Insulin Area Under The Curve Research Articles

Abstract 4116298: Once Weekly Utreglutide (GL0034), a Glucagon-like Peptide-1 Receptor Agonist, at 4 × 450 µg Doses Reduces Blood Pressure, Lipids, and Body Weight in Post-menopausal Females: A Phase I Study

Background: Utreglutide (GL0034), a novel, once weekly glucagon-like peptide-1 receptor agonist (GLP-1RA), previously demonstrated significant reductions in body weight (BW) after a single dose ascending study in individuals with obesity . BW reductions after pharmacological treatment of obesity with GLP-1RA is associated with blood pressure (BP) lowering effects. Aim: This phase I study assessed the safety, tolerability, and cardio-metabolic effects of utreglutide after multiple ascending doses in post-menopausal female volunteers with overweight and obesity. Methods: In this randomized, double-blind, placebo-controlled study 12 post-menopausal female volunteers with overweight/obesity, aged 18 to 65 years old with a body mass index (BMI) ≥26 kg/m 2 were randomized (9:3) to subcutaneous utreglutide fixed doses (4 × 450 µg); or placebo once weekly for four weeks. Safety, tolerability, and key cardio-metabolic parameters were assessed. Biomarker measurements included oral glucose tolerance test (OGTT) insulin and glucose area under the curve (AUC), systolic- and diastolic BP, lipid profile (triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL), creatinine, potassium, BW and leptin. Results: Utreglutide was generally well tolerated and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Reductions in OGTT AUCs of insulin ( p <0.05) and glucose ( p <0.01) were noted on Day 23 after four weeks treatment with Utreglutide. This was accompanied by a decrease ( p <0.001) in mean systolic and diastolic BP on Day 23 from baseline (BL). On Day 23, significant reductions in TC ( p <0.01), LDL ( p <0.05) and non-HDL ( p <0.05) were observed. BW reduction versus BL ( p <0.001) was 2.0 kg and 1.8 kg respectively on Day 29 and End of Study (EoS). Leptin levels significantly reduced from BL on Day 23 ( p< 0.01) and EoS ( p <0.001). No significant changes were observed for TG, creatinine and potassium (Table). Conclusions: Once weekly utreglutide dosing for four weeks at a dose of 450 µg in post-menopausal females with overweight and obesity, demonstrated clinically relevant reductions of systolic and diastolic BP. This was associated with improved performance of OGTT AUC of insulin and glucose, lipids, BW and leptin with an overall good tolerability and with potential to demonstrate cardio-metabolic benefits.

Impact of allulose on blood glucose in type 2 diabetes: A meta-analysis of clinical trials

ObjectiveThis meta-analysis aims to evaluate the impact of allulose on blood glucose levels in patients with type 2 diabetes mellitus (T2DM). Primary outcomes include postprandial blood glucose, while secondary outcomes are time in range (TIR), time above range (TAR), fasting plasma glucose (FPG), and insulin area under the curve (AUC). MethodsA systematic search was conducted across PubMed/MEDLINE, Web of Science, Scopus, and Cochrane Library until May 20, 2024. Randomized controlled trials assessing the effect of allulose on glycemic parameters in T2DM patients were included. Data were synthesized using a random-effects meta-analysis model, and the quality of studies was assessed using the Cochrane Risk of Bias tool. ResultsSix studies involving 126 participants were included. Allulose significantly reduced glucose AUC (SMD: −0.6662, 95 % CI [-1.1360, −0.1964], p = 0.0054) with moderate heterogeneity (I2 = 58.3 %). Insulin AUC showed a non-significant reduction (SMD: −0.3648, 95 % CI [-0.7783, 0.0488], p = 0.0839). FPG demonstrated a non-significant reduction (MD: −5.8925, 95 % CI [-20.4892, 8.7043], p = 0.4288), while TAR significantly decreased (MD: −8.8204, 95 % CI [-14.4101, −3.2307], p = 0.0020). No significant changes were observed in TIR (MD: 7.1211, 95 % CI [-1.6028, 15.8450], p = 0.1096). ConclusionAllulose demonstrated a significant reduction in postprandial glucose levels and TAR, supporting its role as a dietary intervention for glycemic control in T2DM patients. The findings are robust, though further research is needed to confirm its long-term effects on insulin sensitivity and metabolic health.

