Great debate: pre-diabetes is not an evidence-based treatment target for cardiovascular risk reduction.

With the increasing burden of diabetes as a cause of macro- and microvascular disease linked to the epidemics of obesity, attention is being paid to dysglycaemic states that predict and precede the development of type 2 diabetes. Such conditions, termed pre-diabetes, are characterized by fasting plasma glucose, or plasma glucose levels on an oral glucose tolerance test, or values of glycated haemoglobin intermediate between 'normal' values and those characterizing diabetes. These last are by definition associated, in epidemiological terms, with a higher incidence of microvascular disease-mostly retinopathy. Pre-diabetes overlaps with the components of the 'metabolic syndrome'-among which are excess visceral adiposity; hypertension; hypertriglyceridaemia; high levels of small, dense low-density lipoproteins; and metabolic-associated fatty liver disease. There is little doubt that pre-diabetes has important prognostic implications, especially for the occurrence of myocardial infarction, ischaemic stroke, and peripheral arterial disease. It is disputed, however, whether pre-diabetes is itself an actionable disease entity, in addition to the risk factors characterizing it. Because of this uncertainty, the latest European Society of Cardiology guidelines chose not to include pre-diabetes as a treatment target for atherosclerotic cardiovascular disease, at variance from the three previous editions of such guidelines. This is spurring a debate, the Pro and Contra arguments featured in the present debate article.

Identification and validation of gestational diabetes subgroups by data-driven cluster analysis.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is a heterogeneous condition. Given such variability among patients, the ability to recognise distinct GDM subgroups using routine clinical variables may guide more personalised treatments. Our main aim was to identify distinct GDM subtypes through cluster analysis using routine clinical variables, and analyse treatment needs and pregnancy outcomes across these subgroups. METHODS: In this cohort study, we analysed datasets from a total of 2682 women with GDM treated at two central European hospitals (1865 participants from Charité University Hospital in Berlin and 817 participants from the Medical University of Vienna), collected between 2015 and 2022. We evaluated various clustering models, including k-means, k-medoids and agglomerative hierarchical clustering. Internal validation techniques were used to guide best model selection, while external validation on independent test sets was used to assess model generalisability. Clinical outcomes such as specific treatment needs and maternal and fetal complications were analysed across the identified clusters. RESULTS: Our optimal model identified three clusters from routinely available variables, i.e. maternal age, pre-pregnancy BMI (BMIPG) and glucose levels at fasting and 60 and 120 min after the diagnostic OGTT (OGTT0, OGTT60 and OGTT120, respectively). Cluster 1 was characterised by the highest OGTT values and obesity prevalence. Cluster 2 displayed intermediate BMIPG and elevated OGTT0, while cluster 3 consisted mainly of participants with normal BMIPG and high values for OGTT60 and OGTT120. Treatment modalities and clinical outcomes varied among clusters. In particular, cluster 1 participants showed a much higher need for glucose-lowering medications (39.6% of participants, compared with 12.9% and 10.0% in clusters 2 and 3, respectively, p<0.0001). Cluster 1 participants were also at higher risk of delivering large-for-gestational-age infants. Differences in the type of insulin-based treatment between cluster 2 and cluster 3 were observed in the external validation cohort. CONCLUSIONS/INTERPRETATION: Our findings confirm the heterogeneity of GDM. The identification of subgroups (clusters) has the potential to help clinicians define more tailored treatment approaches for improved maternal and neonatal outcomes.

Role of the peripheral chemoreceptors in cardiovascular and metabolic control in type 2 diabetes.

Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes (T2D) and the contribution of the peripheral chemoreceptors to resting cardiovascular and metabolic control. We hypothesized that: (1) adults with T2D exhibit exaggerated peripheral chemoreflex sensitivity; (2) the peripheral chemoreceptors contribute to cardiovascular dysfunction in T2D; and (3) attenuation of peripheral chemoreceptor activity improves glucose tolerance in T2D. Seventeen adults with diagnosed T2D [six males/11 females; aged 54 ± 11 years; glycated haemoglobin (HbA1c) 7.6 ± 1.5%] and 20 controls without T2D (9 males/11 females; aged 49 ± 13 years, HbA1c 5.2 ± 0.4%) participated in the study. The hypoxic ventilatory response (HVR) was assessed as an index of peripheral chemosensitivity. Resting heart rate, blood pressure and minute ventilation were measured when breathing normoxic followed by hyperoxic air (1.0 F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) to acutely attenuate peripheral chemoreceptor activity. A subset of participants (n = 9 per group) completed two additional visits [normoxia (0.21 F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), hyperoxia (1.0 F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ )] where glucose and insulin were measured for 2 h following an oral glucose challenge. HVR was augmented in adults with T2D (-0.84 ± 0.49 L min-1/%) vs. control (-0.48 ± 0.40 L min-1/%, P = 0.021). Attenuation of peripheral chemoreceptor activity decreased heart rate (P < 0.001), mean blood pressure (P = 0.009) and minute ventilation (P = 0.002); any effect of hyperoxia did not differ between groups. There was no effect of hyperoxia on the glucose (control, P = 0.864; T2D, P = 0.982), nor insulin (control, P = 0.763; T2D, P = 0.189) response to the oral glucose challenge. Peripheral chemoreflex sensitivity is elevated in adults with T2D; however, acute attenuation of peripheral chemoreflex activity with hyperoxia does not restore cardiometabolic function. KEY POINTS: Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes and the contribution of the peripheral chemoreceptors to resting cardiovascular control and glucose tolerance. We observed elevated peripheral chemoreflex sensitivity in adults with diabetes which was associated with glycaemic control (i.e. glycated haemoglobin). Notably, acute attenuation of peripheral chemoreflex activity with hyperoxia did not restore cardiometabolic function in the individuals studied.

The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.

In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate production despite normal oxygen levels and functional mitochondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is independent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immunoprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.

Estimating insulin sensitivity and ß-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and ß-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and ß-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

Normalization of impaired glucose tolerance after kidney transplantation is associated with improved ß-cell function.

Our previous study revealed that over 50% of recipients with pretransplant impaired glucose tolerance (IGT) improved to normal glucose tolerance after kidney transplantation. However, the mechanism is unclear. We aimed to investigate whether the changes in glucose tolerance are associated with ß-cell function and insulin resistance in Japanese kidney transplant recipients with pretransplant IGT. Of the 265 recipients who received kidney transplantation, 54 with pretransplant IGT were included. We divided the recipients into improvement and nonimprovement groups according to the change in the area under the curve for glucose obtained from the oral glucose tolerance test (OGTT). ß-Cell function was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and the disposition index (DI). Insulin resistance was estimated by the Matsuda index (MI) and the homeostasis model assessment of insulin resistance (HOMA-IR). ISSI-2 and DI increased significantly after transplantation in the improved group (P < 0.01, P < 0.05, respectively), but not in the nonimproved group. ΔISSI-2 and ΔDI were significantly and positively associated with pretransplant 60-min OGTT plasma glucose levels (both P < 0.01). There were no differences in MI or HOMA-IR between these two groups after transplantation. In recipients not on pretransplant dialysis, a significant negative association was found between Δblood urea nitrogen (BUN) and ΔDI (correlation coefficient = -0.48, P < 0.05). In pretransplant IGT recipients, improvements in glucose tolerance after kidney transplantation were linked to improvements in ß-cell function. The higher the 60-min OGTT plasma glucose level, the greater the improvement in posttransplant ß-cell function. Improvements in BUN after transplantation were associated with improvements in ß-cell function.NEW & NOTEWORTHY In recipients with pretransplant impaired glucose tolerance, improvements in glucose tolerance after kidney transplantation were associated with improvements in ß-cell function. The higher the pretransplant 60-min OGTT plasma glucose level, the greater the improvement in posttransplant ß-cell function. Although glucose tolerance is known to be impaired after transplantation, the present study focused on the reason for the improvement in glucose tolerance rather than the development of posttransplantation diabetes mellitus.

