Glucose Challenge Research Articles

Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

Isolated bovine pancreatic islets as an alternate in vitro model for diabetes research.

Background & objectives Isolation of functional pancreatic islets for diabetes research and clinical islet transplantation stands as a big challenge despite the advancements in the field. In this context, the non-availability of human/animal tissues is one of the major impediments to islet-based research, which has tremendous scope for translation. The current study explores the feasibility of using the bovine pancreas as an alternative source to isolate pancreatic islets and assess its functionality for in vitro studies. Methods The bovine pancreas was collected from a registered slaughterhouse and transported in an ice-cold medium - Hank's Balanced Salt Solution (HBSS) to the laboratory. Islets were isolated by sequential collagenase digestion followed by a two-step filtration and purification by density gradient separation method. After isolation, islets were identified with dithizone staining and the islet function was assayed in vitro for assessing the dynamic insulin secretory function by monitoring the glucose-stimulated insulin secretion (GSIS), in response to low and high glucose. Staining techniques were also used to understand the cytoarchitecture of the bovine pancreas. Results The islet yield was 157±23 islets per gram of pancreas and was viable. The cold ischaemia time was reduced to 60-75 min. The islets released insulin with glucose stimulation. The insulin release was observed more with high glucose (28 mM) than with low glucose (2.8 mM). Dithizone staining confirmed the presence of islets after isolation and the size of islets ranged from 50 to 600 µm size. The mantled islets (islets with acinar tissue) were also noted with the pure islets in culture. Hematoxylin and eosin (H&E) and aldehyde- fuchsin showed islets interspersed in the acinar tissue of the bovine pancreas. Special stain defined the islets better than regular staining. Fluorescent and diaminobenzidine (DAB) staining with insulin, glucagon and somatostatin revealed the arrangement of the cells in each islet. The beta cells were majorly found in the islet core with alpha cells interspersed with the delta cells in the periphery. Interpretation & conclusions The isolation procedure described in this study yielded viable islets for in vitro studies which showed a differential response to glucose challenge, confirming their viability. We provide a simple and reproducible method for small-scale isolation of functional islets from the bovine pancreas. This model proffers the beginner a hands-on in islet experiments and helps to re-iterate the process that could be extrapolated to other pancreatic tissues as well as to expand on diabetes research.

Twin Pregnancy Complicated by Gestational Diabetes Mellitus: Maternal and Neonatal Outcomes.

The risk of gestational diabetes mellitus (GDM) in twin pregnancies is more than double that of singleton pregnancies. Although twin pregnancies present unique challenges for fetal growth and prenatal management, the approach to GDM diagnosis and treatment is the same regardless of plurality. Data on pregnancy outcomes for individuals with GDM and a twin pregnancy are limited and conflicting. To describe the maternal characteristics associated with GDM in twin pregnancies and to assess the associated pregnancy outcomes compared to twin pregnancies unaffected by GDM. A retrospective cohort study was conducted at Mayo Clinic, Rochester, Minnesota, USA, and included predominantly Causasian women aged 18 to 45 years who received prenatal care for a twin pregnancy from 2017-2022. Maternal characteristics and a broad spectrum of pregnancy outcomes were evaluated. Universal GDM screening involved a 50 g oral glucose challenge test +/- a 100 g oral glucose tolerance test. GDM was diagnosed in 23% pregnancies (n = 104/452). Compared to those without, women with GDM had known risk factors including a higher prepregnancy body mass index (31.1vs 26.3 kg/m2; P < .01) and a prior history of GDM (21.7 vs 5.9%; P < .01). There were no differences in maternal pregnancy complications or neonatal outcomes between groups. Attendance at postpartum glucose testing among women with GDM was poor at 27.9% (29/104). These data suggest that women with twin pregnancies share a similar GDM risk profile to those with singleton pregnancies and provide reassuring evidence that current management for GDM twin pregnancies produces similar outcomes to twin pregnancies without GDM.

