Effects of gestational diabetes on human placental glucose uptake, transfer, and utilisation

Aims/hypothesis. Gestational diabetes is associated with complications for the offspring before, during and after delivery. Poor maternal glucose control, however, is a weak predictor of these complications. Given its position at the interface of the maternal and fetal circulations, the placenta possibly plays a crucial part in protecting the fetus from adverse effects from the maternal diabetic milieu. We hypothesised that gestational diabetes may result in changes in placental function, particularly with respect to the uptake, transfer, and/or utilisation of glucose. We aimed to examine glucose transport and utilisation in intact human placental lobules from women with gestational diabetes and those from normal pregnancies. Method. Dual perfusion of an isolated placental lobule was done on placentae from diet treated gestational diabetic (n = 7) and normal pregnant patients (n = 9) using maternal glucose concentrations of 4, 8, 16 and 24 mmol/l in random order over a 4-h experiment. Results were expressed in μmol · min^–1· g^–1. Results. d-glucose uptake from the maternal circulation (control 0.492 vs gestational diabetes mellitus 0.248, at 8 mmol/l maternal glucose), d-glucose utilisation by the placenta (0.255 vs 0.129), d-glucose transfer to the fetal circulation (direct 0.979 vs 0.402; net transfer 0.269 vs 0.118) and l-lactate maternal release into both the fetal (0.052 vs 0.042) and maternal (0.255 vs 0.129) circulation were significantly reduced during in vitro perfusion of placentae from patients with gestational diabetic pregnancies. Transfer of ³H-l-glucose also significantly reduced in the diabetic group (8.1 % vs 2.6 %). Conclusion/interpretation. These results suggest that placental transport and metabolism of d-glucose is altered during gestational diabetes. [Diabetologia (2000) 43: 576–582] Received: 21 October 1999 and in revised form: 15 December 1999     

Placental lipid transport and content in response to maternal overweight and gestational diabetes mellitus in human term placenta

Background and aimsPlacental lipid transport is altered in women with high prepregnancy body mass index (pre-BMI) or gestational diabetes (GDM), which consequently affects foetal growth. However, the interaction of maternal overweight (OW) and GDM on placental lipid metabolism and possible adaptations are less studied. We aimed to examine whether maternal OW or GDM is the main factor disrupting placental lipid processing in human term placenta.Methods and resultsA total of 152 lean (18.5 ≤ pre-BMI ≤ 23.9 kg/m²) and OW (24 ≤ pre-BMI ≤ 27.9 kg/m²) pregnant women with or without GDM with a scheduled delivery by caesarean section were recruited. Maternal venous blood samples were used to measure metabolic parameters during pregnancy. Term placentas and cord blood were collected at delivery to determine placental lipid metabolism and foetal circulating lipid levels. Maternal OW significantly increased the placental mRNA expression of genes involved in lipid metabolism (FAT/CD36, FATP1, FATP4, FATP6, and PPAR-α), elevated placental lipid content (triglyceride, cholesterol), enhanced placental mTORC1-rpS6 and ERK1/2 signalling, increased cord blood insulin levels and birth weight. Neonatal birth weight was positively correlated with maternal pre-BMI, placental ERK1/2 signalling and cord blood insulin. There was an interaction between OW and GDM in regulating key placental fuel transport and storage gene expression (LPL, FATP6, FABP7, PPAR-α, PPAR-β, PPAR-γ, IR-β, GLUT1, SNAT2, SNAT4, and LAT1).ConclusionMaternal OW mainly affects placental lipid metabolism, which may contribute to foetal overgrowth and may impact long-term offspring health. GDM plays a less significant role in affecting placental lipid transfer and other mechanisms may be involved.     

Continuous glucose monitoring metrics and pregnancy outcomes in insulin-treated diabetes: A post-hoc analysis of the GlucoMOMS trial

Aim

To investigate the association between continuous glucose monitoring (CGM) metrics and perinatal outcomes in insulin-treated diabetes mellitus in pregnancy.

Materials and Methods

In a post-hoc analysis of the GlucoMOMS randomized controlled trial, we investigated the association between the metrics of an offline, intermittent CGM, glycated haemoglobin (HbA1c) and perinatal outcomes per trimester in different types of diabetes (type 1, 2 or insulin-treated gestational diabetes mellitus [GDM]). Data were analysed using multivariable binary logistic regression. Outcomes of interest were neonatal hypoglycaemia, pre-eclampsia, preterm birth, large for gestational age (LGA) and Neonatal Intensive Care Unit (NICU) admission. The glucose target range was defined as 3.5–7.8 mmol/L (63–140 mg/dL).