Metabolic-associated fatty liver disease is characterized by a post-oral glucose load hyperinsulinemia in individuals with mild metabolic alterations.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remain unclear. We compared the glucose metabolism, insulin resistance, insulin secretion, and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a body mass index (BMI) between 25 and 40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3 h 75 g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic ß-cell function. Fifty percent of participants had MAFLD. Median age (IQR) [57 (45-65) vs. 57 (44-63) yr] and sex (60% vs. 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (P < 0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity, and first-phase pancreatic ß-cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (P < 0.02). Among individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance while exhibiting lower first phase ß-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede T2D.NEW & NOTEWORTHY Using an oral glucose tolerance test, we found hyperinsulinemia, lower insulin sensitivity, lower insulin clearance, and lower first-phase pancreatic ß-cell function in individuals with MAFLD. This may explain part of the increased risk of incident type 2 diabetes in this population. These data also highlight implications of hyperinsulinemia and impaired insulin clearance in the progression of MAFLD to type 2 diabetes.

Reframing prediabetes: A call for better risk stratification and intervention.

Prediabetes is an intermediate state of glucose homeostasis whereby plasma glucose concentrations are above normal but below the threshold of diagnosis for diabetes. Over the last several decades, criteria for prediabetes have changed as the cut points for normal glucose concentration and diagnosis of diabetes have shifted. Global consensus does not exist for prediabetes criteria; as a result, the clinical course and risk for type 2 diabetes vary. At present, we can identify individuals with prediabetes based on three glycemic tests (hemoglobin A1c, fasting plasma glucose, and 2-h plasma glucose during an oral glucose tolerance test). The majority of individuals diagnosed with prediabetes meet only one of these criteria. Meeting one, two, or all glycemic criteria changes risk for type 2 diabetes, but this information is not widely known and does not currently guide intervention strategies for individuals with prediabetes. This review summarizes current epidemiology, prognosis, and intervention strategies for individuals diagnosed with prediabetes and suggests a call for more precise risk stratification of individuals with prediabetes as elevated (one prediabetes criterion), high risk (two prediabetes criteria), and very high risk (three prediabetes criteria). In addition, the roles of oral glucose tolerance testing and continuous glucose monitoring in the diagnostic criteria for prediabetes need reassessment. Finally, we must reframe our goals for prediabetes and prioritize intensive interventions for those at high and very high risk for type 2 diabetes.

The role of glycated hemoglobin in the diagnosis of prediabetes and diabetes mellitus in young women with polycystic ovary syndrome.

OBJECTIVE: To compare glycated hemoglobin (HbA1c) and the oral glucose tolerance test (OGTT) for the diagnosis of prediabetes and diabetes in young women with polycystic ovary syndrome (PCOS). PATIENTS AND DESIGN: This cross-sectional study included 154 women aged 20-40 years with a diagnosis of PCOS, who were screened for prediabetes and diabetes by the OGTT and HbA1c. Women with diabetes, hyperprolactinemia, thyroid or adrenal diseases, and anemia and users of hormonal contraception or corticosteroids were excluded. MEASUREMENTS: Clinical, biochemical and ultrasound data were collected from the electronic medical records. The women were classified as having normal glucose metabolism, prediabetes, or diabetes based on the diagnostic tests. Sensitivity and specificity were calculated and the Kappa method was used to assess agreement between the two methods. RESULTS: According to the OGTT and HbA1c values, 79.2% and 76% of the women were within the normal range, respectively, 16.8% and 19.5% had prediabetes, and 4% and 4.5% had diabetes (p > .05). The Kappa coefficient of 0.41 (95% confidence interval: 0.24-0.58) indicated medium agreement between methods. Considering the OGTT as the gold standard, the specificity of HbA1c was 89.5% and sensitivity was 85.7% in the diagnosis of prediabetes and 100% and 66.7%, respectively, in the diagnosis of diabetes. CONCLUSION: The HbA1c, when compared to the OGTT, showed high sensitivity and specificity in the diagnosis of prediabetes in young women with PCOS.

Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. CONCLUSION: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.

Dynamic pattern of postprandial bile acids in paediatric non-alcoholic fatty liver disease.