Pancreatic Beta Cell Function in Infants Varies by Maternal Weight.

The Asian Indian Beta Cell function (ABCs) in Infants Study examined the associations of maternal weight on infant pancreatic beta cell function across 7 months postpartum. Pregnant women aged 18-35 years were recruited in Hyderabad, India. Women were classified by first trimester weight as underweight (UW), BMI < 18.5 kg/m2; normal weight (NW), BMI 18.5-22.9 kg/m2; or overweight (OW), BMI 23.0 through <28.5 kg/m2. At age > 7 months, infants had an oral glucose tolerance test (OGTT, 1.75 g glucose/kg bodyweight) following a 3 h fast. Infant blood samples were assayed for C-peptide and glucose. Infant beta cell function (HOMA2-B; disposition index, DI) and insulin resistance (HOMA2-IR) were compared across maternal weight groups. Mothers (UW n = 63; NW n = 43; OW n = 29) had similar age at delivery and second trimester 50 g glucose challenge test results. Cord HOMA2-B values were 51% greater for IUW (83.5, SD 55.2) and 44% greater for IOW (79.9, SD 60.8) vs. INW (55.4, SD 51.5), forming a U-shaped relationship between maternal weight and HOMA2-B. No qualitative differences in HOMA2-IR were found at birth. However, at 7 months postpartum, HOMA2-IR changed most within IUW (-64% median reduction) and changed the least in IOW (-7% median reduction). At seven months postpartum, DI was higher in IUW vs. the other groups (geometric mean IUW 1.9 SD 2.5; INW 1.3 SD 2.6 or vs. IOW mean 1.2 SD 3.7), reflecting a +49% difference in DI. Evidence from this study illustrates adaptations in the pancreatic functional response of infants associated with the maternal nutritional environment.

MTOR Inhibition Prolongs Survival and Has Beneficial Effects on Heart Function After Onset of Lamin A/C Gene Mutation Cardiomyopathy in Mice.

Mutations in LMNA encoding nuclear envelope proteins lamin A/C cause dilated cardiomyopathy. Activation of the AKT/mTOR (RAC-α serine/threonine-protein kinase/mammalian target of rapamycin) pathway is implicated as a potential pathophysiologic mechanism. The aim of this study was to assess whether pharmacological inhibition of mTOR signaling has beneficial effects on heart function and prolongs survival in a mouse model of the disease, after onset of heart failure. We treated male LmnaH222P/H222P mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival. Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% (P=0.018) reduction in left ventricular end-diastolic diameter and a 39% (P=0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in LmnaH222P/H222P mice, by 9% (P=0.0348) and 11% (P=0.0206), respectively, compared with placebo (n=20). These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by LMNA mutations and that further study is warranted.

Abstract 1876: Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth

Abstract Background: Upregulated glucose metabolism is one of the strategies cancer cells use to fuel their abnormal cell growth and division. Targeting the cancer-specific glucose transporter GLUT-1 is a promising approach to restrict glucose uptake and challenge the metabolic needs of tumor cells. Antibodies, as opposed to small molecule inhibitors, are an attractive modality to therapeutically target complex muti-pass membrane transporters. Here we report the development of antibodies that very specifically block the function of only GLUT-1. Methods: Monoclonal antibodies against GLUT-1 were generated using virus-like particles. For immunization, chickens were used as they are evolutionarily distant from mammals and can produce antibodies with prolonged CDR3-s in VH, which could facilitate their binding to the limited extracellular region of GLUT-1. Antibody discovery was performed with HybriFree B cell cloning technology followed by functional screens with 2-deoxyglucose uptake interference or cell proliferation measurements. Results: The discovered antibodies specifically bind to GLUT-1 with low nanomolar EC50 values and do not target other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and rewires the metabolism of GLUT-1-dependent cancer cells to rely on oxidative phosphorylation. This results in a significantly synergistic cancer proliferation inhibition with ICO-33 and OXPHOS inhibitor combinations in doses that do not inhibit proliferation as single agents. ICO-33 and OXPHOS inhibitor treatment is well-tolerated and demonstrates a drastic tumor growth inhibition in in vivo colorectal and pancreatic cancer models. Conclusions: We describe the discovery of highly specific monoclonal antibodies targeting GLUT-1. We further demonstrate that the restriction of the much-needed glucose uptake by ICO-33 makes cancer cells highly susceptible to OXPHOS inhibitor co-therapy both in vitro and in vivo, validating the antibody as a promising candidate for clinical development. Citation Format: Siret Tahk, Kai Virumae, Korneelia Anton, Paule Hermet, Robin Pau, Mario Plaas, Maiken Abel, Denis Belitškin, Luciano Galdieri, Steven Garner, Jillian Krings, Kaleb Collver, Emily Schultz, Kaitlyne Powers, Alastair King, Francisca Neethling, Anu Planken, Mart Ustav, Joan Terya, Andres Mannik, Mart Ustav. Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1876.

