Glucose Challenge Research Articles

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

Predictive capacity of fetal pancreatic circumference for gestational diabetes mellitus.

To assess the capacity of fetal pancreatic size, before standard blood glucose testing for screening and diagnosis, to predict maternal gestational diabetes mellitus (GDM). This was a retrospective cohort study of low-risk pregnant women recruited during routine second-trimester fetal anatomical screening at 20-25 weeks' gestation at two ultrasound units in Israel between 2017 and 2020. The predictive performance of fetal pancreatic circumference ≥ 80th and ≥ 90th centiles and glucose challenge test (GCT) was examined for the outcome of GDM. The independent-samples t-test was used to compare mean pancreatic circumference centile between pregnancies with GDM and those without GDM. Diagnostic performance was evaluated with 2 × 2 contingency tables and receiver-operating-characteristics (ROC) curves. Overall, 195 women were selected for statistical analysis. Twenty-four (12.3%) women were diagnosed subsequently with GDM. The mean ± SD fetal pancreatic circumference centile was significantly higher in the GDM group compared with the non-GDM group (82.4 ± 14.6 vs 62.8 ± 27.6; P < 0.001). The pancreatic circumference centile was correlated positively with the estimated fetal weight centile (Pearson's coefficient, 0.243; P = 0.001). The 80th centile cut-off for pancreatic circumference had the highest sensitivity (70.8%) and positive predictive value (23.3%) for future maternal GDM, with the best trade-off between sensitivity and specificity achieved at the 75th centile cut-off (sensitivity, 79%; specificity, 60%). The GCT had better specificity (90.2%) and negative predictive value (97.9%) compared with both cut-offs in pancreatic circumference. The area under the ROC curve was higher for pancreatic circumference compared with GCT (0.71 vs 0.64) and only the former was statistically significant (P = 0.001). Fetal pancreatic circumference has a higher positive predictive capacity compared with GCT. Measuring pancreatic circumference can identify pregnancies at high risk for maternal GDM, thereby promoting earlier diagnosis and treatment, decreasing the time period during which the fetus is exposed to high maternal glucose levels and improving infant outcome. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Tanycyte radial morphology and proliferation are influenced by fibroblast growth factor receptor 1 and high-fat diet.

Fibroblast growth factor receptor 1 (FGFR1) is a widely expressed, membrane-bound receptor that transduces extracellular signals from FGF ligands and cadherins, resulting in intracellular signals influencing cellular growth, proliferation, calcium, and transcription. FGF21 and FGF2 stimulate the proliferation of tanycytes, specialized radial astrocytes along the ventricle of the hypothalamus, and influence metabolism. Tanycytes are in a privileged position between the cerebrospinal fluid, the blood supply in the median eminence, and neurons within nuclei in the hypothalamus. The effect of FGFR1 signaling upon tanycyte morphology and metabolism was examined in adult mice with conditional deletion of the Fgfr1 gene using the Fgfr1flox/flox; Nestin-Cre+ line. Loss of Fgfr1 resulted in shorter β tanycytes along the medial eminence. Control Fgfr1flox/flox littermates and Fgfr1flox/flox, Nestin-Cre+ (Fgfr1 cKO) knockout mice were placed on a 1-month long high-fat diet (HFD) or a normal-fat diet (NFD), to investigate differences in body homeostasis and tanycyte morphology under an obesity inducing diet. We found that FGFR1 is a vital contributor to tanycyte morphology and quantity and that it promotes stem cell maintenance in the hypothalamus and hippocampal dentate gyrus. The Fgfr1 cKO mice developed impaired tolerance to a glucose challenge test on a HFD without gaining more weight than control mice. The combination of HFD and loss of Fgfr1 gene resulted in altered β and α tanycyte morphology, and reduced stem cell numbers along the third ventricle of the hypothalamus and hippocampus.

Proteomic Analysis of Rap1A GTPase Signaling-Deficient C57BL/6 Mouse Pancreas and Functional Studies Identify an Essential Role of Rap1A in Pancreas Physiology.