BACKGROUND: Dysregulation of bile acids (BAs), as important signalling molecules in regulating lipid and glucose metabolism, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, static BA profiles during fasting may obscure certain pathogenetic aspects. In this study, we investigate the dynamic alterations of BAs in response to an oral glucose tolerance test (OGTT) among children with NAFLD. METHODS: We recruited 230 subjects, including children with overweight/obesity, or complicated with NAFLD, and healthy controls. Serum BAs, 7-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) were quantified during OGTT. Clinical markers related to liver function, lipid metabolism and glucose metabolism were assessed at baseline or during OGTT. FINDINGS: Conjugated BAs increased while unconjugated ones decreased after glucose uptake. Most BAs were blunted in response to glucose in NAFLD (p > .05); only glycine and taurine-conjugated chenodeoxycholic acid (CDCA) and cholic acid (CA) were responsive (p < .05). Primary BAs were significantly increased while secondary BAs were decreased in NAFLD. C4 and FGF19 were significantly increased while their ratio FGF19/C4 ratio was decreased in NAFLD. The dynamic pattern of CDCA and taurine-conjugated hyocholic acid (THCA) species was closely correlated with glucose (correlation coefficient r = .175 and -.233, p < .05), insulin (r = .327 and -.236, p < .05) and c-peptide (r = .318 and -.238, p < .05). Among which, CDCA was positively associated with liver fat content in NAFLD (r = .438, p < .05). Additionally, glycochenodeoxycholic acid (GCDCA), CDCA and THCA were potential biomarkers to discriminate paediatric NAFLD from healthy controls and children with obesity. INTERPRETATION: This study provides novel insights into the dynamics of BAs during OGTT in paediatric NAFLD. The observed variations in CDCA and HCA species were associated with liver dysfunction, dyslipidaemia and dysglycaemia, highlighting their potential roles as promising diagnostic and therapeutic targets in NAFLD.

Greater risk of type 2 diabetes progression in multifetal gestations with gestational diabetes: the impact of obesity.

BACKGROUND: The relationship between gestational diabetes mellitus and adverse outcomes in multifetal pregnancies is complex and controversial. Moreover, limited research has focused on the risk of gestational diabetes mellitus progression to type 2 diabetes mellitus specifically in multifetal pregnancies, resulting in conflicting results from existing studies. OBJECTIVE: This study aimed to assess the risk of gestational diabetes mellitus progression to type 2 diabetes mellitus between singleton and multifetal pregnancies in a large cohort of parturients with a 5-year follow-up. STUDY DESIGN: A retrospective study was conducted on a prospective cohort of pregnant individuals with pregnancies between January 1, 2017, and December 31, 2020, followed up to 5 years after delivery. Glucose levels during pregnancy were obtained from the Meuhedet Health Maintenance Organization laboratory system and cross-linked with the Israeli National Diabetes Registry. The cohort was divided into 4 groups: singleton pregnancy without gestational diabetes mellitus, singleton pregnancy with gestational diabetes mellitus, multifetal pregnancy without gestational diabetes mellitus, and multifetal pregnancy with gestational diabetes mellitus. Gestational diabetes mellitus was defined according to the American Diabetes Association criteria using the 2-step strategy. Univariate analyses, followed by survival analysis that included Kaplan-Meier hazard curves and Cox proportional-hazards models, were used to assess differences between groups and calculate the adjusted hazard ratios with 95% confidence intervals for progression to type 2 diabetes mellitus. RESULTS: Among 88,611 parturients, 61,891 cases met the inclusion criteria. The prevalence of type 2 diabetes mellitus was 6.5% in the singleton pregnancy with gestational diabetes mellitus group and 9.4% in the multifetal pregnancy with gestational diabetes mellitus group. Parturients with gestational diabetes mellitus, regardless of plurality, were older and had higher fasting plasma glucose levels in the first trimester of pregnancy. The rates of increased body mass index, hypertension, and earlier gestational age at delivery were significantly higher in the gestational diabetes mellitus group among patients with singleton pregnancies but not among patients with multifetal pregnancies. Survival analysis demonstrated that gestational diabetes mellitus was associated with adjusted hazard ratios of type 2 diabetes mellitus of 4.62 (95% confidence interval, 3.69-5.78) in singleton pregnancies and 9.26 (95% confidence interval, 2.67-32.01) in multifetal pregnancies (P<.001 for both). Stratified analysis based on obesity status revealed that, in parturients without obesity, gestational diabetes mellitus in singleton pregnancies increased the risk of type 2 diabetes mellitus by 10.24 (95% confidence interval, 6.79-15.44; P<.001) compared with a nonsignificant risk in multifetal pregnancies (adjusted hazard ratio, 9.15; 95% confidence interval, 0.92-90.22; P=.059). Among parturients with obesity, gestational diabetes mellitus was associated with an increased risk of type 2 diabetes mellitus for both singleton and multifetal pregnancies (adjusted hazard ratio, 3.66; [95% confidence interval, 2.81-4.67; P<.001] and 9.31 [95% confidence interval, 2.12-40.76; P=.003], respectively). CONCLUSION: Compared with gestational diabetes mellitus in singleton pregnancies, gestational diabetes mellitus in multifetal pregnancies doubles the risk of progression to type 2 diabetes mellitus. This effect is primarily observed in patients with obesity. Our findings underscore the importance of providing special attention and postpartum follow-up for patients with multifetal pregnancies and gestational diabetes mellitus, especially those with obesity, to enable early diagnosis and intervention for type 2 diabetes mellitus.