Results

Of the 147 participants (N = 50 type 1 diabetes, N = 94 type 2 diabetes/insulin-treated GDM) randomized to the CGM group of the GlucoMOMS trial, 115 participants had CGM metrics available and were included in the current study. We found that, in pregnancies with type 1 diabetes, a higher second trimester mean glucose was associated with LGA (odds ratio 2.6 [95% confidence interval 1.1–6.2]). In type 2 and insulin-treated gestational diabetes, an increased area under the curve above limit was associated with LGA (odds ratio 10.0 [95% confidence interval 1.4–72.8]). None of the CGM metrics were associated with neonatal hypoglycaemia, pre-eclampsia, shoulder dystocia, preterm birth and NICU admission rates for pregnancies complicated by any type of diabetes.

Conclusion

In this study, in type 2 diabetes or insulin-treated GDM, the glucose increased area under the curve above limit was associated with increased LGA. In type 1 diabetes, the mean glucose was the major determinant of LGA. Our study found no evidence that other CGM metrics determined adverse pregnancy outcomes.     

Relationships between gut microbiota,plasma glucose and gestational diabetes mellitus

Aims/IntroductionTo investigate the changes in the gut microbiome in the second trimester of pregnancy associated with later‐diagnosed gestational diabetes mellitus (GDM) and their relationship with fasting serum levels of metabolites, especially glucose.Materials and MethodsWe carried out a case–control study with 110 GDM patients and 220 healthy pregnant women who provided fecal samples for 16S ribosomal ribonucleic acid sequencing in the second trimester of pregnancy.ResultsOur results showed that GDM patients had lower α‐diversity that was significantly associated with glycemic traits. Principal coordinates analysis showed significantly different microbial communities, as within GDM patients, seven genera within the phylum Firmicutes and two within the phylum Actinobacteria were significantly decreased, and four genera within phylum Bacteroidetes were increased. In addition, microbiota co‐occurrence network analysis was carried out, and decreased genera within the phylum Firmicutes in GDM patients showed a significant negative correlation with oral glucose tolerance test values. Finally, microbial gene functions related to glycan biosynthesis and metabolism were found to be enriched in GDM patients.ConclusionsOur results show the relationship between changed gut microbiota composition in the second trimester of pregnancy before the diagnosis of GDM and fasting serum levels of metabolites, which might inform the diagnosis, prevention and treatment of GDM.     

Hyperglycaemia-induced subcellular redistribution of GLUT1 glucose transporters in cultured human term placental trophoblast cells

Aims/hypothesis. We have recently shown that hyperglycaemia down-regulates the GLUT1 glucose transport system of term placental trophoblast. The reduction in GLUT1 protein alone was, however, not sufficient to explain the decrease in net glucose uptake, suggesting additional mechanisms. Therefore, we hypothesised that hyperglycaemia in vitro leads to a GLUT1 translocation from the trophoblast surface to intracellular sites.¶Methods. This was tested in our study by determining the subcellular distribution of GLUT1 in human term placental trophoblast (n = 5 placentas) cultured for 48 h with 5 compared with 25 mmol/l d-glucose in vitro using immunogold labelling.¶Results. Electron microscopic examination of cell profiles showed that 73 % of total GLUT1 molecules reside in the trophoblast plasma membrane under basal conditions. The reduced GLUT1 expression (–20 %; p < 0.05) after culture of the cells with 25 mmol/l glucose was accompanied by an internalisation of plasma membrane GLUT1, resulting in a loss of 40 % (p < 0.05) in cell surface transporter labelling. Western blotting identified a characteristically broad band between 55–65 kDa, confirming the specificity of the GLUT1 antiserum.¶Conclusion/interpretation. We postulate that in addition to down-regulating human GLUT1 protein concentrations, glucose exerts its autoregulatory effect on hexose transport in term placental trophoblast by altering GLUT1 partitioning between the plasma membrane and intracellular sites in favour of the latter. [Diabetologia (2000) 43: 173–180]     

A combination of HbA1c, fasting glucose and BMI is effective in screening for individuals at risk of future type 2 diabetes: OGTT is not needed

