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In this pragmatic, randomized trial comparing one-step screening for gestational diabetes mellitus with two-step screening, one-step screening resulted in more diagnoses of gestational diabetes mellitus but did not affect the incidence of adverse perinatal and maternal outcomes.

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity 1 . However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available 2 , then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality 3 , we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test ( P  = 9.8 × 10 −5 ), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D ( P  = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings. Mendelian randomization analyses using genotyping data, gut metagenomic sequence and fecal short-chain-fatty-acid levels from 952 individuals combined with GWAS data show evidence of a causal effect of the gut microbiome on metabolic traits.

Background We piloted a randomised controlled trial (RCT) comparing pregnancy outcomes among women with booking gestational diabetes (GDM) receiving immediate or deferred treatment. Methods Consecutive, consenting women < 20 weeks gestation, with GDM risk factors attending the hospital book-in clinic, completed an oral glucose tolerance test (OGTT). Clinicians were blinded to OGTT results. Women fulfilling World Health Organisation GDM criteria were randomised to either clinic referral /ongoing treatment (Treated Group n  = 11), or no treatment (No Treatment Group n  = 10). Women without ‘Booking GDM’ (‘Decoys’ n  = 58) and those in the No Treatment Group had a repeat OGTT at 24–28 weeks (with GDM treated if diagnosed). Midwives and mothers were asked to complete surveys and attend focus groups before and after the study respectively regarding their experiences and expectations of the study protocol. Results Sufficient women completed each step of the RCT. Gestation at OGTT was late at 18 ± 2 weeks with Treated and No Treatment groups largely similar. At 24–28 weeks gestation, GDM was present in 8/9 (89%) in the No Treatment group and 11/56 (20%) Decoys. NICU admission was highest in the Treated group (36% vs 0% p  = 0.043), largely due to small for gestational age, and Large for Gestational Age babies greatest in the No Treatment group (0% vs 33% p  = 0.030). Conclusion An RCT deferring ‘Booking GDM’ treatment is feasible. Most women with untreated ‘Booking GDM’ in mid 2nd trimester had GDM at 24–28 weeks. Early treatment may have both benefits and harms. A full RCT is needed. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12615000974505. Registered 17th May 2015; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=369100&isReview=true Retrospectively Registered.

Aims/hypothesis The hyperglycaemic clamp technique and the frequently sampled IVGTT are unsuitable techniques to assess beta cell function (BCF) in large cohorts. Therefore, the aim of this study was to evaluate the discriminatory ability of simple OGTT-based BCF indices for prediction of prediabetes (meaning impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. Methods Glucose metabolism status was assessed by 2 h 75 g OGTT at baseline ( n  = 476, mean age 59.2 years, 38.7% women) and after 7 years of follow-up ( n  = 416) in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (1999–2009). Baseline plasma glucose, insulin and C-peptide values during OGTTs were used to calculate 21 simple indices of BCF. Disposition indices (BCF index × Matsuda index), to compensate for the prevailing level of insulin resistance, were calculated for the BCF indices with the best discriminatory abilities. The discriminatory ability of the BCF indices was estimated by the area under the receiver operating characteristics curve (ROC AUC) with an outcome of incident prediabetes ( n  = 73) or type 2 diabetes ( n  = 60 and n  = 18 cases, respectively, in individuals who were non-diabetic or had normal glucose metabolism at baseline). Results For incident prediabetes ( n  = 73), all ROC AUCs were less than 70%, whereas for incident type 2 diabetes, I 30 /I 0 , CP 30 /CP 0 , ΔI 30 /ΔG 30 , ΔCP 30 /ΔG 30 (where I, CP and G are the plasma concentrations of insulin, C-peptide and glucose, respectively, at the times indicated), and corrected insulin response at 30 min had ROC AUCs over 70%. In at-baseline non-diabetic individuals, disposition indices ΔI 30 /ΔG 30 , ΔCP 30 /ΔG 30 and corrected insulin response at 30 min had ROC AUCs of over 80% for incident type 2 diabetes. Moreover, these BCF disposition indices had significantly better discriminatory abilities for incident type 2 diabetes than the Matsuda index alone. Conclusions/interpretation BCF indices reflecting early-phase insulin secretion have the best ability to discriminate individuals who will develop prediabetes and type 2 diabetes. Of these, ΔCP 30 /ΔG 30 , often referred to as the C-peptidogenic index, performed consistently well.

Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. M Matsuda and R A DeFronzo Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7886, USA. Abstract OBJECTIVE: Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. RESEARCH DESIGN AND METHODS: In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. RESULTS: The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. CONCLUSIONS: Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.

Aims To compare the prevalence of GDM and pregnancy outcomes between the one‐step and two‐step methods of universal screening among Thai pregnant women. Methods A randomized controlled trial was conducted on singleton Thai pregnant women at a gestational age of 24–28 weeks. They were randomly assigned to either the one‐step method group (a universal 75‐gm 2‐h oral glucose tolerance test: OGTT) or the two‐step method group (a universal 50‐gm oral glucose challenge test followed by a 100‐gm 3‐h OGTT). The women received standard antenatal care. The prevalence of GDM and obstetric outcomes were compared. Results A total of 143 women meeting the inclusion criteria were randomly allocated into the one‐step group (72 cases) and the two‐step group (71 cases). The prevalence of GDM was significantly higher in the one‐step group than in the two‐step group, with rates of 24/73 (33.3%) vs 8/70 (11.3%); P value 0.002; relative risk of 2.96, 95% CI: 1.43–6.14, respectively. Demographic data and maternal and neonatal outcomes were comparable between the two groups. Conclusions The one‐step method can markedly increase the prevalence of GDM to nearly three times that of the two‐step method, leading to a substantial increase in care costs and burdens without clear benefits. Convincingly, the one‐step method as a new approach may not be suitable for universal screening in a busy antenatal care setting, especially in low‐resource health centers in developing countries or among populations with a high prevalence of GDM. The one‐step method can markedly increase the prevalence of GDM to nearly three times that of the two‐step method, leading to a substantial increase in care costs and burdens without clear benefits. Convincingly, the one‐step method as a new approach may not be suitable for universal screening in a busy antenatal care setting, especially in low‐resource health centers in developing countries or among populations with a high prevalence of GDM.

An independent association exists between sleep apnea and diabetes. Animal models suggest exposure to intermittent hypoxia, a consequence of sleep apnea, results in altered glucose metabolism and fasting hyperglycemia. However, it is unknown if acute exposure to intermittent hypoxia increases glucose concentrations in nondiabetic humans. We hypothesized plasma glucose would be increased from baseline following 3 h of intermittent hypoxia in healthy humans independent of any effect on insulin sensitivity. Eight (7M/1F, 21–34 years) healthy subjects completed two study visits randomized to 3 h of intermittent hypoxia or continuous normoxia, followed by an oral glucose tolerance test. Intermittent hypoxia consisted of 25 hypoxic events per hour where oxygen saturation (SpO2) was significantly reduced (Normoxia: 97 ± 1%, Hypoxia: 90 ± 2%, P < 0.01). Venous plasma glucose concentrations were measured on both visits before and after the 3 h protocol. No changes in plasma glucose were observed from baseline after 3 h of continuous normoxia (5.1 ± 0.2 vs. 5.1 ± 0.1 mmol/L, P > 0.05). In contrast, circulating glucose concentrations were increased after 3 h of intermittent hypoxia when compared to baseline (5.0 ± 0.2 vs. 5.3 ± 0.2 mmol/L, P = 0.01). There were no detectable changes in insulin sensitivity following intermittent hypoxia when compared to continuous normoxia, as assessed by the oral glucose tolerance test (P > 0.05). Circulating glucose is increased after 3 h of intermittent hypoxia in healthy humans, independent of any lasting changes in insulin sensitivity. These novel findings could explain, in part, the high prevalence of diabetes in patients with sleep apnea and warrant future studies to identify underlying mechanisms. Circulating glucose is increased after 3 h of intermittent hypoxia in healthy humans, independent of any lasting changes in insulin sensitivity. These novel findings could explain, in part, the high prevalence of diabetes in patients with sleep apnea and warrant future studies to identify underlying mechanisms.