Efficacy of Lisosan G (fermented wheat) on reactive hypoglycemia after bariatric surgery.

post-bariatric hypoglycemia (PBH) is considered a chronic complication after gastric bypass (RYGB) impacting roughly 30% of patients. Current treatments often focus on nutritional interventions to reduce the frequency of episodes. This prospective study evaluated the effectiveness of Lisosan G (LG), a fermented wheat-based supplement added to the diet, in mitigating PBH episodes and elucidating its mechanism of action on the gut-pancreas axis. twenty subjects with PBH, who had undergone RYGB between 2015 and 2018, were enrolled. Subjects underwent clinical examination, blood test, and a 3-hour oral glucose load test (OGTT). Then, they were monitored for 2-weeks on a free diet with continuous glucose monitoring (CGM), which was extended for another 2-weeks after introduction of LG supplementation (5g, twice daily) on the same diet. Finally, subjects repeated OGTT and blood test. PBH was defined as interstitial glucose ≤54mg/dl. after treatment, a marked reduction in PBH time was observed (75[23-113] vs 16 [0-33], minutes, p<0.001). During OGTT, there was an increase in glucose nadir (44±11 vs 56±10, mg/dl, p=0.038), and a significantly decrease in total GLP-1 AUC (7.6±4.1 vs 6.5±3.8, nmol/L*min, p=0.043), in potentiation factor ratio (p=0.037) and in total insulin AUC (57±12 vs 49±9, nmol/L*min, p=0.043). LG effectively reduces PBH frequency and duration, probably by attenuating GLP-1 concentrations and leading to a decrease in the second phase of insulin secretion in response to glucose. These findings underscore the promise of LG as a novel adjunct therapy for PBH, particularly when added to the diet, and emphasize the need for further exploration into its microbiota-modulating and anti-inflammatory effects.

Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.

Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.

Fasting as an intervention to alter the impact of simulated night-shift work on glucose metabolism in healthy adults: a cluster randomised controlled trial.

Night-shift work causes circadian misalignment and impairs glucose metabolism. We hypothesise that food intake during night shifts may contribute to this phenomenon. This open-label, multi-arm, single-site, parallel-group controlled trial involved a 6 day stay at the University of South Australia's sleep laboratory (Adelaide, SA, Australia). Healthy, non-shift-working adults without obesity (N=55; age 24.5 ± 4.8 years; BMI 24.8 ± 2.8 kg/m2) were assigned to the next available run date and cluster randomised (1:1:1) to fasting-at-night (N=20), snack-at-night (N=17), or meal-at-night (N=18) conditions. One participant withdrew from each group, prior to starting the study. Due to study design, neither participants nor people collecting their measurements could be blinded. Statistical and laboratory staff were concealed to study allocation. Participants were fed at calculated energy balance, with the macronutrient composition of meals being similar across conditions. The primary outcomes were a linear mixed-effects model of glucose, insulin and NEFA AUC in response to a 75 g OGTT that was conducted prior to and after 4 consecutive nights of shift work plus 1 night of recovery sleep. Insulin sensitivity, insulinogenic and disposition indexes were also calculated. Night-shift work impaired insulin sensitivity, as measured by insulin AUC (p=0.035) and the insulin sensitivity index (p=0.016) across all conditions. Insulin secretion, as measured by the insulinogenic index, was increased in the fasting-at-night condition only (p=0.030), resulting in a day×condition interaction in glucose AUC (p<0.001) such that glucose tolerance was impaired in the meal-at night (+2.00 [95% CI 1.45, 2.56], p<0.001) and snack at-night (+0.96 [0.36, 1.56], p=0.022) conditions vs the fasting-at-night (+0.34 [-0.21, 0.89]) condition. A day×condition interaction was also observed in NEFA AUC (p<0.001), being higher in the meal-at-night (+0.07 [0.03, 0.10]. p=0.001) and snack-at-night (0.01 [-0.03, 0.05], p=0.045) conditions vs the fasting-at-night condition (-0.02 [-0.06, 0.01]). No adverse events occurred. The timing of food intake has a critical effect on glucose metabolism during simulated night-shift work, which was readily amendable to a meal re-timing intervention. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001556437 FUNDING: This work was funded by the National Health and Medical Research Council (NHMRC), APP1099077.

7718 Dysregulated BCAA catabolism and insulin secretory response in the early stages of insulin resistance in mature adolescents

