, but further investigations are needed.

Topics: Adolescent; Adult; Adult Children; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Follow-Up Studies; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Young Adult

Variation in TCF7L2 gene is associated with type 2 diabetes and with gestational diabetes mellitus in several populations, but there are no data in Mexican women with gestational diabetes mellitus. In this study, we examined metabolic and hormonal measurements as well as TCF7L2 genetic variants.. We selected 108 pregnant women with normal glucose tolerance and 90 with gestational diabetes mellitus according to 2010 American Diabetes Association criteria matched for gestational week. We collected data on blood pressure, body mass index (BMI) and concentrations of blood glucose, HbA1c , lipids profile, insulin and glucagon-like peptide-1 (GLP-1). The genotyping of rs7903146 and rs12255372 polymorphisms were made with polymerase chain reaction-restriction fragment length polymorphism.. Actual and pre-gestational BMI, fasting glucose and HbA1c were higher (p < 0.001), and high-density lipoprotein cholesterol was lower (p < 0.02) in gestational diabetes mellitus women than euglycemic women. No significant differences were found for lipids, insulin and homeostasis model assessment-insulin resistance. Gestational diabetes mellitus women had high GLP-1 levels (32 vs 24, p < 0.004) and decreased β-cell function (266 vs 438, p < 0.001). The frequency of rs12255372 risk allele in gestational diabetes women was significantly higher than that in euglycemic women (χ²  = 8.96; p < 0.003) and confers a risk for gestational diabetes mellitus (OR = 9.1, 95% CI 2.8-29, p < 0.0002; and OR = 4.3, 95% CI 1.6-11.4, p < 0.003 based on dominant and co-dominant model, respectively). The generalized linear model showed that low beta function, high pre-gestational BMI and rs12255372 risk allele are independently associated with gestational diabetes.. The elevated GLP-1 levels in gestational diabetes women suggested some abnormality in insulin secretion. The low β-cell function, high pre-gestational BMI and rs12255372 risk allele are risk factors independently associated with the development of gestational diabetes.

Topics: Adult; Alleles; Body Mass Index; Cholesterol, HDL; Cross-Sectional Studies; Diabetes, Gestational; Female; Genetic Association Studies; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Maternal Nutritional Physiological Phenomena; Mexico; Overweight; Polymorphism, Single Nucleotide; Pregnancy; Transcription Factor 7-Like 2 Protein; Young Adult

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

Topics: Animals; Animals, Newborn; Blood Glucose; Cell Proliferation; Diabetes, Gestational; Disease Models, Animal; Female; Glucagon; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Organ Size; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Weight Gain

What is already known about this subject Children born to women with gestational diabetes have greater risk for obesity. Obesity in adults and children is associated with blunted postprandial gut hormone responses. What this study adds Children of women with gestational diabetes have a blunted postprandial response of GLP-1. Children of women with gestational diabetes have high fasting PYY concentrations.. Intrauterine exposure to gestational diabetes mellitus (GDM) increases risk for obesity. Obesity is associated with a blunted postprandial gut hormone response, which may impair satiety and thereby contribute to weight gain. The postprandial response of gut hormones among children of women with GDM has not previously been investigated.. To examine whether children of women with GDM have suppressed peptide-tyrosine-tyrosine (PYY) and glucagon-like-peptide-1 (GLP-1), and higher concentrations of ghrelin, following a meal challenge. A secondary objective was to investigate associations of these hormones with children's free-living energy intake.. Children (n = 42) aged 5-10 years were stratified into two groups: offspring of GDM mothers (OGD) and of non-diabetic mothers (CTRL). Body composition was measured by dual-energy X-ray absorptiometry, and circulating PYY, GLP-1 and total ghrelin were measured during a liquid meal challenge. Energy intake was assessed by three 24-h diet recalls.. Between-groups analyses of fasting and incremental area under the curve (AUC) found no differences in ghrelin. Incremental AUC for GLP-1 was greater among the CTRL vs. OGD (P < 0.05), and fasting PYY, but not incremental AUC, was higher among OGD vs. CTRL (P < 0.01). Associations of fasting and incremental AUC for each gut hormone with children's usual energy intake did not differ significantly by group.. Further research is needed to more fully examine the potential role of postprandial GLP-1 suppression and high-fasting PYY concentrations on the feeding behaviour and risk for obesity among children exposed to GDM in utero.