Background Post transplantation diabetes mellitus (PTDM) is a common and serious complication after renal transplantation with significant morbidity and mortality. Metformin has proven benefits in the general population and might be advantageous in the prevention and management of PTDM. Methods Trans plantation and Diab etes (Transdiab) is a single-centre, unblinded, pilot randomised controlled trial assessing the feasibility, tolerability and efficacy of metformin after renal transplantation in patients with impaired glucose tolerance (IGT). Participants had an oral glucose tolerance test (OGTT) in the 4–12 weeks post-transplantation; those with IGT were randomised to standard care or standard care and metformin 500 mg twice daily and followed up for 12 months. Results Seventy eight patients had an OGTT over 24 months, 25 of them had IGT, of those, 19 patients were randomised, giving a feasibility of recruitment of 24.4%. Ten patients were randomised to metformin and 9 patients to standard care. Tolerability and efficacy was similar between the 2 groups with no serious adverse events. There was no difference in secondary outcomes relating to the metabolic profile. Conclusions The use of metformin post renal transplantation appeared feasible and safe. Larger randomised controlled trials (RCTs) are needed to establish and confirm the efficacy and safety of metformin post renal transplantation . Trial registration Australian New Zealand Clinical Trials Registry ACTRN12614001171606 . Date of registration 7/11/2014.

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m 2 , HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m 2 , HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7–36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R 2  = 0.13, p  < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment ( p  < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion ( p  > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

There is no consensus regarding optimal standard for diagnosis of gestational diabetes mellitus (GDM). In this study, use of 75 g glucose load in non-fasting state [Diabetes in Pregnancy Study Group of India (DIPSI) criteria] as a diagnostic test for GDM in pregnant women was compared with different oral glucose tolerance tests (OGTTs). This prospective study included 936 pregnant women, who underwent plasma glucose evaluation two hours after the challenge of 75 g glucose load irrespective of the timing of last meal (DIPSI criteria for GDM). After three days, standard 75 g OGTT was done in all women irrespective of previous plasma glucose value. Accuracy of the first result was compared to OGTT using cut-offs as per the World Health Organization (WHO) and International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for the diagnosis of GDM. Of the total 936 pregnant women, 73 (7.8%) patients had plasma glucose value ≥140 mg/dl when measured two hours after glucose load. When comparing with the WHO and IADPSG criteria, the sensitivity values were 65.1 and 74.1 per cent, respectively, and the corresponding specificity values were 96.3 and 96.9 per cent, respectively. On comparing with the WHO OGTT, only 41 of the 73 (56.2%) were true positives, whereas when IADPSG criteria were used, true positives were 46 (63%). False negative cases were also present when classified by the WHO and IADPSG criteria though in lesser numbers than false positives. The positive predictive values (PPVs) for the WHO and IADPSG criteria were 56.1 and 63 per cent, respectively, and their corresponding negative predictive values were 97.7 and 97.9 per cent, respectively. Our findings showed that when 75 g glucose load in non-fasting state was used as a diagnostic test for GDM, almost one quarter of patients with GDM escaped diagnosis as sensitivity values were low. On the other hand, some GDM cases were falsely labelled as normal as this test did not account for cases of fasting hyperglycaemia. In addition, comparison with other OGTTs showed low PPVs. Hence, use of DIPSI criteria for diagnosing GDM must be reconsidered till further validation.