Abstract Disclosure: A. Basin: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. D. Hsia: None. D.A. D'Alessio: None. C.B. Newgard: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that surrogate markers of insulin resistance (IR) and insulin secretion are differentially associated with branched-chain amino acids (BCAAs) and their catabolites the branched-chain ketoacids (BCKAs). In this longitudinal study, we determined if baseline levels of BCAAs, BCKAs or the BCKA/BCAA ratio are associated with changes in IR, insulin secretion, and insulin secretion adjusted for IR after a one year follow up in adolescents aged 18-21 yr without Type 2 diabetes. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) at baseline and one year follow up in 10 adolescents with normal weight and 10 adolescents without Type 2 diabetes but with overweight/obesity and mild IR. After an overnight fast of 8-12 hours, participants had fasting blood samples drawn and consumed 1.75 g/kg, to a maximum of 75 g glucose solution as the initiation of an OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: At one year follow up groups were comparable in age, sex, race, ethnicity and pubertal status. Participants with overweight/obesity had higher BMI (22.5±1.3 vs 36.2±9.7), BF% (16.8±8.4 vs 37.9±10.2), leptin, and diastolic blood pressure than lean participants. They were also more insulin resistant as evidenced by higher HOMA-IR . AUC glucose,AUC insulin, and IGI were comparable across groups, as were fasting BCAA levels and BCKA/BCAA ratio. As with baseline levels, follow-up BCAA levels correlated positively with AUC insulin, HOMA-IR, and IGI at 30 min and negatively with totaland HMW-adiponectin, and Matsuda Index, but did not correlate with BMI or % body fat. Likewise at follow up, BCKAs correlated negatively with total and HMW-adiponectin and did not correlate with Matsuda Index, or HOMA-IR. In association models adjusted for baseline age, sex, and BMI, higher baseline levels of the BCKA, α-keto-β-methylvalerate (KMV, isoleucine catabolite), and a higher BCKA/BCAA ratio were associated with a relative reduction in acute insulin secretion as reflected in a reduction in 15 min IGI at 1 year follow up. Conclusions: In this cohort of adolescents without Type 2 diabetes and with varying degrees of adiposity and insulin sensitivity, we identified KMV as a marker associated with a subsequent reduction in acute glucose-stimulated insulin secretion at one year follow up.These findings suggest that dysregulated BCAA catabolism is associated with loss of compensatory insulin secretion in the face of IR and may play a role in progression to impaired glucose tolerance and development of Type 2 diabetes. Presentation: 6/1/2024

Lipid profile is similar in both subjects with high 1-hour postload glucose and 2-hour postload glucose and is related to cardio-metabolic profile in prediabetes

AimThe study aimed to investigate a lipid profile in people with normal glucose tolerance (NGT), NGT and 1hrOGTT > 8.6 mmol/l, and impaired glucose tolerance (IGT); and to assess its association with some cardio-metabolic parameters. Material and methodsA total of 90 subjects, of mean age 46.7 ± 10.5 years and mean BMI of 32.0 ± 6.3 kg/m2 were enrolled. They were divided into 3 groups: 19 with NGT, 22 with NGT and 1hrOGTT > 8.6 mmol/l, and 49 with IGT; and subdivided into 2 subgroups according to HOMA-IR: 40 with HOMA-IR < 2.5 and 50 with HOMA-IR ≥ 2.5. Body composition (Inbody 720) and advanced glycation end products (AGE Reader) were assessed. Two functional tests (OGTT; MMTT) were performed and AUC for glucose, insulin and triglycerides were calculated. ResultsThere was no difference across the glucose tolerance groups for all evaluated lipids. The results showed higher AUCinsulin during OGTT (p = 0.037 and 0.020), AUCtriglycerides during MMTT (p = 0.048) and triglycerides/HDL ratio (p = 0.064 and 0.016) in the 1hrOGTT and IGT subgroups with HOMA-IR ≥ 2.5 in comparison to those with HOMA-IR < 2.5. AUCtriglycerides during OGTT is independently related to body composition, b-cell function and insulin sensitivity; and AUCtriglycerides during MMTT is independently related to blood pressure and hsCRP in prediabetes. Triglycerides/HDL-C ratio emerged as an independent contributor to glycaemia and insulinemia. ConclusionOur results demonstrate a similar lipid profile in subjects with 1hrOGTT > 8.6 mmol/l and IGT, whereas increased AUCtriglycerides during OGTT, AUCtriglycerides during MMTT and triglycerides/HDL-C ratio have been found in the subgroups with insulin resistance. The triglycerides/HDL-C ratio outlined as an independent predictor of insulin secretion and action, and postload triglycerides appear to be independently related to most of the metabolic parameters.

The effect of post-oral bitter compound interventions on the postprandial glycemia response: A systematic review and meta-analysis of randomised controlled trials