Objective. To identify a screening model that predicts high risk of future type 2 diabetes and is useful in clinical practice. Design and methods. Incident case‐referent study nested within a population‐based health survey. We compared screening models with three risk criteria and calculated sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and attributable proportion. We used fasting plasma glucose (FPG) alone or with an oral glucose tolerance test (OGTT), glycosylated haemoglobin A (HbA1c) (normal range 3.6–5.3%), body mass index (BMI), triglycerides and family history of diabetes (FHD). Setting. Participants in a health survey at all primary care centres (n = 33 336) and subjects with diagnosed type 2 diabetes in primary and hospital care (n = 6088) in Umeå during 1989–2001. Subjects. Each of the 164 subjects who developed clinically diagnosed type 2 diabetes (median time to diagnosis of 5.4 years) and 304 sex‐ and age‐matched referents without diabetes diagnosis. Results. Screening models with at least one criterion present had sensitivities of 0.90–0.96, specificities of 0.43–0.57 and PPVs of 8–9%. Combinations of the criteria, FPG ≥ 6.1 mmol L^?1 (capillary plasma), HbA1c ≥ 4.7% and BMI ≥ 27 in men and BMI ≥ 30 in women, had sensitivities, specificities and PPVs of 0.66%, 0.93% and 32%, and 0.52%, 0.97% and 46% respectively. Using FHD as one of three risk criteria showed comparable results. Addition of triglycerides or OGTT did not improve the prediction. Conclusions. The combination of HbA1c, FPG and BMI are effective in screening for individuals at risk of future clinical diagnosis of type 2 diabetes. OGTT or FHD is not necessary.     

Abnormal glucose transport and GLUT1 cell-surface content in fibroblasts and skeletal muscle from NIDDM and obese subjects

Summary Glucose transport and GLUT1 expression were studied in fibroblasts from 7 lean and 5 obese non-insulin-dependent diabetic (NIDDM) subjects with at least 2 NIDDM first-degree relatives and from 12 lean and 5 obese non-diabetic subjects with no family history of diabetes. The obese individuals also had a strong family history of obesity. Fibroblasts from all of the subjects exhibited no difference in insulin receptor binding, autophosphorylation, and kinase and hexokinase activity. At variance, basal 2-deoxyglucose (2-DG) uptake and ³H-cytochalasin B binding were 50 % increased in cells from individuals with NIDDM (p < 0.001) and/or obesity (p < 0.01) as compared to the lean non-diabetic subjects. Insulin-dependent (maximally stimulated – basal) 2-DG uptake and cytochalasin B binding were decreased three-fold in cells from the diabetic and/or obese subjects (p < 0.01). GLUT1 mRNA and total protein levels were comparable in fibroblasts from all the groups. However, basal GLUT1 cell-surface content was 50 % greater in fibroblasts from the NIDDM and/or obese subjects as compared to the lean non- diabetic individuals while insulin-dependent GLUT1 recruitment at the cell surface was diminished threefold. Increased basal GLUT1 content in the plasma membrane was also observed in skeletal muscle of 4 NIDDM and 3 non-diabetic obese individuals (p < 0.05 vs the lean non diabetic subjects). Basal 2-DG uptake in fibroblasts from diabetic/obese individuals and lean control subjects strongly correlated with the in vivo fasting plasma insulin concentration of the donor. A negative correlation was demonstrated between the magnitude of insulin-dependent glucose uptake by the fibroblasts and plasma insulin levels in vivo. We conclude that a primary abnormality in glucose transport and GLUT1 cell-surface content is present in fibroblasts from NIDDM and obese individuals. The abnormal GLUT1 content is also present in skeletal muscle plasma membranes from NIDDM and obese individuals. [Diabetologia (1997) 40: 421–429] Received: 9 August 1996 and in final revised form: 11 December 1996     

The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy

Background and aims

Women with gestational diabetes mellitus (GDM) have an enhanced cardiovascular risk factor profile at 3-months postpartum and an elevated risk of future cardiovascular disease, as compared to their peers. Recently, it has emerged that even mild dysglycemia on antepartum oral glucose tolerance test (OGTT) predicts an increased risk of future cardiovascular disease, although it is not known whether there exists an identifiable high-risk subgroup within this patient population. Since gestational impaired glucose tolerance (GIGT) due to isolated hyperglycemia at 1-h during the OGTT (1-h GIGT) bears metabolic similarity to GDM, we hypothesized that, like GDM, 1-h GIGT may predict a high-risk postpartum cardiovascular phenotype.