Ras-related Rap1A GTPase is implicated in pancreas β-cell insulin secretion and is stimulated by the cAMP sensor Epac2, a guanine exchange factor and activator of Rap1 GTPase. In this study, we examined the differential proteomic profiles of pancreata from C57BL/6 Rap1A-deficient (Null) and control wild-type (WT) mice with nanoLC-ESI-MS/MS to assess targets of Rap1A potentially involved in insulin regulation. We identified 77 overlapping identifier proteins in both groups, with 8 distinct identifier proteins in Null versus 56 distinct identifier proteins in WT mice pancreata. Functional enrichment analysis showed four of the eight Null unique proteins, ERO1-like protein β (Ero1lβ), triosephosphate isomerase (TP1), 14-3-3 protein γ, and kallikrein-1, were exclusively involved in insulin biogenesis, with roles in insulin metabolism. Specifically, the mRNA expression of Ero1lβ and TP1 was significantly (p < 0.05) increased in Null versus WT pancreata. Rap1A deficiency significantly affected glucose tolerance during the first 15-30 min of glucose challenge but showed no impact on insulin sensitivity. Ex vivo glucose-stimulated insulin secretion (GSIS) studies on isolated Null islets showed significantly impaired GSIS. Furthermore, in GSIS-impaired islets, the cAMP-Epac2-Rap1A pathway was significantly compromised compared to the WT. Altogether, these studies underscore an essential role of Rap1A GTPase in pancreas physiological function.

Does the gestational age at which the glucose challenge test (GCT) is conducted influence the diagnosis of gestational diabetes mellitus (GDM)?

This study's objective is to investigate disparities in the rates of gestational diabetes mellitus (GDM) diagnosis, influenced by the timing of the glucose challenge test GCT. This retrospective cohort study included women with singleton or twin pregnancies exhibiting abnormal GCT result between 24 and 28 weeks of gestation, followed by an oral glucose tolerance test OGTT during the same period. Data regarding pregnancy follow-up from patients' deliveries at a singular tertiary medical from 2014 to 2022 were retrieved. The probability of GDM diagnosis was stratified based on the gestational week of the GCT and the definition of a positive OGTT, delineated by one or two abnormal values. The study included 636 women with abnormal GCT between 24 and 28weeks of gestation. Of them, 157 unerwent the GCT between 24.0 and 24.6weeks, 204 between 25.0 and 25.6weeks, 147 between 26.0 and 26.6weeks, and 128 between 27.0 and 28.6weeks. We found that the highest incidence of GDM, defined by one or two pathological values of the OGTT, following the initial screening with a GCT, where abnormal results were defined as values exceeding 140mg/dL, was diagnosed in patients who underwent GCT between 26.0 and 26.6weeks of gestation. Conversely, the lowest rates were observed in patients screened between 24.0 and 24.6weeks of gestation. The timing of screening for GDM using the GCT significantly affects the rate of diagnosis. Clinicians managing pregnancies should consider this data when formulating treatment plans.

Inadequate Glucagon Suppression During OGTT in Prediabetes: A Systematic Review and Meta-analysis.

Glucagon plays a role in the development of type 2 diabetes, yet its role in prediabetes (preDM) remains uncertain. To evaluate glucagon levels in the fasting state and its response to glucose inhibition in preDM through meta-analysis. A systematic search across Pubmed, Embase, Web of Science, and Cochrane Library identified studies assessing glucagon levels during 75 g oral glucose tolerance test (OGTT) in both preDM and normal glucose tolerance (NGT) cohorts. Data on glucagon, glucose, and insulin were pooled using a random-effect model. Although glucagon levels decreased in both preDM and NGT groups upon glucose challenge, glucagon levels at 0 hours, 0.5 hours, 1 hour, and 1.5 hours in preDM were significantly higher compared to NGT, despite higher glucose levels at all time points and higher insulin levels at 0 hours, 1 hour, 1.5 hours, and 2 hours during OGTT. Subgroup analysis revealed that in studies using the radioimmunoassay method, glucagon levels in preDM were higher at 0.5 hours and 1 hour than NGT, while in studies using the ELISA method, glucagon levels were similar to those of the NGT group despite higher glucose in preDM compared to NGT. Fasting glucagon level was inadequately suppressed in both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Responsiveness to glucose inhibition was preserved in IFG, while glucagon level in IGT group at 0.5 hours after glucose intake was not suppressed and was higher than NGT. Glucagon was not adequately suppressed during OGTT in preDM. Glucagon dysregulation is a contributing mechanism underlying both IFG and IGT.

