Oral Glucose Challenge Research Articles

Evaluating the causal effect of circulating proteome on the glycemic traits: Evidence from Mendelian randomization.

Exploring the mechanisms underlying abnormal glycemic traits is important for deciphering type 2 diabetes and characterizing novel drug targets. This study aimed to decipher the causal associations of circulating proteins with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) using large-scale proteome-wide Mendelian randomization (MR) analyses. Genetic data on plasma proteomes were obtained from ten proteomic genome-wide association studies (GWAS). Both cis- and cis+trans-protein quantitative trait loci (pQTLs) MR analyses were conducted. Bayesian colocalization, Steiger filtering analysis, assessment of protein-altering variants, and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings. Protein-protein interaction, pathway enrichment analysis, and evaluation of drug targets were performed. Thirty-three proteins were identified with causal effects on FG, FI, or HbA1c but not 2hGlu in the cis-pQTLs analysis, and 93 proteins had causal effects on glycemic traits in the cis+trans-pQTLs analysis. Most proteins were either considered druggable or drug targets. In conclusion, many novel circulating protein biomarkers were identified to be causally associated with glycemic traits. These biomarkers enhance the understanding of molecular etiology and provide insights into the screening, monitoring, and treatment of diabetes.

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±11years; glycated haemoglobin (HbA1c) 7.6±1.5%] and 20 controls without T2D (9 males/11 females; aged 49±13years, 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 ) to acutely attenuate peripheral chemoreceptor activity. A subset of participants (n=9 per group) completed two additional visits [normoxia (0.21 ), hyperoxia (1.0 )] where glucose and insulin were measured for 2h following an oral glucose challenge. HVR was augmented in adults with T2D (-0.84±0.49Lmin-1/%) vs. control (-0.48±0.40Lmin-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.

Investigation of 50 g Oral Glucose Challenge Test Efficacy in Pregnant with and Without Risk Factors in Gestational Diabetes Screening

Investigation of 50 g Oral Glucose Challenge Test Efficacy in Pregnant with and Without Risk Factors in Gestational Diabetes Screening

Altered glucose kinetics occurs with aging: a new outlook on metabolic flexibility.

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios [RER = carbon dioxide production (V̇co2)/oxygen consumption (V̇o2)] during a 2-h 75-g oral glucose tolerance test (OGTT). After an 12-h overnight fast, 28 participants, 15 young (21-35 yr; 7 men and 8 women) and 13 older (60-80 yr; 7 men and 6 women), received venous primed-continuous infusions of [6,6-2H]glucose and [3-13C]lactate with a [Formula: see text] bolus. After a 90-min metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 min post glucose consumption, peaked at 60 min, and remained elevated. As assessed by rates of appearance (Ra) and disposal (Rd) and metabolic clearance rate (MCR), glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population after the oral glucose challenge. Finally, there were no differences in 12-h fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population after a glucose challenge. Furthermore, those physiological deficits are not detected from changes in RER during an OGTT.NEW & NOTEWORTHY To determine metabolic flexibility in response to an OGTT, we studied healthy young and older men and women to determine glucose kinetics and changes in RER. Compared to young subjects, glucose kinetics were suppressed in older healthy individuals during an OGTT. Surprisingly, the age-related changes in glucose flux were not reflected in RER measurements; thus, RER measurements do not give a complete view of metabolic flexibility in healthy individuals.

Bacteroides uniformis CECT 7771 requires adaptive immunity to improve glucose tolerance but not to prevent body weight gain in diet-induced obese mice