Methods and results

In this prospective cohort study, 485 women underwent antepartum OGTT, followed by cardiovascular risk factor assessment at 3-months postpartum. The antepartum OGTT identified 4 gestational glucose tolerance groups: GDM (n = 137); 1-h GIGT (n = 39); GIGT at 2- or 3-h (2/3-h GIGT)(n = 50); and normal glucose tolerance (NGT)(n = 259). After adjustment for age, ethnicity, breastfeeding and waist circumference, mean levels of the following cardiovascular risk factors progressively increased from NGT to 2/3-h GIGT to 1-h GIGT to GDM: LDL cholesterol (p = 0.0026); total cholesterol:HDL (p = 0.0030); apolipoprotein B (p = 0.004); apolipoprotein B:apolipoprotein A1 (p = 0.026); leptin (p = 0.018); and C-reactive protein (p = 0.011).

Conclusions

Amongst women without GDM, 1-h GIGT predicts an enhanced postpartum cardiovascular risk factor profile. It thus emerges, that amongst young women with mild dysglycemia in pregnancy, those with 1-h GIGT may comprise an unrecognized patient population at risk for future cardiovascular disease.     

Measurement of glucose metabolism and insulin secretion during normal pregnancy and pregnancy complicated by gestational diabetes

Summary Gestational diabetes affects 2–3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2–3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6, 6-²H₂]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose K_d) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16±0.11 vs 1.78±0.23%/min; p<0.05) and post-partum (1.47±0.22 vs 2.59±0.43%/min; p<0.05) and increased significantly in the control women after delivery (p<0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p<0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p<0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2±42.7 pmol/kg) compared with post-partum values (58.3±25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5±9.3 pmol/kg) and after delivery (57.7±15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.Abbreviations BMI Body mass index - GCMS gas chromatography mass spectrometry - GDM gestational diabetes mellitus - HOMA homeostasis model assessment - IVGTT intravenous glucose tolerance test - OGTT oral glucose tolerance test - Sab above basal insulin secretion - Sb basal insulin secretion - K_d glucose disappearance - CV coefficient of variation - AIR_glucose acute insulin response to glucose - SI insulin sensitivity index - SG glucose effectiveness     

Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients

Aims/hypothesis: We aimed to examine the mechanisms by which rosiglitazone improves glycaemic control in Type II (non-insulin-dependent) diabetic patients. Methods: Altogether 29 diet-treated diabetic patients were assigned at random to rosiglitazone, 8 mg/day (n = 15), or placebo (n = 14) for 12 weeks. Patients received 75 g OGTT and two-step euglycaemic insulin (40 and 160 mU/m²min) clamp with 3-³H-glucose, ¹⁴C-palmitate and indirect calorimetry. Results: After 12 weeks, rosiglitazone reduced fasting plasma glucose (195 ± 11 to 150 ± 7 mg/dl, p < 0.01), mean plasma glucose (PG) during OGTT (293 ± 12 to 236 ± 9 mg/dl, p < 0.01), and HbA_{1 c} (8.7 ± 0.4 to 7.4 ± 0.3 %, p < 0.01) without changes in plasma insulin concentration. Basal endogenous glucose production (EGP) declined (3.3 ± 0.1 to 2.9 ± 0.1 mg/kg FFM · min, p < 0.05) and whole body glucose metabolic clearance rate increased after rosiglitazone (first clamp step: 2.8 ± 0.2 to 3.5 ± 0.2 ml/kg FFM · min, p < 0.01; second clamp step: 6.7 ± 0.6 to 9.2 ± 0.8, p < 0.05) despite increased body weight (86 ± 4 to 90 ± 4 kg, p < 0.01) and fat mass (33 ± 3 to 37 ± 3 kg, p < 0.01). Fasting plasma non-esterified fatty acid (NEFA) (735 ± 52 to 579 ± 49 μEq/l, p < 0.01), mean plasma NEFA during OGTT (561 ± 33 to 424 ± 35, p < 0.01), and basal NEFA turnover (18.3 ± 1.5 to 15.5 ± 1.2 μEq/kg FM · min, p < 0.05) decreased after rosiglitazone. Changes in EPG and mean plasma glucose (PG) during OGTT correlated with changes in basal EGP (r = 0.54; r = 0.58), first EGP (r = 0.36; r = 0.41), first MCR (r = –0.66; r = –0.68), second MCR (r = –0.49; r = –0.54), fasting plasma NEFA (r = 0.53; r = 0.49), and NEFA during OGTT (r = 0.66; r = 0.66). Conclusion/interpretation: Rosiglitazone increases hepatic and peripheral (muscle) tissue insulin sensitivity and reduces NEFA turnover despite increased total body fat mass. These results suggest that the beneficial effects of rosiglitazone on glycaemic control are mediated, in part, by the drug's effect on NEFA metabolism. [Diabetologia (2001) 44: 2210–2219] Received: 20 May 2001 and in revised form: 9 August 2001     