Abdominal subcutaneous fat thickness combined with a 50-g glucose challenge test at 24-28 weeks of pregnancy in predicting gestational diabetes mellitus

Background This investigation aimed to analyse the efficacy of abdominal subcutaneous fat thickness (ASFT) value >18.1 mm combined with a 50-g glucose challenge test (GCT) between 24-28 weeks of gestation in predicting gestational diabetes mellitus (GDM) cases. Methods This cross-sectional study was carried out from February 2021 to December 2022. All pregnant women received a 50-g GCT at 24-28 weeks of pregnancy for the GDM screening. Pregnant women with a blood glucose value between 140-190 mg/dl experienced 100 g OGTT. Even if 50-g GCT was normal, 100-g OGTT was offered to patients with an ASFT value above 18.1 mm Results Among the 728 pregnant women we enrolled, 154 (21.2%) cases were screened as positive. The number of patients who first screened positive and determined to be GDM after the 100-g oral glucose tolerance test (OGTT) was 43 (5.9%). A total of 67 cases (9.2%) had an ASFT measurement above 18.1 mm. Two cases with a negative 50-g GCT and ASFT <18.1 mm were diagnosed as GDM in the later weeks of pregnancy. A 50-g GCT combined with ASFT measurement above 18.1 mm predicted GDM with a sensitivity of 87.9%, a specificity of 88.7%, a positive predictive value (PPV) of 36.0%, and a negative PV (NPV) of 99.7%. Conclusions A 50-g GCT combined with ASFT measurement that can be easily and accurately obtained during routine antenatal care in the second trimester might be a beneficial indicator for predicting GDM cases.

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic β cells

Pancreatic β cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as β cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in β cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in β cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in β cells.