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.

Forward programming of hiPSCs towards beta-like cells using Ngn3, Pdx1, and MafA

Transplantation of stem cell-derived β-cells is a promising therapeutic advancement in the treatment of type 1 diabetes mellitus. A current limitation of this approach is the long differentiation timeline that generates a heterogeneous population of pancreatic endocrine cells. To address this limitation, an inducible lentiviral overexpression system of mature β-cell markers was introduced into human induced-pluripotent stem cells (hiPSCs). Following the selection of the successfully transduced hiPSCs, the cells were treated with doxycycline in the pancreatic progenitor induction medium to support their transition toward the pancreatic lineage. Cells cultured with doxycycline presented the markers of interest, NGN3, PDX1, and MAFA, after five days of culture, and glucose-stimulated insulin secretion assays demonstrated that the cells were glucose-responsive in a monolayer culture. When cultured as a spheroid, the markers of interest and insulin secretion in a static glucose-stimulated insulin secretion assay were maintained; however, insulin secretion upon consecutive glucose challenges was limited. Comparison to human fetal and adult donor tissues identified that although the hiPSC-derived spheroids present similar markers to adult insulin-producing cells, they are functionally representative of fetal development. Together, these results suggest that with optimization of the temporal expression of these markers, forward programming of hiPSCs towards insulin-producing cells could be a possible alternative for islet transplantation.

The Diagnostic Value of the 50-Gram Glucose Challenge Test at Various Cut-off Levels Combined with Clinical Risk Factors in Predicting the Diagnosis of Gestational Diabetes Mellitus

The Diagnostic Value of the 50-Gram Glucose Challenge Test at Various Cut-off Levels Combined with Clinical Risk Factors in Predicting the Diagnosis of Gestational Diabetes Mellitus

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

Fetal abdominal obesity in women with one value abnormality on diagnostic test for gestational diabetes mellitus.

Previous studies have shown that fetal abdominal obesity (FAO) was already observed at the time of gestational diabetes mellitus (GDM) diagnosis and persisted until delivery despite management in older and/or obese women. In this study, we investigated whether fetuses of women with milder hyperglycemia than GDM have accelerated abdominal growth, leading to adverse pregnancy outcomes. We retrospectively reviewed the medical records of 7,569 singleton pregnant women who were universally screened using a 50-g glucose challenge test (GCT) and underwent a 3-h 100-g oral glucose tolerance test (OGTT) if GCT result was ≥140mg/dL. GDM, one value abnormality (OVA), and normal glucose tolerance (NGT, NGT1: GCT negative, NGT2: GCT positive & OGTT negative) were diagnosed using Carpenter-Coustan criteria. With fetal biometry data measured simultaneously with 50-g GCT, relative fetal abdominal overgrowth was investigated by assessing the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference(AC) per actual GA by the last menstruation period(LMP), biparietal diameter(BPD) or femur length(FL), respectively. FAO was defined as FAOR ≥90th percentile The FAORs of GA-AC/GA-LMP and GA-AC/GA-BPD were significantly higher in OVA subjects compared to NGT subjects but not in NGT2 subjects. Although the frequency of FAO in OVA (12.1%) was between that of NGT (9.6%) and GDM (18.3%) without statistically significant difference, the prevalence of large for gestational age at birth and primary cesarean delivery rates were significantly higher in OVA (9.8% and 29.7%) than in NGT (5.1% and 21.5%, p<0.05). Particularly, among OVA subjects with FAO, the prevalence (33.3% and 66.7%) was significantly higher than in those without FAO (9.7% and 24.2%, p<0.05). The degree of fetal abdominal growth acceleration in OVA subjects was intermediate between that of NGT and GDM subjects. OVA subjects with FAO at the time of GDM diagnosis were strongly associated with adverse pregnancy outcomes.