BackgroundThe metabolic disturbances of obesity can be mitigated by strategies modulating the gut microbiota. In this study, we sought to identify whether innate or adaptive immunity mediates the beneficial metabolic effects of the human intestinal bacterium Bacteroides uniformis CECT 7771 in obesity.MethodsWe evaluated the effects of orally administered B. uniformis on energy homeostasis, intestinal immunity, hormone levels, and gut microbiota in wild-type and Rag1-deficient mice with diet-induced obesity. We also assessed whether B. uniformis needed to be viable to exert its beneficial effects in obesity and to directly induce immunoregulatory effects.ResultsThe administration of B. uniformis to obese mice improved glucose tolerance and insulin secretion, restored the caloric intake suppression after an oral glucose challenge, and reduced hyperglycemia. The pre- and post-prandial glucose-related benefits were associated with restoration of the anti-inflammatory tone mediated by type 2 macrophages and regulatory T cells (Tregs) in the lamina propria of the small intestine. Contrastingly, B. uniformis administration failed to improve glucose tolerance in obese Rag1-/- mice, but prevented the increased body weight gain and adiposity. Overall, the beneficial effects seemed to be independent of enteroendocrine effects and of major changes in gut microbiota composition. B. uniformis directly induced Tregs generation from naïve CD4+ T cells in vitro and was not required to be viable to improve glucose homeostasis but its viability was necessary to prevent body weight gain in diet-induced obese wild-type mice.ConclusionsHere we demonstrate that B. uniformis modulates the energy homeostasis in diet-induced obese mice through different mechanisms. The bacterium improves oral glucose tolerance by adaptive immunity-dependent mechanisms that do not require cell viability and prevents body weight gain by adaptive immunity-independent mechanisms which require cell viability.4U7c4GKqHnKBBCB4_RfnuDVideo

Associations of Abnormal Maternal Glucose Regulation in Pregnancy with Offspring Adiposity, Insulin Resistance, and Adipokine Markers During Childhood and Adolescence

To examine the associations of abnormal maternal glucose regulation in pregnancy with offspring adiposity, insulin resistance, adipokine, and inflammatory markers during childhood and adolescence. Project Viva is a prospective prebirth cohort (n=2128 live births) initiated from 1999 through 2002 in Eastern Massachusetts, US. During the second trimester of pregnancy, clinicians used 2-step oral glucose challenge testing to screen for gestational diabetes mellitus. In the offspring, we measured anthropometry, insulin resistance, adipokines, lipids, and inflammatory markers in mid-childhood (n=1107), early adolescence (n=1027), and mid-adolescence (n=693). We used multivariable linear regression models and generalized estimating equations adjusted for child age and sex, and for maternal age, race/ethnicity, education, parity, and smoking during pregnancy; we further adjusted for prepregnancy body mass index (BMI). In mid-adolescence (17.1 [0.8] years of age), offspring of mothers with gestational diabetes mellitus (n=27) had a higher BMI z-score (β; 95% Cl; 0.41 SD; 0.00, 0.82), sum of skinfolds (8.15mm; 2.48, 13.82), homeostatic model assessment for insulin resistance (0.81 units; 0.13, 1.50), leptin z-score (0.40 SD; 0.01, 0.78), and leptin/adiponectin ratio z-score (0.51 SD; CI 0.09, 0.93) compared with offspring of mothers with normoglycemia (multivariable-adjusted models). The associations with BMI, homeostatic model assessment for insulin resistance, and adiponectin seemed stronger in mid-adolescence compared with earlier time points. The associations were attenuated toward the null after adjustment for maternal prepregnancy BMI. Exposure to gestational diabetes mellitus is associated with higher adiposity, insulin resistance, and altered adipokines in mid-adolescence. Our findings suggest that the peripubertal period could be a key time for the emergence of prenatally programmed metabolic abnormalities.

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.

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.

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

Plasma undercarboxylated osteocalcin dynamics with glycemic stress reflects insulin sensitivity and beta-cell function in humans with and without T2DM