Abstract P346: Effect of Low-Fat versus Low-Carbohydrate Diet on Visceral Fat

Introduction: A healthy low fat (HLF) and healthy low carbohydrate (HLC) diet are common strategies for weight loss that vary in their effects on adiposity and metabolism. Visceral adipose tissue (VAT) is the major contributor to metabolism deregulation, beyond subcutaneous adipose tissue (SAT). Despite strong biological evidence that a HLC diet preferentially decreases VAT relative to SAT, the difficulty in measuring adipose sub-types has impeded its use in diet trials. To address this research gap, we measured VAT and SAT in a secondary analysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) weight loss trial to compare the effects of HLF and HLC diets and potential effect modification by sex and insulin resistance status. Hypothesis: We hypothesized that a HLC diet is associated with greater VAT loss compared with a HLF diet. Secondly, we hypothesized that men and those with greater baseline insulin secretion assigned to HLC diet would experience greater VAT loss. Methods: DIETFITS was a single-site, parallel-group, weight loss diet trial, randomizing 609 adults with overweight and obesity to a HLC or HLF diet for 12 months. Data collection occurred at baseline, 6 months, and 12 months. Insulin resistance status was proxy measured using insulin concentration 30 minutes after a glucose challenge (INS 30). In this secondary analysis, we measured VAT and SAT in the abdominal region by reanalyzing the dual-energy x-ray absorptiometry (DXA) scans. We fit a linear mixed model to evaluate the change in VAT after 6 and 12 months on HLF and HLC, with fixed effects: time, diet, and their interaction; and a random effect for repeated observations. We built separate models for each of the secondary hypotheses, with additional fixed effects INS 30 and sex, respectively. Results: We included 449 participants with baseline DXA (60% women; mean age 40 years). From baseline to 6-months, participants assigned to a HLC diet experienced a significant 10.6 cm 2 (95% CI: 5.1, 16.1) greater decrease in mean VAT compared to those assigned to a HLF diet. The 12-month difference in diets attenuated to 5.5 cm 2 (95% CI: -0.1, 11.1). Contrary to our hypothesis, INS 30 did not modify the diet-related changes in VAT. Among men, both diets resulted in a 12-month decrease in VAT. The HLC diet was associated with a 12.1 cm 2 (95% CI: 1.6, 22.7) greater loss of VAT compared to HLF. Among women, HLF but not HLC was associated with decreased VAT, and there was no difference in VAT loss between diets 1.8 cm 2 (95% CI: -4.1, 7.6). Models controlling for SAT indicated that VAT decreased independently of SAT. Conclusion: These findings contribute to the understanding of the nuanced impacts of HLF and HLC diets on adipose sub-types and underscore the relevance of considering sex in designing effective dietary interventions targeting VAT reduction and metabolic health.

Genetic Evidence of Causal Relation Between Intestinal Glucose Absorption and Early Postprandial Glucose Response: A Mendelian Randomization Study.

The post-prandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose-co-transporter-1 (SGLT1). This study utilizes Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1547 subjects with class II/III obesity from the ABOS cohort, the study employs SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype served as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-minute post-load glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results showed that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study linked a one standard deviation decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mM/L. MR analysis paralleled these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decreases of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early post-load glucose response. This finding has a potential translational impact on managing early glucose response in type 2 diabetes.

Shared genetic architecture between periodontal disease and type 2 diabetes: a large scale genome-wide cross-trait analysis

PurposeTo investigate the relationship between abnormal glucose metabolism, type 2 diabetes (T2D), and periodontal disease (PER) independent of Body Mass Index (BMI), we employed a genome-wide cross-trait approach to clarify the association.MethodsOur study utilized the most extensive genome-wide association studies conducted for populations of European ancestry, including PER, T2D, fasting glucose, fasting insulin, 2-hour glucose after an oral glucose challenge, HOMA-β, HOMA-IR (unadjusted or adjusted for BMI) and HbA1c.ResultsWith this approach, we were able to identify pleiotropic loci, establish expression-trait associations, and quantify global and local genetic correlations. There was a significant positive global genetic correlation between T2D (rg = 0.261, p = 2.65 × 10−13), HbA1c (rg = 0.182, p = 4.14 × 10−6) and PER, as well as for T2D independent of BMI (rg = 0.158, p = 2.34 × 10−6). A significant local genetic correlation was also observed between PER and glycemic traits or T2D. We also identified 62 independent pleiotropic loci that impact both PER and glycemic traits, including T2D. Nine significant pathways were identified between the shared genes between T2D, glycemic traits and PER. Genetically liability of HOMA-βadjBMI was causally associated with the risk of PER.ConclusionOur research has revealed a genetic link between T2D, glycemic traits, and PER that is influenced by biological pleiotropy. Notably, some of these links are not related to BMI. Our research highlights an underlying link between patients with T2D and PER, regardless of their BMI.

Effect of blood flow restriction and electrical muscle stimulation on human glycemic response to a glucose challenge.