Topics: Adult; Area Under Curve; Blood Glucose; Body Mass Index; Child; Child, Preschool; Diabetes, Gestational; Energy Intake; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Pediatric Obesity; Peptide YY; Postprandial Period; Pregnancy; Prenatal Exposure Delayed Effects

We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established.. Eleven women with GDM [plasma glucose (PG) concentration at 120 min after a 75-g oral glucose tolerance test (OGTT): 10.0 ± 0.9 mM (mean ± SD); age: 31 ± 6 years; body mass index (BMI): 31.6 ± 6.4 kg/m(2) ; haemoglobin A1c (HbA1c): 5.6 ± 0.5%] and eight pregnant women with NGT (PG(120 min), OGTT : 5.7 ± 0.7 mM; age: 28 ± 3 years; BMI: 29.7 ± 5.4 kg/m(2) ; HbA1c: 5.4 ± 0.3%) were investigated with a 4-h liquid meal test during third trimester (TT) and 3-4 months postpartum (PP). All patients with GDM re-established NGT following delivery.. Pregnancy was associated with low postprandial GLP-1 responses. Patients with GDM exhibited reduced postprandial GLP-1 responses compared to their PP levels [area under curve (AUC): 5.5 ± 1.3 vs. 8.4 ± 3.2 nM × min, p=0.005], but the difference among NGT women (7.3 ± 2.8 vs. 8.8 ± 2.0 nM × min, p=0.066) was not statistically significant. Pregnancy did not influence postprandial responses of the other incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in any of the groups, but GDM patients were characterized by greater postprandial GIP responses during both TT and PP compared to NGT subjects.. Pregnancy is associated with reduced postprandial GLP-1 responses (most pronounced in patients with GDM) that normalize after delivery. In contrast, postprandial GIP responses seem unaffected by pregnancy but is increased in GDM patients.

Topics: Adult; Area Under Curve; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Diabetes, Gestational; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Postpartum Period; Postprandial Period; Pregnancy

Gestational diabetes mellitus (GDM) predisposes women to future development of Type 2 diabetes mellitus (DM2) and the two conditions share similar metabolic alterations. Recent observations suggest that a defective glucose stimulated insulin secretion by glucagon-like peptide-1 (GLP- 1) plays a role in the pathogenesis of DM2. Whether such a defect is impaired in GDM remains to be ascertained.. We have determined GLP-1 secretion in response to oral glucose tolerance test (OGTT) in GDM and normal glucose tolerance (NGT) during and after pregnancy.. 100-g-3h OGTT was performed in 12 GDM and 16 NGT women at 27.3 ± 4.1 weeks of gestation, for determination of plasma GLP-1, glucose, insulin, and C-peptide. Insulin sensitivity (ISI) and insulin secretion (first and second phase); as well as ISI-secretion index (ISSI) were also derived.. NGT and GDM women were comparable for age pre-pregnancy body mass index (BMI) and weight gain. GDM had higher glucose area under the curve (AUC): 27,575.5 ± 3448 vs 20,685.88 ± 2715 mg/dl min (p<0.01), but lower first-phase insulin secretion (993.12±367 vs 1376.61 ± 423, p<0.05) and ISSI compared to controls (3873.23 ± 1185 vs 6232.13 ± 1734, p<0.001). When we examined GLP-1 mean levels in relation to mean glycemic values, GLP-1 secretion was inappropriately low with respect to mean glycemic values in GDM compared to NGT. At follow-up, AUCGLP-1 was significantly lower in post-partum GDM compared to post-partum NGT women (2542 ± 273 vs 10,092 ± 7367 pmol·l-1·min-1, p<0.05, respectively).. Our study suggests that GLP-1 secretion in GDM women is inadequate for the prevailing glycemic levels both in pregnancy and post partum. Moreover, we cannot exclude that other important aspects of the incretin effect may be involved in GDM development.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Diabetes, Gestational; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Middle Aged; Pregnancy; Pregnancy Complications