Background & AimsThe post-oral sensing of bitter compounds by a family of bitter taste receptors (TAS2Rs) is suggested to regulate postprandial glycemia in humans. However, reports are inconsistent. This systematic review used meta-analysis to synthesise the impact of bitter compound interventions on the postprandial glycaemic response in humans. MethodsElectronic databases (Medline, PubMed, and Web of Science) were systematically searched from inception to April 2024 to identify randomised controlled trials reporting the effect of interventions utilising post-oral bitter compounds vs. placebo on postprandial plasma glucose levels at t=2h (2h-PPG), and area under the curve (AUC) of glucose, insulin, and c-peptide. The random-effect and subgroup analysis were performed to calculate pooled weighted mean differences (WMD), overall and by predefined criteria. ResultsForty-six studies (within 34 articles) were identified; 29 and 17 studies described chronic and acute interventions, respectively. The chronic interventions reduced 2h-PPG (n= 21, WMD= -0.35 mmol/L, 95%CIs= -0.58, -0.11) but not AUC for glucose or insulin. Subgroup analysis showed the former was particularly evident in individuals with impaired glycemia, interventions longer than three months, or quinine family administration. The acute interventions did not improve the postprandial glycemia response, but subgroup analysis revealed a decrease in AUC-glucose after quinine family administration (n=4 WMD= -90.40 (nmol × time/L), 95%CIs= -132.70, -48.10). ConclusionChronic bitter compound interventions, particularly those from the quinine family, may have therapeutic potential in those with glycemia dysregulation. Acute intervention of the quinine family may also improve postprandial glucose. Given the very low quality of the evidence, further investigations with more rigorous methods are still required.

Oral glucose tolerance test curve shape in Mexican children and adolescents with and without obesity.

Mexican children with obesity are at a higher risk of developing type 2 diabetes mellitus (T2DM). The aim of the study was to compare oral glucose tolerance test (OGTT) characteristics: time of peak glucose, glucose level≥155 mg/dL at 1 h, presence of metabolic syndrome (MetS), sensitivity, secretion, and oral disposition index (oDI) in children with and without obesity, according to oral glucose tolerance curve shape: monophasic or biphasic. Cross-sectional study including 143 children. Groups were divided into (a)obese: biphasic (B-Ob) (n=55) and monophasic (M-Ob) (n=50), (b)without obesity: biphasic (B-NonOb) (n=20) and monophasic (M-NonOb) (n=18). Late glucose peak was more frequent in the M-Ob group (p<0.001). Glucose levels≥155 mg/dL and MetS were more frequent in the M-Ob group but did not show significance. The groups with obesity (biphasic and monophasic) had higher indices of insulin resistance and insulin secretion compared to the nonobese groups (biphasic and monophasic) (p<0.001). AUC glucose was higher in the M-Ob group (p<0.05), and AUC insulin was higher in the M-NonOb group. oDI (Matsuda) was significantly lower in the M-Ob group compared to the other groups (p<0.001), and oDI-HOMA IR was higher in M-NonOb group (p=0.03). All OGTT parameters could help to identify Mexican children at increased risk of developing T2DM, not only fasting plasma glucose and 2 h glucose. M-Ob in non-T2DM Mexican children reflects an early defect in glucose metabolism. Higher level of IR indexes in M-NonOb vs. B-NonOb could indicate an increased risk for T2DM of genetic origin.

The effect of a pre-meal snack and/or postprandial exercise on breakfast glycemic excursion in adults with cystic fibrosis: A pilot study

Background & AimsCystic fibrosis (CF)-related diabetes (CFRD), a common comorbidity in CF, is often preceded and characterized with elevated postprandial glycaemia (PPG). In the general population, the consumption of a pre-meal protein snack and/or physical activity (PA) hinder the elevation of PPG levels. Our objective is to evaluate the effect of a pre-meal snack and/or post-meal PA on PPG excursions in CF. MethodsThis is a double-blinded randomized controlled crossover interventional study in 14 adults with CF, with 4 interventions: placebo pre-meal snack + no PA (control: CTL), pre-meal soy snack + no PA (SK), placebo pre-meal snack + PA (PA), and pre-meal soy snack + PA (SK+PA). The pre-meal soy snack or placebo beverage (vanilla flavoured water) is served at 8 am, followed by a standardized breakfast at 9 am and, postprandially, 5 repeated bouts of 3-min walk every 30 mins or sedentary activity. Blood glucose and insulin were measured every 15 to 30 minutes during the interventions. ResultsPlasma glucose (PG) was higher 30 mins after snack consumption compared to placebo beverage. One-hour post-breakfast, PG levels were lower during both PA interventions than with sedentary behavior. However, the overall 3h post-breakfast glucose area under the curve (AUC) was similar between interventions. Post-breakfast 3h insulin AUC was significantly lower during the SK+PA intervention compared to the sedentary behavior interventions. ConclusionRepeated short bouts of post-meal physical activity may positively impact PPG control in adults with CF, with or without the addition of a pre-meal soy snack. A pre-meal snack alone does not improve PPG.