To determine whether reduced tissue oxygen availability through blood flow restriction (BFR) alone, or in combination with electrically induced muscle contractions, can improve glucose clearance after an acute glucose challenge. In a randomized crossover design, 21 young participants (females: 12) were allocated to perform 1) electrical muscle stimulation (EMS), 2) BFR, 3) EMS + BFR or 4) no treatment (control). Participants completed each condition immediately preceding a 2h oral glucose tolerance test (100g). Primary analyses were performed on the glucose area under the curve (AUC) at time points 0-30, 30-120, and 0-120min. Secondary analyses were performed on glycemic responses based on biological sex and estimated muscle phenotype. Compared to the control (322±25mM∙min), the 0-30min AUC was reduced following EMS (293±22mM∙min, p = 0.0004), and EMS + BFR (298±36mM∙min., p = 0.006), whereas BFR in isolation did not differ (306±30mM∙min, p = 0.1). The 30-120 and 0-120min glucose AUCs were similar across conditions. Based on effect size from the control conditions, our secondary analysis suggests different 0-30min glycemic responses after EMS + BFR between females (dz = 0.206) vs. males (dz = 1.461) and/or slow (dz = 0.426) vs. fast (dz = 1.075) muscle phenotype. Reducing tissue oxygen availability with BFR did not augment the effects of EMS in the overall group; however, we provide preliminary data to suggest possible sex and/or muscle phenotypic responses in glycemic regulation with these modalities.

Non-invasive blood glucose estimation method based on the phase delay between oxy- and deoxyhemoglobin using visible and near-infrared spectroscopy.

Many researchers have attempted to estimate blood glucose levels (BGLs) noninvasively using near-infrared (NIR) spectroscopy. However, the optical absorption change induced by blood glucose is weak in the NIR region and often masked by interference from other components such as water and hemoglobin. Instead of using direct optical absorption by glucose, this study proposes an index calculated from oxy- and deoxyhemoglobin signals that shows a good correlation with BGLs while using conventional visible and NIR spectroscopy. The metabolic index, which is based on tissue oxygen consumption, was derived through analytical methods and further verified and reproduced in a series of glucose challenge experiments. Blood glucose estimation units were prototyped by utilizing commercially available smart devices. Our experimental results showed that the phase delay between the oxy- and deoxyhemoglobin signals in near-infrared spectroscopy correlates with BGL measured by a conventional continuous glucose monitor. The proposed method was also confirmed to work well with visible spectroscopy systems based on smartphone cameras. The proposed method also demonstrated excellent repeatability in results from a total of 19 oral challenge tests. This study demonstrated the feasibility of non-invasive glucose monitoring using existing photoplethysmography sensors for pulse oximeters and smartwatches. Evaluating the proposed method in diabetic or unhealthy individuals may serve to further increase its practicality.

The predictive value of first trimester maternal serum pregnancy-associated plasma protein-a (papp-a) level in predicting gestational diabetes mellitus

Aims: The aim of this study is to evaluate the predictive value of first trimester biochemical markers in the subsequent development of gestational diabetes mellitus. Methods: Data were retrospectively collected from the file records of 361 pregnant patients, who were admitted to the 1st Obstetrics and Gynecology Clinic at Sisli Etfal Education and Training Hospital for first trimester prenatal screening test between 11-14 weeks of their gestation and who later had undergone 50 gram glucose challenge test at 24-28 weeks of their gestation, between November 2007 and February 2011. Age, patient weight, Crown rump length (CRL), gestational week, Pregnancy-Associated Plasma Protein-A (PAPP-A) concentration, PAPP-A multiple of median (MoM) value, Beta-human koryonik gonadotropin (B-HCG) concentration, B-HCG MoM value, 50 and 100 g oral glucose challange test result were recorded from the files. Gestational diabetes was diagnosed according to National Diabates Data Grup cutt-off values and criteria. The association between first trimester biochemical markers and subsequent development of gestational diabetes was evaluated. Results: In this study low PAPP-A and/or HCG MoM values and increased Nuchal translucency (NT) MoM values were found to be statistically significant for subsequent development of gestational diabetes. Conclusion: GDM is an important health problem that carries many risks of complications for both mother and fetus. Pregnant women with GDM may have high blood sugar levels before diagnosis at 24 weeks of gestation, so fetal growth may be negatively affected by maternal hyperglycemia. Use of first trimester screening maternal serum biomarkers may lead to early diagnosis of GDM and interventions to improve maternal and fetal outcomes.