内脂素与肥胖和糖代谢异常的关系

目的 探讨内脂素与肥胖和糖代谢异常的关系.方法 根据受检者的血糖、病程和肥胖程度分为正常糖耐量(NGT组)、糖调节受损(IGR组)、初诊2型糖尿病(T2DM,A组)、已诊T2DM(B组)、肥胖组和非肥胖组,用ELISA法测定各组空腹血浆内脂素,分析其与体质量指数、腰围(WC)、腰臀比、血糖、血脂、血压、真胰岛素、胰岛素抵抗指数和胰岛β细胞功能指数等关系.结果 A、B组内脂素水平明显高于NGT组(P<0.05,<0.01),B组高于A组(P<0.05),肥胖组高于非肥胖组(P<0.01).内脂素水平与糖化血红蛋白、WC呈独立正相关,与糖负荷后2h胰岛素呈独立负相关.结论 血浆内脂素与肥胖和糖代谢状态有关,可能在T2DM发病中起重要作用.     

Placental maternally expressed gene 3 differentially methylated region methylation profile is associated with maternal glucose concentration and newborn birthweight

Aims/IntroductionEmerging evidence shows that epigenetic modifications occurring during fetal development in response to intrauterine exposures could be one of the mechanisms involved in the early determinants of adult metabolic disorders. This study aimed to investigate whether the placental maternally expressed gene 3 (MEG3) deoxyribonucleic acid (DNA) methylation profile is associated with maternal gestational diabetes mellitus status and newborn birthweight.Materials and MethodsSamples for measurement were collected from 23 women with gestational diabetes mellitus and 23 healthy controls. MEG3 gene expression and DNA methylation levels were assessed using quantitative real‐time polymerase chain reaction and MethylTargetTM, respectively. Pearson correlation analyses were used to examine associations between placental DNA methylation levels and clinical variables of interest. The associated results were adjusted by multivariate linear regression for maternal age, body mass index, height, gestational age and newborn sex as confounders.ResultsWe found that the DNA methylation levels in the MEG3 differentially methylated region were significantly different between the gestational diabetes mellitus and control groups on the maternal side of the placenta (40.64 ± 2.15 vs 38.33 ± 2.92; P = 0.004). Furthermore, the mean MEG3 DNA methylation levels were correlated positively with maternal fasting glucose concentrations (R = 0.603, P < 0.001) and newborn birthweight (R = 0.568, P < 0.001).ConclusionsThe placental DNA methylation status in the MEG3 differentially methylated region was correlated with maternal glucose concentrations and newborn birthweight. These epigenetic adaptations might contribute to late‐onset obesity, underlining the adverse intrauterine environment.     

Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM

Summary We investigated the response of the glucose transport system to insulin, in the presence of ambient glucose concentrations, in isolated skeletal muscle from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) (age, 55±3 years, BMI 27.4±1.8 kg/m²) and seven healthy control subjects (age, 54±3 years, BMI 26.5±1.1 kg/m²). Insulin-mediated whole body glucose utilization was similar between the groups when studied in the presence of ambient glucose concentrations (approximately 10 mmol/l for the NIDDM patients and 5 mmol/l for the control subjects). Samples were obtained from the vastus lateralis muscle, by means of an open muscle biopsy procedure, before and after a 40-min insulin infusion. An increase in serum insulin levels from 54±12 to 588±42 pmol/l, induced a 1.6±0.2-fold increase in glucose transporter protein (GLUT4) in skeletal muscle plasma membranes obtained from the control subjects (p<0.05), whereas no significant increase was noted in plasma membrane fractions prepared from NIDDM muscles, despite a similar increase in serum insulin levels. At concentrations of 5 mmol/l 3-O-methylglucose in vitro, insulin (600 pmol/l) induced a 2.2-fold (p<0.05) increase in glucose transport in NIDDM muscles and a 3.4-fold (p<0.001) increase in the control muscles. Insulin-stimulated 3-O-methylglucose transport was positively correlated with whole body insulin-mediated glucose uptake in all participants (r=0.78,p<0.001) and negatively correlated with fasting plasma glucose levels in the NIDDM subjects (r=0.93,p<0.001). Muscle fibre type distribution and capillarization were similar between the groups. Our results suggest that insulin-stimulated glucose transport in skeletal muscle from patients with NIDDM is down-regulated in the presence of hyperglycaemia. The increased flux of glucose as a consequence of hyperglycaemia may result in resistance to any further insulin-induced gain of GLUT4 at the level of the plasma membrane.     

Correlations of serum visfatin and metabolisms of glucose and lipid in women with gestational diabetes mellitus

Aims/Introduction

Visfatin is a newly discovered adipocytokine hormone, which exerts an insulin‐like effect by binding to the insulin receptor‐1. However, the role of visfatin in human gestational diabetes mellitus (GDM) remains controversial. The purpose of the present study was to investigate the correlation between serum visfatin and metabolism of glucose and lipid in GDM.

Materials and Methods

This was a prospective study. A total of 38 GDM patients and 35 age‐ and body mass index‐matched controls were studied between January 2012 and October 2013. Fasting serum levels of visfatin, fasting plasma glucose, hemoglobin A1c and lipid profile were measured. Two‐tailed t‐tests and Pearson''s correlation coefficient were used to analyze the data.

Results

Perinatal visfatin levels were negatively correlated with fasting plasma glucose, insulin resistance index and triglycerides in controls (r = −0.47, −0.51, −0.57, respectively; P < 0.05), and positively correlated with high‐density lipoprotein cholesterol (r = 0.32, P < 0.05). A positive correlation with visfatin level only appeared in weight gain and body mass index in women with GDM (r = 0.36, 0.45, respectively; P < 0.05).

Conclusions

Visfatin appears to be involved in glucose and lipid metabolism regulation and insulin resistance, suggesting a role in GDM pathogenesis.     

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

Summary The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-³H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 ± 0.6, 15.7 ± 0.7, and 26.3 ± 1.1 μmol/kg · min). In NIDDM (10.5 ± 0.2, 12.1 ± 1.0, and 17.5 ± 1.1 μmol/kg · min), and IDDM (11.2 ± 0.8, 12.9 ± 1.0, and 15.6 ± 1.1 μmol/kg · min) glucose disposal was lower during all three steps (p < 0.05–0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+ 4.4 ± 0.7 μmol/kg · min) only at + 11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+ 3.1 ± 0.7; + 3.5 ± 0.9, and + 10.8 ± 1.7 μmol/kg · min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = + 0.5 ± 1.5; NIDDM = + 0.2 ± 0.6 μmol/kg · min) and non-oxidative glucose metabolism was hampered (IDDM = + 1.8 ± 1.5, + 3.1 ± 1.7, and + 4.3 ± 1.8; NIDDM = + 0.7 ± 0.6, 2.1 ± 0.9, and + 7.0 ± 0.8 μmol/kg · min; p < 0.05–0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. In conclusion: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients. [Diabetologia (1997) 40: 687–697] Received: 20 August 1996 and in revised form: 5 March 1997     

Substrate source utilisation in long-term diagnosed type 2 diabetes patients at rest,and during exercise and subsequent recovery