Fetal sex effects on maternal health can now be tested via randomization: A first-in-class illustration in cows on glucoregulatory outcomes

BackgroundThe maternal-offspring relationship, such as whether fetal sex influences maternal health, is essential to explore to advance prenatal and maternal health. While associations exist between fetal sex and maternal health outcomes, it is unclear whether these reflect a causal relationship. ObjectiveTo demonstrate that fetal sex can be randomly assigned to test the causal effect of fetal sex on maternal outcomes. MethodsHolstein dairy cows were stratified and randomized using sealed opaque envelopes to be artificially inseminated with either X- or Y-sorted bull semen until 40 cows became pregnant. Monthly body weight measurements were recorded, and an intravenous glucose tolerance test was performed 30 days before the expected calving day. The primary outcome was insulin area under the curve (AUC), and secondary outcomes were clearance rate, half-life, and AUC for glucose, insulin, and non-esterified fatty acid concentrations. An intention-to-treat (ITT) approach using multiple imputation was employed for primary analysis, and an as-treated (AT) approach was used for secondary analysis. ResultsWe demonstrated that we could successfully randomize the assignment of fetal sex to dams and test for causal effects of fetal sex on glucoregulatory outcomes using dairy cows as a model. Insulin AUC was not statistically different between groups (ITT p = 0.857, AT p = 0.874), and other outcomes were also not statistically different (p > 0.05). ConclusionWe demonstrated that causal effects of fetal sex on maternal outcomes can be causally tested in dairy cows. Our study did not provide statistical evidence to support an effect of fetal sex on maternal glucose-related outcomes.

Increasing particle size of oat flours decreases postprandial glycemia and increases appetite in healthy adults

Consumption of oats is associated with lowered risks of type 2 diabetes and obesity. However, many oat-based products (e.g., breakfast cereals) use finely milled flours but are associated with health claims based on oats of larger particle sizes. The objective of this study was to test the hypothesis that increasing oat flour particle size will result in lower postprandial glycemia and appetite. Using a randomized-controlled, crossover design, 20 participants (10 males, 10 females; age: 25.3 ± 1.0 years; body mass index: 23.2 ± 0.6 kg/m2) consumed a serving of porridge made using 40 g of coarse (675.7 ± 19.6 µm), whole (443.3 ± 36.2 µm), fine (96.0 ± 2.1 µm), or a commercial (375.9 ± 14.8 µm) oat flour unmatched in available carbohydrate, protein, and dietary fiber content. After a 12-hour overnight fast, blood glucose, insulin, and appetite were measured at 15 to 30-minute intervals over 120 minutes posttreatment consumption. Coarse and whole flours led to lower blood glucose between 30 and 60 minutes (P < .02). Blood glucose area under the curve (AUC) was lower after coarse than fine and commercial oat flours (P < 0.03), and after whole than fine oat flour (P < .002). Both coarse and whole oat flours resulted in lower insulin AUC than finer flours (P < .05). Appetite AUC was lower after the commercial than coarse flour (P < .007). Controlling milling to produce coarser oat flour to add to common foods may have health benefits. This study was registered at ClinicalTrials.gov (NCT05291351).

The Effect of Adding Protein to a Carbohydrate Meal on Postprandial Glucose and Insulin Responses: A Systematic Review and Meta-Analysis of Acute Controlled Feeding Trials

BackgroundProtein influences acute postprandial glucose and insulin responses, but the effects of dose, protein type, and health status are unknown. ObjectivesWe aimed to determine the acute effect of adding protein to carbohydrate on postprandial responses and identify effect modifiers. MethodsWe searched MEDLINE, EMBASE, and Cochrane databases through 30 July, 2023 for acute, crossover trials comparing acute postprandial responses elicited by carbohydrate-containing test meals with and without added protein in adults without diabetes or with type 2 (T2DM) or type 1 (T1DM) diabetes mellitus. Group data were pooled separately using generic inverse variance with random-effects models and expressed as the ratio of means with 95% confidence interval. Risk of bias and certainty of evidence (Grading of Recommendations Assessment, Development, and Evaluation) were assessed. ResultsIn 154 trial comparisons of animal, dairy, and plant proteins (without diabetes, n = 22, 67, 32, respectively; T2DM, n = 14, 16, 3, respectively), each gram protein per gram available carbohydrate (g/g) reduced the glucose area under the curve (AUC) less in adults with T2DM than in those without diabetes (−10% compared with −50%, P < 0.05) but increased the insulin AUC similarly (+76% compared with +56%). In subjects without diabetes, each g/g of dairy and plant protein reduced glucose AUC by 52% and 55%, respectively, and increased the insulin AUC by 64% and 45%, respectively (all P < 0.05). Animal proteins significantly reduced the glucose AUC by 31% and increased the insulin AUC by 37% (pooled effects) but without a significant dose-response. In adults with T2DM, animal protein reduced the glucose AUC by 13% and increased the insulin AUC by 105%, with no significant dose-response. Dairy protein reduced the glucose AUC by 18% (no dose-response), but each g/g increased the insulin AUC by 34% (P < 0.05). In adults with T1DM, protein increased the glucose AUC by 40% (P < 0.05, n = 5). Data source (reported AUC compared with calculated AUC) and study methodology quality significantly modified some outcomes and contributed to high between-study heterogeneity. ConclusionsIn people without diabetes, adding dairy or plant protein to a carbohydrate-containing meal elicits physiologically significant reductions in glucose AUC and increases insulin AUC. Animal protein may slightly reduce the glucose AUC and may increase the insulin AUC. In people with T2DM, protein may not have such large and consistent effects. Further research is needed to determine if the effects of protein differ by health status and protein source.This study was registered at PROSPERO as CRD42022322090.