Oxytocin does not acutely improve glucose tolerance in men with type 2 diabetes.

AIM: To assess oxytocin's acute glucoregulatory impact in men with type 2 diabetes in the context of our previous findings that oxytocin improves ß-cell responsivity in healthy men. METHODS: In a double-blind, crossover comparison, intranasal oxytocin (24 IU) and placebo, respectively, were administered to 25 fasted men with non-insulin-treated type 2 diabetes (age ± standard error of the mean, 63.40 ± 1.36 years; body mass index, 27.77 ± 0.66 kg/m2; HbA1c, 6.86% ± 0.08%; Homeostatic Model Assessment of Insulin Resistance (HOMA-IR, 3.44 ± 0.39) 60 minutes before an oral glucose tolerance test (oGTT). Key outcomes were compared with previous results in men with normal weight or obesity. RESULTS: Oxytocin compared with placebo increased plasma oxytocin concentrations and reduced the heart rate, but did not alter glucose metabolism in the 3 hours after oGTT onset (area under the curve, glucose, 2240 ± 80.5 vs. 2190 ± 69.5 mmol/L × min; insulin, 45 663 ± 4538 vs. 44 343 ± 4269 pmol/L × min; C-peptide, 235 ± 5.1 vs. 231 ± 15.9 nmol/L × min). CONCLUSIONS: This outcome contrasts with the oxytocin-induced attenuation of early postprandial glucose excursions in normal-weight individuals, but is in line with the absence of respective effects in men with obesity. We conclude that insulin resistance in type 2 diabetes is associated with decreased sensitivity to the acute glucoregulatory effect of oxytocin in male individuals.

The impact of an oral glucose load on IFN-γ-release in persons infected with Mycobacterium tuberculosis.

BACKGROUND AND OBJECTIVE: To diagnose tuberculosis infection (TBI), whole blood is incubated with M.tuberculosis (Mtb)-specific peptides and the release of interferon-γ (IFN-γ) is measured in IFN-γ-release assays (IGRAs). Hyperglycaemia and fluctuations in blood glucose may modulate IFN-γ-release. Here, we investigated if glucose intake affects IFN-γ-release or IGRA results in IGRAs taken during an oral glucose tolerance test (OGTT). METHODS: Persons with TB disease (TB) or TBI underwent a standard 75-g OGTT at the start and end of treatment for TB or TBI. Blood for the IGRA QuantiFERON-TB Gold Plus (QFT) containing Mtb-specific tubes (TB1 and TB2), a non-specific mitogen tube (MIT) and an empty control tube (NIL) was drawn at sample-timepoints -15 (baseline), 60, 90, 120 and 240 min during the OGTT. Blood glucose was measured in parallel at all timepoints. IFN-γ-release (after subtraction of NIL) at each timepoint was compared with baseline using linear-mixed-model analysis. RESULTS: Twenty-four OGTTs from 14 participants were included in the final analysis. Compared to baseline, IFN-γ-release was increased at sample-timepoint 240 min for TB1; geometric mean (95% confidence interval) 3.0 (1.5-6.2) vs 2.5 (1.4-4.4) IU/mL (p = 0.047), and MIT; 182.6 (103.3-322.9) vs 146.0 (84.0-254.1) IU/mL (p = 0.002). Plasma glucose levels were not associated with IFN-γ-release and the QFT test results were unaffected by the OGTT. CONCLUSION: Ingestion of glucose after a 10-h fast was associated with increased IFN-γ-release after 240 min in the MIT tube. However, there was no association between plasma glucose levels at the QFT sampling timepoint and IFN-γ-release. Furthermore, the QFT test results were not affected by glucose intake. The overall effect of an OGTT and prevailing plasma glucose levels on IFN-γ-release in IGRAs seem limited. TRIAL REGISTRATION: Trial registration ID: NCT04830462 ( https://clinicaltrials.gov/study/NCT04830462 ). Registration date: 05-Apr-2021.