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetes, Gestational; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liraglutide; Peptides; Pregnancy; Venoms

Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy.. The study group (GDM) consisted of 13 gestational women with diabetes mellitus in whom GDM was diagnosed according to the World Health Organization criteria (75-g oral glucose tolerance test (OGTT)). The control group consisted of 13 pregnant women with normal glucose tolerance (NGT), matched according to age and duration of pregnancy. For all patients, plasma glucose, insulin, GLP-1 and GIP concentrations were evaluated after an OGTT, i.e. at 0, 30, 60, 90 and 120 min after glucose load.. Fasting plasma glucose concentrations were similar in both groups, but the 0-120 min area under the curve (AUC) for glucose was significantly greater in the GDM group than in the NGT group (p < 0.0005). Fasting insulin concentration was higher (p < 0.05) and the 2-h insulin response (AUCtotal) was significantly greater (p = 0.01) in the GDM group than in the NGT group. Insulin resistance was significantly higher in GDM compared with control women (homeostasis model assessment, p = 0.003). Fasting GLP-1 concentrations were higher in the GDM group (p = 0.05), but no differences were observed in GLP-1 response (AUC) between the studied groups. Fasting and stimulated GIP response did not differ between groups at any time of the study (p > 0.05). Positive correlations were observed between fasting GLP-1 and insulin concentration (r = 0.56, p < 0.004) and between fasting GLP-1 and insulin resistance (r = 0.43, p < 0.029).. An impaired secretion of GLP-1 and GIP does not seem to play a major role in the pathogenesis of GDM.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Pregnancy

Women with previous gestational diabetes (pGDM) are at risk of developing Type 2 diabetes. Glucagon-like peptide-1 (GLP-1) potentiates the insulin response to oral glucose, and its secretion is diminished in Type 2 diabetes. The aim of the study was to see if decreased GLP-1 secretion might be an early abnormality in the progression to Type 2 diabetes and would therefore be diminished in women with pGDM.. Eleven women with pGDM and previously documented normal glucose tolerance and 11 control women underwent a 75 g oral glucose tolerance test (OGTT). Circulating plasma glucose, insulin, nonesterified fatty acids (NEFA) and GLP-1 concentrations were sampled.. One of the women with pGDM had impaired glucose tolerance and was excluded from the study. All other women had normal glucose tolerance. The women with pGDM had higher fasting glucose concentrations than controls (5.1; 4.9-5.3 vs. 4.8; 4.4-5.1 mmol/l, median; interquartile range, P = 0.04) and greater circulating glucose area under the curve (AUC) following the oral glucose load (930; 818-1015 vs. 668; 584-737 min x mmol/l, P = 0.0007). Fasting insulin concentrations and total insulin AUC were similar. The initial (0-30 min) insulin response was decreased in the pGDM women (AUC 3981; 2783-4795 vs. 6167; 5009-8145 min x pmol/l, P = 0.05). The initial (0-30 min) GLP-1 response was reduced in the pGDM women (AUC 816; 663-984 vs. 1163; 872-2024 min x pmol/l, P = 0.02).. A reduced initial GLP-1 response to oral glucose may therefore be an early abnormality in the progression to Type 2 diabetes.

Topics: Adult; Area Under Curve; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Peptide Fragments; Pregnancy; Protein Precursors; Secretory Rate