The positive association between hyperuricemia and polycystic ovary syndrome and analysis of related factors.

To examine the potential association between polycystic ovary syndrome (PCOS) and hyperuricemia and to elucidate the underlying contributory factors. Retrospective study on 603 women with PCOS and 604 women without PCOS. Anthropometric features, reproductive hormone profiles, and metabolic parameters were measured and compared between two groups of patients. Examinations of correlations between SUA levels and other parameters were conducted to discern potential correlations. Both serum uric acid levels and the incidence of hyperuricemia exhibited statistically significant elevations in women with PCOS when compared to their counterparts without PCOS. Nonetheless, this statistical difference was not found between the obese subgroup after stratifying study subjects by body mass index (BMI). Pearson's correlation analysis underscored the prominence of BMI as a robust factor influencing SUA levels in women, regardless of their PCOS status. Furthermore, multivariable linear regression model demonstrated significant positive associations between SUA levels and several variables, namely dehydroepiandrosterone sulfate (DHEA-S), free androgen index (FAI), total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), area under the curve for insulin (AUC-I), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Additionally, it is noteworthy that the prevalence of hyperuricemia exhibited a positive association with fasting plasma glucose (FPG) levels, while conversely, it displayed a negative association with estradiol (E2) levels. PCOS is associated with a significant elevation of SUA level and hyperuricemia prevalence. HA, IR, and dyslipidemia may be the mediators in the pathogenesis of hyperuricemia in women with PCOS.

Timing of meal consumption on glucose profiles in Latino adolescents with obesity.

To date, there has been no study investigating how meal-timing impacts glucose and insulin resistance among Latino youth at high risk of type 2 diabetes. A proof-of-concept study was conducted to assess metabolic response to a test-meal consumed in the morning, afternoon, and evening among 15 Latino adolescents with obesity using a within-participant design. Youth, 13 to 19 years of age, with obesity, consumed the same test-meal after a 16 hour fast at three different times on separate days. Immediately after consumption of the test meal, a mixed meal tolerance test (MMTT) was performed. The co-primary outcomes were the area under the curve (AUC) for glucose, insulin, and c-peptide, and insulinogenic index (IGI). Twenty-two youth consented to participate for a 24% recruitment rate (78% female, 100% Latino, mean age 16.5±1.3 years, 70% publicly insured). There was a significantly greater rise in glucose and c-peptide levels following at 4 PM compared to 8 AM (glucose: p = 0.006; c-peptide: p &lt; 0.0001) with no significant association found between insulin levels and timing of meal consumption. Pairwise comparisons showed a greater rise in AUC glucose and c-peptide levels at 4 PM compared to 8 AM (glucose p = 0.003; c-peptide p &lt; 0.001) with no significant association found between insulin AUC and timing of meal consumption (p = 0.09). There was a greater reduction in IGI at 4 PM compared to 8 AM (p = 0.027). Similar to findings in adults at risk for diabetes, Latino youth with obesity show greater insulin resistance in response to a meal consumed in the afternoon and evening compared to early morning food consumption.

Marginal Zinc Deficiency Promotes Pancreatic Islet Enlargement While Zinc Supplementation Improves the Pancreatic Insulin Response in Zucker Diabetic Fatty Rats.

Zinc deficiency has been associated with the worsening of diabetes while zinc supplementation has been proposed to ameliorate diabetes. This study examined the effects of marginal zinc deficiency (MZD) and zinc supplementation (ZS) on obesity, glycemic control, pancreatic islets, hepatic steatosis and renal function of Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed an MZD, zinc control (ZC) or ZS diet (4, 30 and 300 mg Zn/kg diet, respectively), and lean Zucker rats were fed a ZC diet for 8 weeks. MZD and ZS did not alter body weight or whole-body composition in ZDF rats. MZD ZDF rats had reduced zinc concentrations in the femur and pancreas, a greater number of enlarged pancreatic islets and a diminished response to an oral glucose load based on a 1.8-fold greater incremental area-under-the-curve (AUC) for glucose compared to ZC ZDF. ZS ZDF rats had elevated serum, femur and pancreatic zinc concentrations, unchanged pancreatic parameters and a 50% reduction in the AUC for insulin compared to ZC ZDF rats, suggesting greater insulin sensitivity. Dietary zinc intake did not alter hepatic steatosis, creatinine clearance, or levels of proteins that contribute to insulin signaling, inflammation or zinc transport in epididymal fat. Potential adverse effects of ZS were suggested by reduced hepatic copper concentrations and elevated serum urea compared to ZC ZDF rats. In summary, ZS improved the pancreatic insulin response but not the glucose handling. In contrast, reduced zinc status in ZDF rats led to impaired glucose tolerance and a compensatory increase in the number and size of pancreatic islets which could lead to β-cell exhaustion.