Metabolic Responses to an Acute Glucose Challenge: The Differential Effects of Eight Weeks of Almond vs. Cracker Consumption in Young Adults.

This study investigated the dynamic responses to an acute glucose challenge following chronic almond versus cracker consumption for 8 weeks (clinicaltrials.gov ID: NCT03084003). Seventy-three young adults (age: 18-19 years, BMI: 18-41 kg/m2) participated in an 8-week randomized, controlled, parallel-arm intervention and were randomly assigned to consume either almonds (2 oz/d, n=38) or an isocaloric control snack of graham crackers (325 kcal/d, n=35) daily for 8 weeks. Twenty participants from each group underwent a 2-hour oral glucose tolerance test (oGTT) at the end of the 8-week intervention. Metabolite abundances in the oGTT serum samples were quantified using untargeted metabolomics, and targeted analyses for free PUFAs, total fatty acids, oxylipins, and endocannabinoids. Multivariate, univariate, and chemical enrichment analyses were conducted to identify significant metabolic shifts. Findings exhibit a biphasic lipid response distinguished by higher levels of unsaturated triglycerides in the earlier periods of the oGTT followed by lower levels in the latter period in the almond versus cracker group (p-value<0.05, chemical enrichment analyses). Almond (vs. cracker) consumption was also associated with higher AUC120 min of aminomalonate, and oxylipins (p-value<0.05), but lower AUC120 min of L-cystine, N-acetylmannosamine, and isoheptadecanoic acid (p-value<0.05). Additionally, the Matsuda Index in the almond group correlated with AUC120 min of CE 22:6 (r=-0.46; p-value<0.05) and 12,13 DiHOME (r=0.45; p-value<0.05). Almond consumption for 8 weeks leads to dynamic, differential shifts in response to an acute glucose challenge, marked by alterations in lipid and amino acid mediators involved in metabolic and physiological pathways.

Association of postabsorptive glucose and acetate metabolism with feed intake, growth, and efficiency in finishing beef heifers

The objective of this experiment was to determine whether acetate and glucose metabolism and insulin response to glucose are associated with the growth, feed intake, and feed efficiency of finishing heifers. Charolais heifers ( n = 18; initial body weight = 415.7 ± 45.17 kg) were acclimated to restraint with a halter and fed a finishing diet ad libitum using an Insentec feeding system. Following a 12 h fast, a jugular catheter was inserted, and an acetate clearance test was performed followed by a glucose clearance test. Four days after the metabolic tests, heifers began an 84-day DMI and ADG test period. Heifers gained 1.69 ± 0.03 kg/day and consumed 10.4 ± 0.19 kg/day. Acetate and glucose clearance rates were not associated with any production trait ( P ≥ 0.40). Insulin time to peak concentration after the glucose challenge was associated ( r = 0.69; P = 0.003) with G:F, but not peak concentration ( P = 0.45). The increased time to insulin peak could indicate that efficient heifers have pancreatic β-cell dysfunction, which is a contributor to insulin resistance. These data indicate that insulin resistance early in the finishing period could be related to improved feed efficiency in finishing heifers.

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.

Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age

Abstract Aging is associated with impaired signaling between brain regions when measured using resting-state functional magnetic resonance imaging (fMRI). This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we confirmed their robustness across measurement modalities using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20–80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, μage = 26.9 ±11.2 years, N = 36). Then, using a multiscale conductance-based neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels. As such, the approach facilitates the connection between macroscopic brain activity and cellular-level mechanisms.

A Biomineralized Bifunctional Patient-Friendly Nanosystem for Sustained Glucose Monitoring and Control in Diabetes.