This study aimed to better understand the relationship between bone-related biomarkers and nutrient stress in the context of metabolic health. We investigated plasma osteocalcin (OC) during an oral glucose challenge and experimental hyperinsulinemia in Type 2 diabetes (T2DM) and lean healthy controls (LHC). Older individuals with obesity and T2DM (n = 9) and young LHCs (n = 9) underwent a 75g oral glucose tolerance test (OGTT) and a 40 mU/m2/min hyperinsulinemic-euglycemic clamp. Plasma undercarboxylated OC (ucOC) and total OC were measured at baseline, 60mins, and 120mins of the OGTT and clamp via ELISA. In addition, plasma alkaline phosphatase (ALP), leptin, adiponectin, Vitamin D and insulin were measured and indices of insulin sensitivity and β-cell function were derived. The T2DM group had lower (p<0.05) ucOC and ucOC:total OC ratio than LHC during both the OGTT and clamp. Further, baseline ucOC was positively correlated to indices of β-cell function and negatively correlated to indices of insulin resistance when both groups were combined (all p<0.05). Suppression of OC observed in T2DM may be related to glucose intolerance and insulin resistance. Similarly, our data suggest that the observed phenotypic differences between groups are likely a product of long-term glucose dysregulation rather than acute flux in glucose or insulin.

Association of Bone Mineral Density and Bone Turnover Markers with the Risk of Diabetes: Hong Kong Osteoporosis Study and Mendelian Randomization.

Preclinical studies demonstrated that bone plays a central role in energy metabolism. However, how bone metabolism is related to the risk of diabetes in humans is unknown. We investigated the association of bone health (bone mineral density [BMD] and bone turnover markers) with incident type-2 diabetes mellitus (T2DM) based on the Hong Kong Osteoporosis Study (HKOS). A total of 993 and 7160 participants from the HKOS were studied for the cross-sectional and prospective analyses, respectively. The cross-sectional study evaluated the association of BMD and bone biomarkers with fasting glucose and glycated hemoglobin (HbA1c ) levels, whereas the prospective study examined the associations between BMD at study sites and the risk of T2DM by following subjects a median of 16.8 years. Body mass index (BMI) was adjusted in all full models. Mendelian randomization (MR) was conducted for causal inference. In the cross-sectional analysis, lower levels of circulating bone turnover markers and higher BMD were significantly associated with increased fasting glucose and HbA1c levels. In the prospective analysis, higher BMD (0.1 g/cm2 ) at the femoral neck and total hip was associated with increased risk of T2DM with hazard ratios (HRs) of 1.10 (95% confidence interval [CI], 1.03 to 1.18) and 1.14 (95% CI, 1.08 to 1.21), respectively. The presence of osteoporosis was associated with a 30% reduction in risk of T2DM compared to those with normal BMD (HR = 0.70; 95% CI, 0.55 to 0.90). The MR results indicate a robust genetic causal association of estimated BMD (eBMD) with 2-h glucose level after an oral glucose challenge test (estimate = 0.043; 95% CI, 0.007 to 0.079) and T2DM (odds ratio = 1.064; 95% CI, 1.036 to 1.093). Higher BMD and lower levels of circulating bone biomarkers were cross-sectionally associated with poor glycemic control. Moreover, higher BMD was associated with a higher risk of incident T2DM and the association is probably causal. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

An oral glucose tolerance test does not affect cerebral blood flow: role of NOS.

Animal data indicate that insulin triggers a robust nitric oxide synthase (NOS)-mediated dilation in cerebral arteries similar to the peripheral tissue vasodilation observed in healthy adults. Insulin's role in regulating cerebral blood flow (CBF) in humans remains unclear but may be important for understanding the links between insulin resistance, diminished CBF, and poor brain health outcomes. We tested the hypothesis that an oral glucose challenge (oral glucose tolerance test, OGTT), which increases systemic insulin and glucose, would acutely increase CBF in healthy adults due to NOS-mediated vasodilation, and that changes in CBF would be greater in anterior regions where NOS expression or activity may be greater. In a randomized, single-blind approach, 18 young healthy adults (24 ± 5 yr) underwent magnetic resonance imaging (MRI) with a placebo before and after an OGTT (75 g glucose), and 11 of these adults also completed an NG-monomethyl-l-arginine (l-NMMA) visit. Four-dimensional (4-D) flow MRI quantified macrovascular CBF and arterial spin labeling (ASL) quantified microvascular perfusion. Subjects completed baseline imaging with a placebo (or l-NMMA), then consumed an OGTT followed by MRI scans and blood sampling every 10-15 min for 90 min. Contrary to our hypothesis, total CBF (P = 0.17) and global perfusion (P > 0.05) did not change at any time point up to 60 min after the OGTT, and no regional changes were detected. l-NMMA did not mediate any effect of OGTT on CBF. These data suggest that insulin-glucose challenge does not acutely alter CBF in healthy adults.