Aims/hypothesis Disturbances in substrate source metabolism and, more particularly, in fatty acid metabolism, play an important role in the aetiology and progression of type 2 diabetes. However, data on substrate source utilisation in type 2 diabetes are inconclusive. Methods [U-¹³C]palmitate and [6,6-²H₂]glucose tracers were used to assess plasma NEFA and glucose oxidation rates and to estimate the use of muscle- and/or lipoprotein-derived triacylglycerol and muscle glycogen. Subjects were ten male patients who had a long-term (7 ± 1 years) diagnosis of type 2 diabetes and were overweight, and ten matched healthy, male control subjects. Muscle biopsy samples were collected before and after exercise to assess muscle fibre type-specific intramyocellular lipid and glycogen content. Results At rest and during exercise, the diabetes patients had greater values than the controls for palmitate rate of appearance (Ra) (rest, 2.46 ± 0.18 and 1.85 ± 0.20 respectively; exercise, 3.71 ± 0.36 and 2.84 ± 0.20 μmol kg⁻¹ min⁻¹) and rate of disappearance (Rd) (rest, 2.45 ± 0.18 and 1.83 ± 0.20; exercise, 3.64 ± 0.35 and 2.80 ± 0.20 μmol kg⁻¹ min⁻¹ respectively). This was accompanied by significantly higher fat oxidation rates at rest and during recovery in the diabetes patients (rest, 0.11 ± 0.01 in diabetes patients and 0.09 ± 0.01 in controls; recovery, 0.13 ± 0.01 and 0.11 ± 0.01 g/min respectively), despite significantly greater plasma glucose Ra, Rd and circulating plasma glucose concentrations. Furthermore, exercise significantly lowered plasma glucose concentrations in the diabetes patients, as a result of increased blood glucose disposal. Conclusion This study demonstrates that substrate source utilisation in long-term-diagnosed type 2 diabetes patients, in whom compensatory hyperinsulinaemia is no longer present, shifts towards an increase in whole-body fat oxidation rate and is accompanied by disturbances in fat and carbohydrate handling.     

Clinical utility of 1-month postpartum random plasma glucose and glycated hemoglobin combined with pre-pregnancy body mass index for detecting postpartum glucose intolerance in Japanese women with gestational diabetes

During the coronavirus disease 2019 pandemic, the Japanese Society of Diabetes and Pregnancy proposed the use of random plasma glucose and glycated hemoglobin measured 1 month after delivery combined with pre-pregnancy body mass index to detect postpartum glucose intolerance instead of carrying out the oral glucose tolerance test in women with gestational diabetes. We retrospectively evaluated the clinical utility of this strategy to detect postpartum glucose intolerance evaluated by the oral glucose tolerance test after delivery. A total of 275 Japanese women with gestational diabetes were included in the present study. The specificity of 1-month postpartum random plasma glucose and glycated hemoglobin combined with pre-pregnancy body mass index to predict postpartum glucose intolerance was 98.0%, with a negative predictive value of 72.6%. However, sensitivity was 6.4%, with a positive predictive value of 55.6%. In conclusion, this Japanese Society of Diabetes and Pregnancy strategy showed high specificity, but low sensitivity, for detecting glucose intolerance postpartum.     

Gestational diabetes: A link between OGTT,maternal-fetal outcomes and maternal glucose tolerance after childbirth

Background and aimThe relationship among distribution of pathological values at the Oral Glucose Tolerance Test (OGTT), metabolic risk factors and pregnancy outcomes in women with Gestational Diabetes (GDM), has not been clearly identified. We retrospectively compared metabolic and therapeutic parameters, maternal–fetal outcomes and post-partum OGTTs, with respect to the number and distribution of altered values of diagnostic OGTT in pregnancy. Secondly, we assessed whether insulin therapy predictive factors were identifiable.Methods and resultsThis analysis included 602 pregnant women with GDM, followed in Diabetes and Pregnancy Unit of Perugia Hospital from diagnosis to childbirth. All women were diagnosed diabetic upon 75g OGTT, according IADPSG criteria. Women were divided into 3 groups, respect to distribution of diagnostic blood glucose (BG) values at OGTT: Group 1: only fasting BG (OGTT0h); Group 2: 1 and/or 2h (OGTT1-2h); Group 3: both fasting and 1 h and/or 2h (OGTT0+1–2h) BG.Pregnant women with fasting hyperglycemia at OGTT (Groups 1 and 3) had similar metabolic characteristics (weight, prevalence of obesity, gestational weight gain, HbA1c), a greater need for insulin therapy, and a higher risk of impaired glucose tolerance persistence after childbirth, as compared to Group 2. No significant differences were observed in terms of maternal and neonatal outcomes (p > 0.05), except for a greater prevalence of caesarean sections in Group 3.ConclusionThe metabolic characteristics of GDM women are mirrored by OGTT values at diagnosis, but are not associated with adverse pregnancy outcomes. Intensive management and a tailored treatment of GDM improve maternal-neonatal outcomes, regardless of diagnostic values distribution and pre-gestational metabolic characteristics.