#2971 A low-protein diet improves metabolic health and reduces blood uremic toxins in non-diabetic CKD

Abstract Background and Aims Despite the demonstrated efficacy of a low-protein diet (LPD) in slowing the progression of chronic kidney disease (CKD), the underlying mechanisms remain inadequately understood. Given the potential drawbacks, including poor compliance and a risk of malnutrition, gaining insights into the molecular mechanisms driving these benefits is crucial for safe clinical translation. In this study, our objectives were to 1) assess the impact of an LPD on the metabolic health of individuals and mice with CKD; 2) investigate the hypothesis that these effects are mediated by a reduction in uremic toxins; and 3) explore whether the combination of an LPD and supplementation with a strain of Lactiplantibacillus plantarum (strain LpWJL), selected for its ability to enhance growth in a Drosophila model of diet-induced stunting, could synergistically amplify the positive effects of the LPD while minimizing its potential adverse consequences. Method We recruited CKD patients with no diabetes or prediabetes, who were randomized to a LPD and cetoanalogues (0.4 g/kg/day) (n = 5) or a normal diet (ND) (0.8 g/kg/day, n = 6) for 3 months. A glucose tolerance test was measured at baseline and after 3 months. Four groups of mice were studied: a sham group with a ND (n = 4), 5/6th nephrectomized mice with a ND (n = 7), and 5/6th nephrectomized mice with LPD (5% w/w) and LPwjl (n = 7) or placebo (n = 7) for 6 weeks. Blood samples and liver tissues were analyzed with the MxP 500 Quant® (Biocrates) kit by LC-MS/MS (XEVO TQ-XS, Waters). Results Under LPD, beta cell function showed improvement (Matsuda index, P = 0.049, and AUC insulin, P = 0.02). Although the diet did not influence body composition, the LPD group exhibited a reduction in muscle strength (P = 0.02). LPD decreased blood concentration several uremic toxins such as indoxyl sulfate and TMAO. Insulin sensitivity and beta-cell function demonstrated negative correlations with urea, TMAO, and indoxyl sulfate. Mouse studies confirmed the positive impact of LPD on glucose homeostasis but also revealed detrimental effects on lean mass and fat mass. Supplementation with LpWJL during LPD mitigated the loss of fat mass, improved the insulin tolerance test, and enhanced the reduction of certain blood uremic toxins, including indoxyl sulfate. LpWJL supplementation exerted a substantial impact on the hepatic metabolome, resulting in increased triglyceride accumulation and decreased levels of diglycerides, acylcarnitines, and phosphocholines. Conclusion We have highlighted the substantial benefits of a 3-month LPD on markers of glucose homeostasis and uremic toxins in mice and humans without diabetes. LpWJL induced profound modifications in both blood and liver metabolome and was associated with a limitation of trophic alterations in LPD diet-induced CKD mice, while also enhancing glucose homeostasis. Further studies are essential to gain a better understanding of the underlying mechanisms involved.

Sleep Debt and Insulin Resistance: What's Worse, Sleep Deprivation or Sleep Restriction?

Objective To evaluate which condition of sleep debt has a greater negative impact on insulin resistance: sleep deprivation for 24 hours or 4 hours of sleep restriction for 4 nights. Materials and Methods In total, 28 healthy male subjects aged 18 to 40 years were recruited and randomly allocated to two groups: sleep deprivation (SD) and sleep restriction (SR). Each group underwent two conditions: regular sleep (11 pm to 7 am ) and total sleep deprivation for 24 hours (SD); regular sleep (11 pm to 7 am ) and 4 nights of sleep restriction (SR) (1 am to 5 am ). The oral glucose tolerance test (OGTT) was performed, and baseline glucose, insulin, free fatty acids (FFAs), and cortisol were measured. In addition, the area under the curve (AUC) for glucose and insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), and the Matsuda Index (Insulin Sensitivity Index, ISI) were calculated. Results Glucose and insulin had a similar pattern between groups, except at the baseline, when insulin was higher in the sleep debt condition of the SR when compared with the SD ( p < 0.01). In the comparison between regular sleep and sleep debt, the SD had a higher insulin AUC ( p < 0.01) and FFAs ( p = 0.03) after sleep deprivation, and insulin and the insulin AUC increased ( p < 0.01 for both), while the ISI decreased ( p = 0.02) after sleep restriction in the SR. In baseline parameters covariate by the condition of regular sleep, insulin ( p = 0.02) and the HOMA-IR ( p < 0.01) were higher, and cortisol ( p = 0.04) was lower after sleep restriction when compared with sleep deprivation. Conclusion Sleep restriction for 4 consecutive nights is more detrimental to energy metabolism because of the higher insulin values and insulin resistance compared with an acute period of sleep deprivation of 24 hours.