A comparison study of maternal and perinatal outcomes with gestational diabetes mellitus, impaired glucose tolerance, and normal glucose tolerance

Gestational diabetes mellitus (GDM) and impaired glucose tolerance (IGT), which are growing health concerns globally, are the most common metabolic and endocrine perinatal issues. It is a contentious entity with competing policies and procedures. Most physicians in the United States employ a two-step procedure, starting with a 50-g non-fasting oral glucose challenge test at 24 to 28 weeks and moving on to a 100-g fasting test for women who receive a positive screening result. Instead, doctors use the Diabetes in Pregnancy Study Group India (DIPSI) technique and conduct just a 75-g, two-hour fasting oral glucose tolerance test. The prospective observational study was approved by the hospital's institutional ethics committee and was conducted from April 2020 to September 2021 at the department of obstetrics and gynecology at Stanley Medical College Hospital in Chennai, Tamil Nadu, India. The patients were chosen in accordance with the inclusion criteria, which called for first-trimester pregnant women without diabetes mellitus. Both oral and written consent were also obtained. DIPSI performed the screening. The WHO standards have been updated to be a one-step process with a single glycemic value. According to the results of this study, GDM is linked to harmful consequences that might affect both the mother and the foetus. The short- and long-term consequences in both the mother and the newborn can be greatly reduced with early detection and timely therapy of this illness. In this study, birth weights ranging from 2.5 to 3.5 kg were the same for GDM and IGT moms. IGT mothers should also be followed up on, and we should be more watchful at birth, even though we monitor GDM mothers.

Severity of sleep apnea impairs adipose tissue insulin sensitivity in individuals with obesity and newly diagnosed obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common sleep disorder associated with increased risk for the development of type 2 diabetes. While studies have examined the effects of sleep on whole-body insulin sensitivity, little is known about the effects of sleep on adipose tissue insulin sensitivity in patients with OSA. We analyzed if the severity of OSA, measured by apnea-hypopnea index (AHI), is associated with adipose tissue insulin sensitivity. We examined the relationship between sleep parameters and adipose tissue insulin sensitivity in non-diabetic participants with obesity and newly diagnosed OSA who underwent overnight polysomnography and a 2 h oral glucose tolerance test during which circulating free fatty acids were measured. In total, 16 non-diabetic participants with obesity and newly diagnosed OSA (sex, 81.3% males; mean age, 50.9 ± 6.7 y; BMI, 36.5 ± 2.9 kg/m2; AHI, 43 ± 20 events/h) were included in the analysis. In our study participants, AHI is inversely associated with free-fatty acid suppression during oral glucose challenge (R = -0.764, p = 0.001). This relationship persisted even after statistical adjustment for age (R = -0.769, p = 0.001), body mass index (R = -0.733, p = 0.002), waist-to-hip ratio (R = -0.741, p = 0.004), or percent body fat mass (R = -0.0529, p = 0.041). Furthermore, whole-body insulin sensitivity as determined by the Matsuda index was associated with percent REM sleep (R = 0.552, p = 0.027) but not AHI (R = -0.119, p = 0.660). In non-diabetic patients with OSA, the severity of sleep apnea is associated with adipose tissue insulin sensitivity but not whole-body insulin sensitivity. The impairments in adipose tissue insulin sensitivity may contribute to the development of type 2 diabetes.