Design, synthesis and biological evaluation of novel oxazole derivatives as potential hypoglycemic agents.

A series of 2,4-disubstituted-oxazole derivatives have been designed and synthesized based on compound 3a, a promising lead compound developed in our lab. Among these derivatives, the optimized compound 5k exhibited potent hypoglycemic activity, increasing glucose consumption by 60 % in HepG2 cells compared to the solvent control, and its activity was higher than that of metformin. Further investigation indicated that compound 5k exhibited negligible cytotoxic effects at a concentration of 25 µM in HepG2 and 3T3-L1 cells and showed moderate inhibitory activity against various subtypes of human cytochrome P450 subtypes. An oral glucose tolerance test confirmed that 5k is an effective hypoglycemic agent. Additionally, mechanistic studies suggested that 5k may exert its hypoglycemic activity through the activation of the AMPK pathway.

Clinical utility of point-of-care glucose testing in the assessment of gestational diabetes: Prospective cohort study.

OBJECTIVE: To assess the clinical utility of point-of-care (POC) capillary blood glucose (CBG) testing in the assessment of gestational diabetes mellitus (GDM) during oral glucose tolerance test (OGTT). DESIGN: Prospective cohort study. SETTING: Antenatal clinics at King's College Hospital. POPULATION: Women screened for GDM between March and June 2020. METHODS: The CBG was measured using the POC StatStrip® test and the venous plasma glucose (VPG) was measured by Roche analyser (Cobas 8000 c702). GDM was diagnosed based on the 2015 National Institute for Health and Clinical Excellence (NICE) Clinical Guideline criteria. The two methods were compared statistically using Analyse-It 5.40.2. MAIN OUTCOME MEASURES: Diagnostic sensitivity, specificity, positive and negative predictive values (PPV and NPV) for the POC StatStrip® test, compared with VPG measured by reference laboratory method. RESULTS: A total of 230 women were included. The number and percentage of women with glucose concentrations above the GDM threshold using the POC StatStrip® test versus laboratory VPG measurement was 15 (6.5%) versus eight (3.4%) at fasting and 105 (45.6%) versus 72 (31.1%) at 2 h, respectively. The sensitivity and specificity values (and 95% CIs) for the POC StatStrip® test were 88% (52%-99%) and 97% (93%-98%) at fasting and 97% (91%-99%) and 79% (71%-84%) at 2 h, respectively. However, the specificity and the NPV for the POC StatStrip® test for concentrations of ≤5.0 mmol/L at fasting or <7.5 mmol/L at 2 h were 100%, and the sensitivity and the PPV for concentrations of >9.5 mmol/L at 2 h were 100%. CONCLUSIONS: In our cohort the POC measurement of CBG cannot entirely replace the laboratory method for the OGTT; however, it can be used to rule out/rule in GDM for glucose concentrations of ≤5.0 mmol/L at fasting or <7.5/>9.5 mmol/L at 2 h.

Subclinical diabetes confirmed by 75-g OGTT influence on the prognosis of decompensated cirrhosis.