Effects of Metreleptin in Patients with Generalized Lipodystrophy Before vs After the Onset of Severe Metabolic Disease.

Leptin replacement therapy with metreleptin improves metabolic abnormalities in patients with generalized lipodystrophy (GLD). Determine how timing of metreleptin initiation in the clinical course of GLD affects long-term metabolic health. Retrospective analysis of patients ≥ 6 months old with congenital (n=47) or acquired (n=16) GLD treated with metreleptin at the National Institutes of Health since 2001. Least squares means (LSM) for HbA1c, insulin area under the curve (AUC) from oral glucose tolerance tests, triglycerides, urine protein excretion, platelets, transaminases, and aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) for early and late treatment groups, defined by baseline metabolic health, were analyzed during median 72 (24, 108) months follow-up. Compared to late groups, early groups based on metabolic status had higher mean±SEM insulin AUC (20831±1 vs 11948±1), lower HbA1c (5.3±0.3 vs 6.8±0.3%), triglycerides (101±1 vs 193±1 mg/dL), urine protein excretion (85±1.5 vs 404±1.4 mg/24 hr), ALT (30±1 vs 53±1 U/L), AST (23±1 vs 40±1 U/L), and APRI (0.22±1.3 vs 0.78±1.3), and higher platelets (257±24 vs 152±28 K/µL) during follow-up (P<0.05). Compared to patients ≥6 years old at baseline, patients <6 years had lower HbA1c (4.5±0.5 vs 6.4±0.2%) and higher AST (40±1vs 23±1 U/L) during follow (P<0.05). Patients with GLD who initiated metreleptin before the onset of severe metabolic complications had better long-term control of diabetes, proteinuria, and hypertriglyceridemia. Early treatment may also result is less severe progression of liver fibrosis, but further histological studies are needed to determine the effects of metreleptin therapy on liver disease.

Insulin-Mediated Capillary Recruitment Is Absent in the Cutaneous Microvasculature of Women with a History of Gestational Diabetes Mellitus

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater risk of developing cardiovascular disease and type II diabetes compared to women who had an uncomplicated pregnancy (HC). Although the mechanisms underlying this increased risk are unclear, emerging evidence suggests that microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation, persists after pregnancy complicated by GDM. Whether this microvascular dysfunction reduces insulin-mediated responses in these women is unexplored. We hypothesized that insulin-mediated capillary recruitment would be attenuated in women with a history of GDM via NO-dependent mechanisms. 24 women (n=12/group; HC: 35±1 years, 24±4 months post-partum; GDM: 33±1 years, 21±3 months postpartum) underwent intradermal microdialysis, which involved the placement of 2 fibers in the ventral forearm for the local delivery of 10−4M insulin alone or 10−4M insulin+15mM NG-nitro-L-arginine methyl ester (L-NAME, NO-synthase inhibitor). The cutaneous blood flow response to post-occlusive reactive hyperemia (PORH; 5 minutes) was assessed before and during insulin perfusion. Red blood cell flux was measured continuously over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure), normalized to maximum (%CVCmax), and presented as PORH area under the curve (AUC, %CVCmax• sec−1). Microvascular capillary recruitment was assessed as ΔAUC (pre-insulin AUC - insulin AUC). Insulin perfusion increased PORH in HC (pre-insulin: 4066±490 vs. insulin: 7848±978 AUC; p=0.03) but had no effect in GDM (pre-insulin: 3765±293 vs. insulin: 6196±779 AUC; p=0.26). Insulin perfusion did not increase PORH at the L-NAME site in either group (p&gt;0.05). Within groups, L-NAME perfusion reduced insulin-mediated capillary recruitment in HC (control: 3781±1109 vs. L-NAME: 470±945 ΔAUC; p=0.04) but not GDM (control: 2431±796 vs. L-NAME: -41±1014 ΔAUC, p=0.11). These data suggest that insulin-mediated capillary recruitment assessed by PORH in the cutaneous circulation is mediated by NO-dependent mechanisms in healthy women with a history of uncomplicated pregnancy and attenuated in healthy women with a history of GDM. This reduction in insulin-mediated microvascular responses may contribute to the increased risk of cardiovascular disease and type II diabetes in these women. UI Fraternal Order of Eagles Diabetes Research Center Catalyst Grant; NIH HL169201. 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.