Regular blood glucose monitoring and control is necessary for people with type 1 or advanced type 2 diabetes, yet diagnosing and treating patients with diabetes in an accurate, sustained and patient-friendly manner remains limited. Here, a glucose-responsive bifunctional nanosystem (PGOxMns) is constructed via one-pot biomineralisation of manganese dioxide with glucose oxidase and ε-poly-L-lysine. Under hyperglycaemic conditions, the cascade reactions that occur when glucose interacts with PGOxMns can trigger the production of Mn(II), which enhances the magnetic resonance imaging signal. Simultaneously, manganese dioxide catalyses the decomposition of toxic hydrogen peroxide into oxygen, which also maintains glucose oxidase (GOx)activity. In an in vivo model of diabetes, PGOxMns is used to monitor glucose levels (0-20mm) and allowed identification of diabetic mice via T1-weighted MRI. Furthermore, PGOxMns is found to have a high insulin-loading capacity (83.6%), likely due to its positive charge. A single subcutaneous injection of insulin-loaded nanosystem (Ins-PGOxMns) into diabetic mice resulted in a rapid and efficient response to a glucose challenge and prolonged blood glucose level control (< 200mgdL-1) for up to 50h. Overall, this proof-of-concept study demonstrates the feasibility of using biomineralised nanosystems to develop patient-friendly strategies for glucose monitoring and control.

Altered Glucose Kinetics Occurs With Aging

Metabolic flexibility is the ability to respond or adapt to conditional changes in metabolic demand. The purpose of our study was to determine how age affects metabolic flexibility and underlying glucose kinetics in young and older healthy adults. We hypothesized that in response to a glucose challenge: 1) young participants would exhibit greater glucose clearance than older participants, and 2) young participants would have decreased endogenous glucose production via gluconeogenesis. Glucose and lactate tracers, along with gas exchange data were used to measure glucose kinetics and respiratory exchange ratios (RER=VCO2/VO2) to determine metabolic flexibility during a 2-hour 75-gram oral glucose tolerance test (OGTT). After a 12-hour 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) individuals received venous primed continuous infusions of [6,6-2H]glucose, and [3-13C]lactate with a H13CO3− bolus. Following a 90-minute metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. In all study participants arterialized glucose concentrations ([glucose]) rose 15 minutes post-glucose consumption, peaked at 60 minutes, and remained elevated. Older individuals had sustained increases in [glucose] compared to the young. As assessed by rates of appearance (Ra), disposal (Rd) and metabolic clearance (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 during the OGTT. Lastly, there were no differences in RER between young and older volunteers, making RER an incomplete measure of metabolic flexibility in volunteers studied. Our study revealed that glucose kinetics are significantly altered in an aged population following a glucose challenge. Further, these physiological deficits are not detected from changes in RER during an OGTT. Supported by NIH grant R01 AG059715 to GAB. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex-dependent impairment of kidney function in megalin knockout mice

Megalin ( Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. We previously found that knocking out Lrp2 in the opossum kidney (OK) PT cell line leads to differential expression of genes involved in mitochondrial and metabolic function. Additionally, we observed large reductions in sodium glucose co-transporter 2 (Sglt2) transcript (&gt;80%) and protein (~40%) expression levels. While Sglt2 transcript and protein levels in Lrp2 KO in mice were more modestly reduced, male and female KO mice fed regular chow or a Western diet (WD) had increased tolerance to a high glucose challenge compared with control mice. Surprisingly, male Lrp2 KO mice fed a WD developed substantial kidney injury, while female KO mice had significantly less injury. In metabolic studies, Lrp2 KO mice preferentially utilized fatty acid oxidation compared to control mice. We hypothesize that compromised endocytic flux in Lrp2 KO mice impairs mitochondrial and metabolic function to worsen kidney damage in a sex-dependent manner. Current studies are focused on a variety of approaches to test how reduced endocytic capacity impacts mitochondrial function and metabolism in Lrp2 KO cells and control OK cells. We will confirm our findings in age-matched male and female control and Lrp2 KO mice. These studies will help to determine the role of megalin expression and function on PT metabolism, function, and overall health. National Institutes of Health: T32DK061296, T32AG021885-20, RO1 DK125049, RO1 DK118726, S10 OD028596, U54 DK137329. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis

ObjectiveType 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and insulin secretion. MethodsMetabolic profiling was conducted on Gcgrβ-cell−/− and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. ResultsGcgrβ-cell−/− mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrβ-cell−/− 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrβ-cell−/− islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8). ConclusionThese data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D.