BACKGROUND AND AIM: Disorders of glucose metabolism, such as impaired glucose tolerance (IGT) and diabetes mellitus (DM), frequently occur in cirrhosis. We aimed to evaluate who needs to be undertaken a 75-g oral glucose tolerance test (OGTT) to find underlying subclinical diabetes. METHODS: This prospective study included 713 patients with either compensated (Child-Turcotte-Pugh [CTP] class A) or decompensated cirrhosis (CTP class B/C) without previous DM history. All patients underwent a 75-g OGTT. The patients were divided into three groups: normal glucose tolerance (NGT), IGT, and newly diagnosed DM (subclinical DM). RESULTS: Among 713 patients, NGT was diagnosed in 139 (19.5%), IGT in 252 (35.3%), and subclinical DM in 322 (45.2%) patients, respectively. During a median follow-up period of 42.0 months, the cumulative survival rates of patients were as follows: NGT, 75.6%; IGT, 57.6%; and subclinical DM, 54.8%. Overall, IGT (adjusted hazard ratio [aHR], 1.605; 95% confidence interval [CI] = 1.009-2.553; P = 0.046) and subclinical DM (aHR, 1.840; 95% CI = 1.183-2.861; P = 0.001) were identified as independent predictors of mortality. In patients with compensated cirrhosis (n = 415), neither IGT nor subclinical DM conferred a higher mortality risk. However, among patients with decompensated cirrhosis (n = 298), those with IGT (aHR, 2.394; P = 0.015) and subclinical DM (aHR, 2.211; P = 0.022) showed a survival rate worse than those with NGT. In addition, subclinical DM was identified as an independent risk factor for infection (aHR, 2.508; P = 0.007). CONCLUSIONS: IGT and subclinical diabetes by OGTT are associated with an unfavorable prognosis in cirrhosis, and the effect is pronounced in the decompensated state. CLINICALTRIALS: gov, Number NCT04828512 (https://clinicaltrials.gov/ct2/show/NCT04828512).

ASSESSMENT OF 1-HOUR POST-LOAD PLASMA GLUCOSE, THE METABOLIC SYNDROME AND THE FINDRISC SCORE IN THE PREDICTION OF TYPE 2 DIABETES.

OBJECTIVE: To compare the 1-hour post-load glucose (1h-PG) value of an Oral Glucose Tolerance Test (OGTT) with the Metabolic Syndrome (MetS) and the Finish Diabetes Risk Score (FINDRISC) in patients with impaired fasting glucose (IFG) to predict T2DM. METHODS: A cohort study conducted in patients addressed at a general hospital in Lima-Perú. Subjects with IFG performed an OGTT were followed up to seven years for T2DM development. The exposures variables were 1h-PG ≥ 155mg/dL, MetS, and a FINDRISC score ≥ 13 points, and the presence of T2DM was the outcome. The relative risk (RR), confidential interval (CI), and area under the curve (AUROC) were also estimated. RESULTS: Among 324 subjects with IFG, 218 completed the 7-years-follow-up. The mean age was 56.2 ±11.5 years-old, 64.0% were female and 63.8% were overweigh/obese. 36.8% had 1h-PG ≥ 155mg/dL and normal glucose tolerance (NGT), 66.8% had MetS and 64.5% FINDRISC ≥ 13 points. After 7 years, 21.1% of participants developed T2DM, 68.8% of them with 1h-PG ≥ 155mg/dL (p< 0.001), 62.2% with MetS (p= 0.013), and 67.9% with FINDRISC ≥ 13 (p= 0.68). After adjusting by age, sex and BMI, the RR were 3.52 (1.64-7.54; 95%CI), 1.81 (0.96-3.38; 95%CI) and 1.17 (0.51-2.70; 95%CI), for each exposure-variable, respectively. Also, the AUROC were 0.72 (0.60-0.83), 0.63 (0.51-0.75), and 0.51 (0.38-0.63) (p= 0.01), respectively. CONCLUSION: By performing an OGTT in IFG patients, an 1h-PG ≥ 155 mg/dL value may be helpful to predict T2DM at 7 years better than the use of MetS or FINDRISC score.

Prevalence of gestational diabetes mellitus in Pakistan: a systematic review and meta-analysis.

BACKGROUND: A variety of screening tools and criteria are used for the diagnosis of gestational diabetes mellitus (GDM). As a result, the prevalence rate of GDM varied from 4.41% to 57.90% among studies from Pakistan. Beside this disagreement, similar multi-centric studies, community surveys and pooled evidence were lacking from the country. Therefore, this first systematic review and meta-analysis aimed to measure the overall and subgroup pooled estimates of GDM and explore the methodological variations among studies for any inconsistency. METHODS: Using the PRISMA guidelines, seventy studies were identified from PubMed, ScienceDirect, Google Scholar and PakMediNet database. Of them, twenty-four relevant studies were considered for systematic review and nine eligible studies selected for meta-analysis. AXIS was used for measuring quality of reporting, I^2 statistics for heterogeneity among studies and subgroups, funnel plot for reporting potential publication bias and forest plot for presenting pooled estimates. RESULTS: The pooled sample of nine studies was 27,034 (126 - 12,450) pregnant women, of any gestational age, from all four provinces of Pakistan. Overall pooled estimate of GDM was 16.7% (95% CI 13.1 - 21.1). The highest subgroup pooled estimate of GDM observed in studies from Balochistan (35.8%), followed by Islamabad (23.9%), Khyber Pakhtunkhwa (17.2%), Sindh (13.2%), and Punjab (11.4%). The studies that adopted 75g 2-h OGTT had a little lower pooled estimate (16.3% vs. 17.3%); and that adopted diagnostic cut-off values [≥ 92 (F), ≥ 180 (1-h) and ≥ 153 (2-h)] had a greater pooled estimate (25.4% vs. 15.8%). The studies that adopted Carpenter criteria demonstrated the highest subgroup pooled estimate of GDM (26.3%), after that IADPSG criteria (25.4%), and ADA criteria (23.9%). CONCLUSIONS: Along with poor quality of reporting, publishing in non-indexed journals and significant disagreement between studies, the prevalence rate of GDM is high in Pakistan. Consensus building among stakeholders for recommended screening methods; and continuous medical education of the physicians are much needed for a timely detection and treatment of GDM.

Neonatal outcomes according to different glucose threshold values in gestational diabetes: a register-based study.

BACKGROUND: Mild hyperglycaemia is associated with increased birth weight but association with other neonatal outcomes is controversial. We aimed to study neonatal outcomes in untreated mild hyperglycaemia using different oral glucose tolerance test (OGTT) thresholds. METHODS: This register-based study included all (n = 4,939) singleton pregnant women participating a 75 g 2-h OGTT in six delivery hospitals in Finland in 2009. Finnish diagnostic cut-offs for GDM were fasting ≥ 5.3, 1 h ≥ 10.0 or 2-h glucose ≥ 8.6 mmol/L. Women who did not meet these criteria but met the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria (fasting 5.1-5.2 mmol/L and/or 2-h glucose 8.5 mmol/L, n = 509) or the National Institute for Health and Clinical Excellence (NICE) criteria (2-h glucose 7.8-8.5 mmol/L, n = 166) were considered as mild untreated hyperglycaemia. Women who met both the Finnish criteria and the IADPSG or the NICE criteria were considered as treated GDM groups (n = 1292 and n = 612, respectively). Controls were normoglycaemic according to all criteria (fasting glucose < 5.1 mmol/L, 1-h glucose < 10.0 mmol/L and 2-h glucose < 8.5 mmol/L, n = 3031). Untreated mild hyperglycemia groups were compared to controls and treated GDM groups. The primary outcome - a composite of adverse neonatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, birth trauma or perinatal mortality - was analysed using multivariate logistic regression. RESULTS: The risk for the adverse neonatal outcome in untreated mild hyperglycemia was not increased compared to controls (adjusted odds ratio [aOR]: 1.01, 95% confidence interval [CI]: 0.71-1.44, using the IADPSG criteria; aOR: 1.05, 95% CI: 0.60-1.85, using the NICE criteria). The risk was lower compared to the treated IADPSG (aOR 0.38, 95% CI 0.27-0.53) or the treated NICE group (aOR 0.32, 95% CI 0.18-0.57). DISCUSSION: The risk of adverse neonatal outcomes was not increased in mild untreated hyperglycaemia compared to normoglycaemic controls and was lower than in the treated GDM groups. The OGTT cut-offs of 5.3 mmol/L at fasting and 8.6 mmol/L at 2 h seem to sufficiently identify clinically relevant GDM, without excluding neonates with a risk of adverse outcomes.