Insulin signaling in insulin-dysregulated Icelandic horses

The underlying molecular mechanisms leading to insulin dysregulation are poorly understood in horses. Therefore, this study aimed to determine if insulin dysregulation is associated with an altered basal expression and extent of phosphorylation of key proteins of the insulin signaling cascade in liver (LT), muscle (MT), and subcutaneous adipose tissue (AT) under basal and stimulated conditions. Twelve Icelandic horses were subjected (1) to an oral glucose (Gluc PO) challenge and (2) to an intravenous (Ins IV) insulin challenge in a crossover study. Biopsies of LT, MT, and AT were taken in vivo under basal conditions and after Gluc PO and Ins IV stimulation. Corresponding insulin levels were measured by an equine optimized ELISA (Mercodia AB, Uppsala). Insulin levels ≥ 110 µIU/mL at 120 min indicated that six horses were insulin dysregulated (HI), while six were not (NI). Gluc PO stimulation resulted in a more pronounced hyperinsulinemia and hyperglycemia in HI horses compared to NI horses. Western blot analysis of key proteins of the insulin signaling cascade revealed an enhanced phosphorylation of the insulin receptor (InsR) under Gluc PO (P = 0.001) and Ins IV stimulation (P = 0.017) within LT, but not in MT and AT. Phosphorylation of protein kinase B was enhanced under Gluc PO stimulation in all tissues and under Ins IV stimulation in MT and AT, while phosphorylation of adenosine monophosphate protein kinase α was reduced after glucose administration (P = 0.005) in all horses. Interestingly, HI horses had significantly higher amounts of phosphorylated mechanistic target of rapamycin (mTOR) in MT (P = 0.049), irrespective of any stimulation. In LT, the amount of phosphorylated mTOR decreased under Gluc PO conditions in HI horses, while an increase was observed in NI horses (P = 0.015). A major limitation was the inclusion of only Icelandic horses of advanced age since insulin dysregulation could be related to both the equine metabolic syndrome and/or pituitary pars intermedia dysfunction. In summary, insulin signaling appeared to be maintained in both HI and NI Icelandic horses, although post-receptor alterations were observed. Thus, ID might be an equine-specific metabolic condition, in which alterations of the mTOR signaling pathway may play a crucial role, as emphasized by higher mTOR phosphorylation in HI horses.

Abstract 029: Hypertensive Disorder Of Pregnancy Results In Loss Of Pancreatic Beta Cell Area In Female Rat Offspring Without Development Of Glucose Intolerance

Hypertensive disorders of pregnancy can result in increased risk for type 2 diabetes (T2D) in offspring. Reduced pancreatic beta cell area can also influence development of glucose intolerance or T2D. Using a rat model of reduced uterine perfusion pressure (RUPP) which leads to hypertension during pregnancy and intrauterine growth restriction, we previously demonstrated reduced beta cell area in female RUPP offspring vs Sham at embryonic day 19 persisting to postnatal day (PD)13. To determine if this alteration in beta cell area is associated with phenotypic changes in glucose handling as offspring mature, we assessed IPGTT (intraperitoneal glucose tolerance test), OGTT (oral glucose tolerance test) and ITT (insulin tolerance test) in PD14, PD28, 8 week and 6 month female offspring (n=5-11/group). Our results demonstrate no change in fasting blood glucose and no alteration in glucose handling with IP glucose administration at any age. However, peak glucose following oral glucose administration was significantly less in RUPP offspring at PD14 (196.3+/-8.6 mg/dl, RUPP; 218.3+/-9.5 mg/dl, Sham; p=0.05), PD28 (220.0+/-4.1 mg/dl, RUPP; 280.0+/-12.8 mg/dl, Sham; p&lt;0.05) and 6 months (139.6+/-3.8 mg/dl, RUPP; 150.9+/-4.5 mg/dl, Sham; p&lt;0.05) compared to Sham, suggesting the incretin effect on pancreas and non-pancreas tissues is more effective in controlling blood glucose in RUPP offspring vs Sham. In addition, the decrease in glucose level in response to insulin injection in ITT was significantly greater in RUPP offspring vs Sham at PD28 (58.9+/-5.0 mg/dl, RUPP; 78.3+/-8.9 mg/dl, Sham; p&lt;0.05) suggesting increased insulin sensitivity in non-pancreatic tissues in RUPP compared to Sham offspring. Our studies demonstrate female offspring of hypertensive pregnancies are not glucose intolerant by 6 months of age. Despite reduced pancreatic beta cell area in female RUPP offspring early in development, glucose handling was maintained and even improved after oral glucose challenge in older RUPP offspring. Overall, these data suggest that increased peripheral insulin sensitivity may reduce the demand for beta cell function, and our studies reinforce the idea that adverse pregnancy can have a lasting effect on development and function of the pancreas.