Incidence of overt diabetes in pregnancy among women with 50-g glucose challenge test ≥ 200mg/dL.

To determine the incidence of overt diabetes in pregnancy (ODIP) among women with 50-g GCT results ≥ 200mg/dL and compare characteristics and pregnancy outcomes between women with and without gestational diabetes (GDM). A retrospective cohort study was conducted in 212 pregnant women whose 50-g GCT results ≥ 200mg/dL. ODIP was diagnosed from 75-g OGTT if fasting plasma glucose ≥ 126 and/or 2-h plasma glucose ≥ 200mg/dL. Various characteristics and pregnancy outcomes were compared between ODIP and those with and without GDM. Incidence of ODIP was 1.9% of all pregnant women and 23.6% of women with 50-g GCT ≥ 200mg/dL. Women with ODIP and GDM were more likely to be overweight or obese than those without GDM (52%, 39.6%, and 18.2%, p < 0.001). Women with ODIP had significantly higher 50-g GCT results, lower gestational weight gain, and were less likely to deliver vaginally. Insulin therapy was significantly more common in women with ODIP compared to GDM (70.2% vs. 15.4%, p < 0.001). Rates of LGA, macrosomia, and other neonatal outcomes were comparable. BMI ≥ 25kg/m2 and 50-g GCT ≥ 240mg/dL independently increased the risk of any abnormal glucose tolerance [adjusted OR 3.22 (95% CI 1.55-6.70) and 2.28 (95% CI 1.14-4.58)] and ODIP [adjusted OR 9.43 (95% CI 2.15-41.38) and 6.36 (95% CI 2.85-14.18)], respectively. Incidence of ODIP was 23.6% of women with 50-g GCT ≥ 200mg/dL. BMI ≥ 25kg/m2 and 50-g GCT ≥ 240mg/dL independently increased the risk of GDM and ODIP. Neonatal complications were comparable between ODIP and those with and without GDM.

Light stimulation of mitochondria reduces blood glucose levels.

Mitochondria regulate metabolism, but solar light influences its rate. Photobiomodulation (PBM) with red light (670 nm) increases mitochondrial membrane potentials and adenosine triphosphate production and may increase glucose demand. Here we show, with a glucose tolerance test, that PBM of normal subjects significantly reduces blood sugar levels. A 15 min exposure to 670 nm light reduced the degree of blood glucose elevation following glucose intake by 27.7%, integrated over 2 h after the glucose challenge. Maximum glucose spiking was reduced by 7.5%. Consequently, PBM with 670 nm light can be used to reduce blood glucose spikes following meals. This intervention may reduce damaging fluctuations of blood glucose on the body.

Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits

Aims/hypothesisGestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits.MethodsWe collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women’s and Children’s Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels.ResultsWe identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42×10–29), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2 h OGTT glucose levels were 4 out of 4, 6 out of 9, 10 out of 11, 5 out of 7 and 4 out of 4, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM.Conclusions/interpretationOur findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels.Data availabilitySummary statistics for GDM; fasting plasma glucose; 0 h, 1 h and 2h OGTT; and the 55 biomarkers are available in the GWAS Atlas (study accession no.: GVP000001, https://ngdc.cncb.ac.cn/gwas/browse/GVP000001).Graphical

A50 PRODUCTION OF A PANCREATIC AND INTESTINAL HEPATOCYTE NUCLEAR FACTOR 4A DOUBLE KNOCKOUT MOUSE MODEL TO UNRAVEL NEW MECHANISMS CONTROLLING METABOLISM