Characterization of impaired beta and alpha cell function in response to an oral glucose challenge in cystic fibrosis: a cross-sectional study.

The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.

Quality of Antenatal Care Services in Four Accredited Primary Health Care Centers in Cairo, Egypt

Abstract Background Antenatal care (ANC) is a careful, systematic assessment and follow-up of pregnant women, that includes education, counseling, screening, and treatment to assure the best possible health of the mother and her fetus. In order to assure each women gets the best quality of care, quality assessment of all items of antenatal care should be arranged regularly. This study aims to measure the perceived quality of antenatal care services, the adherence of the primary care physician to the Egyptian ministry of health guidelines as well as the overall satisfaction of pregnant women about their antenatal care services. Methods A cross sectional study was conducted from January till April 2021 among women aged 1849 years old who attend antenatal care clinics at four primary health centres in Cairo, Egypt. All health centres included in the study are government run facilities. Results Despite the high overall satisfaction (98%) reported for the antenatal care services, the total quality score was low (&amp;lt;60%), the highest satisfaction was reported from most of accessibility point and cleanliness of the primary care centers, answering inquiries, number of the doctors, discussion of the delivery plan, health education about importance of folic acid and iron supplements, family planning and cost of the service. Lowest satisfaction reported from the PHC was for working hours of the center, history taking, examination time, health education about diet, breastfeeding, and the harmful effects of passive smoking. Although most women reported that they had the majority of the Egyptian antenatal guidelines covered by their physician, items like past medical history, personal hygiene and oral glucose challenge test were missed. Conclusion The findings showed the need for new approaches to upgrade the quality of antenatal care and improve the health education skills for the primary care physicians, despite the high overall satisfaction.

The effect of pre-dosing with metformin on the insulin response to oral sugar in insulin-dysregulated horses.

A single dose of metformin administered 1 h prior to oral glucose challenge was previously shown to reduce insulinaemic responses in horses with experimentally-induced insulin dysregulation (ID). Targeted administration could be useful for controlling post-prandial hyperinsulinaemia in horses with naturally-occurring ID. The objective was to compare the insulinaemic and glycaemic responses to oral sugar testing (OST) performed at different intervals after a single dose of metformin in horses with naturally-occurring ID. We hypothesised that pre-treatment with one dose of metformin would significantly decrease the insulinaemic response to OST. Randomised cross-over in vivo experiment. Eight university-owned adult horses with naturally-occurring ID underwent OST 1, 2 and 6 h following a single oral dose of metformin (30 mg/kg) or 1 h after placebo (240 mL water) with a 7-day washout between treatments over a period of 3 weeks. Plasma insulin, C-peptide and glucose concentrations were measured at 0, 60 and 90 min after 0.45 mL/kg light corn syrup and the effect of treatment (and the interval since dosing) examined using a mixed effects linear regression model. Metformin treatment had no significant effect on plasma glucose, insulin or C-peptide concentrations at any time point compared with placebo (p > 0.05). For OST 1 h post metformin, median (IQR) plasma insulin was 91.3 (62.4-114.9) μIU/mL at 60 min versus 76.2 (59.1-134.5) for placebo (p = 0.8) and 62.7 (31.4-109.7) at 90 min versus 51.8 (29.2-126.3) for placebo (p = 0.9). Small sample size may limit identification of more subtle decreases in insulin concentration with metformin pre-dosing. The results of this study are relevant only for one pre-treatment dose (30 mg/kg) which limits extrapolation to predictions about the effects of longer-term metformin administration on insulin and glucose dynamics in the horse. The results do not support the use of targeted metformin treatment to reduce post-prandial hyperinsulinaemia in horses with naturally-occurring ID.