Abstract Background Hepatocyte nuclear factor (HNF) 4A is a transcription factor mainly found within endodermal organs, including the intestine and pancreas. HNF4A controls the expression of genes associated with glucose transit, glycolytic enzymes, lipid and drug metabolism, and incretin production from intestinal enteroendocrine cells. Mutations within this are linked to various diseases, including maturity-onset diabetes of the young and increased risk of Type 2 diabetes mellitus. However, it remains unclear whether intestinal and pancreatic HNF4A is functionally involved in glucose metabolism. This could be partly due to the lack of suitable experimental model that allow recreating phenotypes associated with hnf4a lost in two key organs involved in controlling body glucose levels. Aims To generate a conditionally mutant mouse line that does not express HNF4A in the intestine or the pancreas and to investigate how glucose metabolism is affected in these mice. Methods Conditional deletion in each organ was achieved by mating VillinCre or InsCreER with Hnf4αloxP/loxP C57BL/6 mice, respectively. The mutant mouse line was then generated by crossing mice Hnf4αloxP/loxP+VillinCre and Hnf4αloxP/loxP+InsCreER. PCR was performed to confirm all genotypes. Male and female mice around 2-3 months were distributed in four groups, including controls, Hnf4α-deleted intestine only, Hnf4α-deleted pancreas only, and Hnf4α-deleted in both organs. HNF4A expression was measured by qPCR, immunoblot and immunofluorescence. Glucose metabolism tests, including oral glucose tolerance (2g/kg) and insulin tolerance (0.75 International Units/kg) were performed. The blood glucose levels were measured after overnight fasting at 15, 30, 60, and 120 min. Results The body weight of four groups of mice remained comparable over experimental time. HNF4A expression was not detected from double mutant mice’s gut epithelial or pancreatic β cells. The oral glucose challenge showed a difference among the group of experimental mice as compared to the control group. After 15 min, blood glucose values of double mutant mice remained higher than control mice, for which glucose clearance was less efficient in the mutants. Insulin tolerance tests demonstrated that double mutant mice behave differently than control mice, suggesting a defect in insulin response. Conclusions These promising preliminary results allow us to obtain and characterize a novel murine model to study glucose metabolic syndrome that could be related to hnf4a gene deletion in both the gut and pancreas. Further studies are needed to establish a mechanism by which the HNF4A transcription factor could interplay between the intestine and the pancreas during whole-body glucose metabolism. Funding Agencies CIHRBourses d’excellence de l'Université de Sherbrooke

Effect of Arterialization on Venous Blood Glucose Concentrations and Implications for Observed Continuous Glucose Monitoring Accuracy.

Background: Heating of the arm and/or hand ("arterialization") is sometimes used in continuous glucose monitoring (CGM) performance studies with the reported aim of reducing differences between venous and capillary glucose concentrations. In this study, the effect of heating on venous glucose concentrations and CGM accuracy was investigated. Methods: A heating pad set to 50°C (122°F) was used with 20 participants to heat either the dominant or nondominant arm and hand. Venous and capillary samples were obtained every 15 min on both arms throughout each of three 6-h glucose challenges. CGM sensors were worn on each upper arm for each of the three visits. Results: Heating of the arm led to a median increase in venous glucose concentrations of +1.4%. No similar effect on capillary concentrations was observed. As a result, the median capillary to venous difference decreased from +5.9% in the nonheated arm to +4.2% in the heated arm. CGM accuracy observed in this study was affected by the selection of heated venous, nonheated venous, or capillary glucose concentrations as comparator data. The heating effect was more pronounced with rapidly decreasing glucose concentrations. Temperatures on the skin did not exceed 40°C (104°F). No adverse events or protocol deviations were associated with the use of the heating pad. Conclusions: Heating of the arm led to a small increase in venous glucose concentrations, but venous concentrations did not reach the level of capillary glucose concentrations. CGM accuracy observed in this study varied depending on the selected comparator data. This study was registered at the German Clinical Trials Register (DRKS00031197).

ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity

BackgroundAsialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity.MethodsASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration.ResultsASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function.ConclusionASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage.