Insulin Curve Research Articles

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.

A Single Dose of Phosphoinositide-3-kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study.

Our objective is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center, double-blind, phase 1 clinical trial randomized healthy adults to take a single oral dose of alpelisib 300 mg (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-hour, 75-g oral glucose tolerance test. Fasting plasma glucose trended higher with alpelisib (mean ± S.D.: 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL), while mean fasting serum insulin increased nearly fivefold (23 ± 12 µU/mL vs. 5 ± 3 µU/mL, respectively) and Homeostasis Model Assessment of Insulin Resistance scored 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was over fourfold greater with alpelisib (22 ± 15 mU/mL x min) than placebo (5 ± 2 mU/mL x min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans. (ClinicalTrials.gov registration: NCT05733455).

The influence of lactation on insulin and glucose metabolism, lipid profile, and cytokines in pregnant mares

Glucose metabolism adapts to gestation, resulting in progressive physiological insulin resistance and increased insulin secretion to maintain maternal euglycemia and glucose availability for the developing fetus. These changes can impact mare fertility and maternal and neonatal health. This is the first comparison of body condition, regional adiposity, insulin and glucose dynamics, lipid metabolism, and cytokine production between lactating and non-lactating mares before, during pregnancy, and early postpartum. Twelve pregnancies from 9 broodmares, five nonlactating (NL) and seven lactating (L), were used. Evaluations were performed on the day of ovulation, at 55, 110, 165, 220, 275, and 330 days of gestation (D55, D110, D165, D220, D275, D330) and 21 days postpartum (21pp). Mares in the L group had lower basal insulin and glucose at the beginning of pregnancy, smaller area under the curve of insulin and glucose, and greater insulin sensitivity and glucose tolerance. Resistin was higher in D110 and D165 than in D0, D275, 330 and 21pp, while leptin was higher in D55, and in D110, at D110 it was equal to D0, D220, and D275, but higher than at D330 and D21pp. As for the groups, L presented lower body condition score (BCS), crest neck score (CNS), rump fat thickness (RUM), basal insulin, glucose area under the curve (AUCg), MIRG and higher RISQI, adiponectin and tumor necrosis factor (TNFα). There was no effect over time in non-esterified fatty acids (NEFA) concentrations between the L mares; in the NL, D275 presented higher concentrations than those of D0, D55, and D110, which in turn were equal to the other time points; there were higher concentrations in NL mares than L in samples D165 and D275. In conclusion, a different metabolic profile during pregnancy was detected, and NL mares were closer to the metabolic threshold for the occurrence of metabolic syndrome during pregnancy. Understanding the impacts of these differences on mare's health and their offspring's future is fundamental as most of our recipient mares for embryo transfer are non-lactating. Therefore, we suggest that further studies be performed to evaluate lactation's influence on mares' metabolic parameters.

Liver fat accumulation is associated with increased insulin secretion independent of total, visceral, and pancreatic fat.

Studies in heterogenous groups of people with respect to sex, body mass index (BMI), and glycemic status (normoglycemia, impaired glucose tolerance, diabetes), indicate no relationship between liver fat accumulation and pancreatic insulin secretion. To better understand the association of liver fat with insulin secretion. Cross-sectional analysis of 61 men with abdominal obesity who had high liver fat (HLF, ≥5.6% by magnetic resonance spectroscopy, n=28) or low liver fat (LLF, n=33), but were balanced on BMI, total body fat, visceral adipose tissue (VAT), and pancreatic fat. A frequently sampled 5-hour oral glucose tolerance test with 11 samples, in conjunction with mathematical modeling, was used to compute indices of insulin sensitivity and insulin secretion (oral minimal model). Compared to subjects with LLF, those with HLF had significantly greater fasting glucose, insulin, C-peptide, and triglyceride; lower high-density lipoprotein-cholesterol; but similar glycated hemoglobin. Areas under the 5-hour curve for glucose, insulin, and C-peptide were greater in the HLF group than the LLF group (by ∼10%, ∼38%, and ∼28%, respectively); fasting and total postprandial insulin secretion rates were ∼37% and ∼50% greater, respectively (all P<0.05); whereas the insulinogenic index was not different. HLF subjects had lower whole-body and hepatic insulin sensitivity, disposition index, and total insulin clearance than LLF subjects (all P<0.05). Accumulation of liver fat is associated with increased insulin secretion independently of total adiposity, abdominal fat distribution, and pancreatic fat. Thereby, hyperinsulinemia in fatty liver disease is partly because of insulin hypersecretion and partly because of impaired insulin clearance.

Postprandial Blood Glucose and Insulin Response in Healthy Adults When Lentils Replace High-Glycemic Index Food Ingredients in Muffins, Chilies and Soups.

This study aimed to assess postprandial blood glucose response (PBGR), relative glycemic response (RGR) and insulin response when 25 g available carbohydrates (AC) is replaced with cooked lentils in the formulation of muffins, chilies and soups. In randomized, crossover studies, healthy adults consumed foods containing 25 g AC from green lentils, red lentils or a control (wheat muffin, n = 24; rice chili, n = 24; potato soup, n = 20). Blood collected at fasting and at 15, 30, 45, 60, 90 and 120 min was analyzed to derive the incremental area under the response curve (iAUC) for glucose, insulin, RGR and maximum concentration (CMAX). Treatment effects were assessed with repeated measures ANOVA. A replacement of 25 g AC with green lentils significantly decreased glucose iAUC compared to chili and soup (p < 0.0001), but not muffin (p = 0.07) controls, while also eliciting a significantly lower insulin iAUC for all three foods (muffin p = 0.03; chili p = 0.0002; soup p < 0.0001). Red lentil foods significantly decreased glucose iAUC (muffin p = 0.02; chili p < 0.0001; soup p < 0.0001) compared to controls, with a significantly lower insulin iAUC for chili and soup (p < 0.0001) but not muffins (p = 0.09). The RGR for muffins, chilies and soups was 88, 58 and 61%, respectively, for green lentils, and 84, 48 and 49%, respectively, for red lentils. PBGR, insulin and RGR are decreased when lentils are incorporated into food products, providing credible evidence to promote carbohydrate replacement with lentil-based foods.

Acute Effects of Dietary Protein Consumption on the Postprandial Metabolic Response, Amino Acid Levels and Circulating MicroRNAs in Patients with Obesity and Insulin Resistance.

The post-nutritional intervention modulation of miRNA expression has been previously investigated; however, post-acute dietary-ingestion-related miRNA expression dynamics in individuals with obesity and insulin resistance (IR) are unknown. We aimed to determine the acute effects of protein ingestion from different dietary sources on the postprandial metabolic response, amino acid levels, and circulating miRNA expression in adults with obesity and IR. This clinical trial included adults with obesity and IR who consumed (1) animal-source protein (AP; calcium caseinate) or (2) vegetable-source protein (VP; soy protein isolate). Glycaemic, insulinaemic, and glucagon responses, amino acid levels, and exosomal microRNAs isolated from plasma were analysed. Post-AP ingestion, the area under the curve (AUC) of insulin (p = 0.04) and the plasma concentrations of branched-chain (p = 0.007) and gluconeogenic (p = 0.01) amino acids increased. The effects of different types of proteins on the concentration of miRNAs were evaluated by measuring their plasma circulating levels. Compared with the baseline, the AP group presented increased circulating levels of miR-27a-3p, miR-29b-3p, and miR-122-5p (p < 0.05). Subsequent analysis over time at 0, 30, and 60 min revealed the same pattern and differences between treatments. We demonstrated that a single dose of dietary protein has acute effects on hormonal and metabolic regulation and increases exosomal miRNA expression in individuals with obesity and IR.

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.

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.

Utilizing the Glucose and Insulin Response Shape of an Oral Glucose Tolerance Test to Predict Dysglycemia in Children with Overweight and Obesity, Ages 8-18 Years.

Common dysglycemia measurements including fasting plasma glucose (FPG), oral glucose tolerance test (OGTT)-derived 2 h plasma glucose, and hemoglobin A1c (HbA1c) have limitations for children. Dynamic OGTT glucose and insulin responses may better reflect underlying physiology. This analysis assessed glucose and insulin curve shapes utilizing classifications-biphasic, monophasic, or monotonically increasing-and functional principal components (FPCs) to predict future dysglycemia. The prospective cohort included 671 participants with no previous diabetes diagnosis (BMI percentile ≥ 85th, 8-18 years old); 193 returned for follow-up (median 14.5 months). Blood was collected every 30 min during the 2 h OGTT. Functional data analysis was performed on curves summarizing glucose and insulin responses. FPCs described variation in curve height (FPC1), time of peak (FPC2), and oscillation (FPC3). At baseline, both glucose and insulin FPC1 were significantly correlated with BMI percentile (Spearman correlation r = 0.22 and 0.48), triglycerides (r = 0.30 and 0.39), and HbA1c (r = 0.25 and 0.17). In longitudinal logistic regression analyses, glucose and insulin FPCs predicted future dysglycemia (AUC = 0.80) better than shape classifications (AUC = 0.69), HbA1c (AUC = 0.72), or FPG (AUC = 0.50). Further research should evaluate the utility of FPCs to predict metabolic diseases.

Donor- and isolation-related predictive factors of in vitro secretory function of cultured human islets.

Human islet preparations designated for research exhibit diverse insulin-secretory profiles. This study aims to assess the impact of donor- and isolation-related factors on in vitro islet secretory function. A retrospective analysis of 46 isolations from 23 pancreata discarded for clinical transplantation was conducted. In vitro islet secretory function tests were performed on Day 1 and Day 7 of culture. Linear mixed-effects models (LMMs) were employed to investigate the relationships between various predictors characterizing the patient and donor characteristics as well as the isolation effectiveness and two functional outcomes including the islet stimulation index (SI) and area under the insulin curve (AUC). Fixed effects were introduced to represent the main effects of each predictor, and backward elimination was utilized to select the most significant fixed effects for the final model. Interaction effects between the timepoint (Day 7 vs. Day 1) and the predictors were also evaluated to assess whether predictors were associated with the temporal evolution of SI and AUC. Fold-change (Fc) values associated with each predictor were obtained by exponentiating the corresponding coefficients of the models, which were built on log-transformed outcomes. Analysis using LMMs revealed that donor body mass index (BMI) (Fc = 0.961, 95% CI = 0.927-0.996, p = 0.05), donor gender (female vs. male, Fc = 0.702, 95% CI = 0.524-0.942, p = 0.04), and donor hypertension (Fc = 0.623, 95% CI = 0.466-0.832, p= <0.01) were significantly and independently associated with SI. Moreover, donor gender (Fc = 0.512, 95% CI = 0.302-0.864, p = 0.02), donor cause of death (cerebrovascular accident vs. cardiac arrest, Fc = 2.129, 95% CI = 0.915-4.946, p = 0.09; trauma vs. cardiac arrest, Fc = 2.129, 95% CI = 1.112-7.106, p = 0.04), pancreas weight (Fc = 1.01, 95% CI = 1.001-1.019, p = 0.03), and islet equivalent (IEQ)/mg (Fc = 1.277, 95% CI = 1.088-1.510, p ≤ 0.01) were significantly and independently associated with AUC. There was no predictor significantly associated with the temporal evolution between Day 1 and Day 7 for both SI and AUC outcomes. This study identified donor- and isolation-related factors influencing in vitro islet secretory function. Further investigations are essential to validate the applicability of these results in clinical practice.

Sex dimorphism in the effect and predictors of weight loss after sleeve gastrectomy.

No sex-specific guidelines for surgical anti-obesity strategies have been proposed, partially due to the controversy regarding sex-related differences in weight loss after bariatric metabolic surgery. To explore sex dimorphism in the effect and predictors of weight loss after sleeve gastrectomy (SG), thereby providing clinical evidence for the sex-specific surgical treatment strategy. In a prospective cohort design, participants scheduled for SG at an affiliated hospital between November 2020 and January 2022 were assessed for eligibility and allocated to the Male or Female group with a 1-year follow-up after surgery. The primary outcome was the sex difference in the weight-loss effect after SG indicated by both percentage of total weight loss (TWL%) and excess weight loss (EWL%). The secondary outcome was the analysis of sex-specific preoperative predictors of weight loss after SG based on univariate and multivariate analyses. Independent predictors were obtained to construct a nomogram model. The discrimination, calibration, and clinical utility of the nomogram were based on receiver operating characteristic curve, concordance index, calibration curve, and decision curve analysis, respectively. Ninety-five male and 226 female patients were initially included. After propensity score matching by baseline body mass index (BMI), 85 male and 143 female patients achieved comparable TWL% and EWL% for 1 year after SG. For male patients, baseline BMI, area under the curve for insulin during oral glucose tolerance test, and progesterone were independent predictors of weight loss after SG. Baseline BMI, age, thyroid stimulating hormone, and Self-Rating Anxiety Scale score were independent predictors for female patients. No obvious sex difference is detected in the weight-loss effect after SG. Sex dimorphism exists in the predictors of weight loss after SG. Further research with long-term and a multicenter design is needed to confirm the predictive model.

Insulin Sensitivity, Islet Cell Function, and Incretin Axis in Pregnant Women With and Without Gestational Diabetes Mellitus.

The aim of this study was to compare insulin sensitivity, islet cell function, and incretin axes in pregnant subjects with GDM and normal healthy controls. Pregnant women at 24 to 28 weeks of gestation were subjected to a 75 g oral glucose tolerance test (OGTT). Samples for glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were collected at 0, 30, 60, and 120 min during the OGTT. The Matsuda index (MI) and insulin secretion and sensitivity index-2 (ISSI-2) were assessed. The glucagon suppression index (GSI) was calculated along with the area under the curve (AUC) for glucose, insulin, glucagon, GLP-1, and GIP. A total of 48 pregnant women (25 GDM and 23 controls) were finally analysed. The MI and ISSI-2 were low in the GDM group [4.31 vs. 5.42; P = 0.04], [1.99 vs. 3.18, P ≤ 0.01] respectively). Total AUCglucagon was higher in the GDM group (7411.7 vs. 6320.1, P = 0.02). GSI30 was significantly lower in the GDM group (-62.6 vs. -24.7, P = 0.03). Fasting GLP-1 levels were low in GDM women (17.3 vs. 22.2, P = 0.04). The total AUCGLP-1 positively correlated with total GSI in the GDM group. Asian-Indian GDM women have high insulin insensitivity, islet cell dysfunction, and low fasting GLP-1. Incretin axis dysfunction plays a potential role in their islet cell dysfunction.

Association of GLP-1 secretion with parameters of glycemic control in women after gestational diabetes mellitus

IntroductionWomen with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes, while the exact mechanisms underlying its pathophysiology are still unclear. We investigated...

Insulin dysregulated horses metabolic responses to forage pellets

Hyperinsulinemia-associated laminitis (HAL) is the primary concern for insulin dysregulated (ID) equids and their insulin response to the consumption of oral, nonstructural carbohydrates (NSC) has been shown to be a risk predictor for HAL development. This randomized, crossover study's objective was to examine the insulinemic responses to 3 forage pellets (1 g/kg BW) (timothy hay, TH, 9.5 % CP & 10 % NSC DM; alfalfa hay, AH, 16.3 % CP & 9.8 % NSC DM; timothy-alfalfa hay; TAH, 17.2 % CP & 9.8 % NSC DM) along with a positive (dehulled oats; OG, 14.7 % CP & 59.7 % NSC DM) and negative dietary challenge control (low-NSC; LNSC, 12.8 % CP & 5.4 % NSC DM) of ID (n = 8; 16.1 ± 2.2 yr; 565.4 ± 99.1 kgs.) and non-ID (NID; n = 7; 17.0 ± 2.8 yr; 583.6 ± 57.9 kgs.) horses. ID horses had higher positive incremental area under the curve for insulin (IAUCi) (ID: 890 ± 925 µIU/mL*minute vs. NID: 225 ± 228 µIU/mL*minute), peak (ID: 101.5 ± 80.72 µIU/mL vs. NID: 25.7 ± 7.2 µIU/mL), and delta (ID: 45.5 ± 77.1 µIU/mL vs. NID: 4.9 ± 5.3 µIU/mL) insulin for all forage pellets compared to NID (p < 0.01). ID horses IAUCi for the forage pellets was not different compared to the LNSC (218 ± 327 µIU/mL*minute) but was different from OG (10,522 ± 4,565 µIU/mL*minute). ID horses’ lack of an augmented insulinemic response to the low NSC forage pellets (fed in small amounts) indicates that they could be a safe feedstuff for ID animals.

Comparison of one novel and four established diagnostic tests for insulin dysregulation in ponies

Several tests have been advocated for diagnosis of insulin dysregulation (ID). Tests using simple sugars may not reflect the response to naturally ingested carbohydrates. This study aimed to evaluate agreement between the oral glucose test (OGT), the oral sugar test (OST), a novel oral test using a proprietary cereal (WEET), the IV combined glucose-insulin tolerance test (CGIT) and fasted basal insulin (FI) for diagnosis of ID. Each of the five tests above was performed on a group of six normal and six insulin dysregulated mixed-breed ponies in a randomised crossover study. Area under the curve (AUC) and maximum concentration of insulin from OGT, OST and WEET showed strong to very strong bivariate correlations (r = 0.85–0.94, and r = 0.87–0.92, respectively; P ≤ 0.001) and were significantly different between tests (associated with dose of carbohydrate) and between CGIT-positive and -negative ponies. Dichotomous results showed substantial agreement between OST and both WEET (κ = 0.65; P = 0.02) and OGT (κ = 0.67; P = 0.01) and between CGIT and both OST (κ = 0.63; P = 0.03) and OGT (κ = 0.67; P = 0.01), and no agreement between FI, which had low sensitivity, and all other tests (κ = 0.15 – 0.31; P > 0. 05). Palatability of WEET was variable, resulting in one pony being excluded for analysis of WEET data. Further work on development of an oral test using a more palatable feedstuff and appropriate cut-offs or diagnostic thresholds for tests of ID is warranted.

The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.

The N221D variant in PCSK1 is highly prevalent in childhood obesity and can influence the metabolic profile.

To study the prevalence and influence on metabolic profile of the prohormone-convertase-1 (PCSK1) N221D variant in childhood obesity, proven its role in the leptin-melanocortin signaling pathway as in proinsulin and other prohormone cleavage. Transversal study of 1066 children with obesity (mean age and BMI Z-score 10.38 ± 3.44 years and +4.38 ± 1.77, respectively), 51.4 % males, 54.4 % prepubertal, 71.5 % Caucasians and 20.8 % Latinos. Anthropometric and metabolic features were compared between patients carrying the N221D variant in PCSK1 and patients with no variants found after next generation sequencing analysis of 17 genes (CREBBP, CPE, HTR2C, KSR2, LEP, LEPR, MAGEL2, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, SIM1, TBX3 and TUB) involved in the leptin-melanocortin pathway. No variants were found in 531 patients (49.8 %), while 68 patients carried the PCSK1 N221D variant (42 isolately, and 26 with at least one additional gene variant). Its prevalence was higher in Caucasians vs. Latinos (χ2 7.81; p<0.01). Patients carrying exclusively the PCSK1 N221D variant (n=42) showed lower insulinemia (p<0.05), HOMA index (p<0.05) and area under the curve for insulin in the oral glucose tolerance test (p<0.001) and higher WBISI (p<0.05) than patients with no variants, despite similar obesity severity, age, sex and ethnic distribution. The N221D variant in PCSK1 is highly prevalent in childhood obesity, influenced by ethnicity. Indirect estimation of insulin resistance, based on insulinemia could be byassed in these patients and underestimate their type 2 diabetes mellitus risk.

Cortisol secretion and abnormalities of glucose metabolism in nondiabetic patients with hypertension.

Glycometabolic changes are associated with hypercortisolism in Cushing's syndrome. Because impaired glucose tolerance (IGT) and insulin resistance are frequently detected in patients with essential hypertension, we hypothesized that in these patients, early glycometabolic abnormalities might be related to differences in regulation of cortisol secretion. In a cross-sectional study, we included 155 nondiabetic, essential hypertensive patients who were free of organ complications. The homeostasis model assessment (HOMA) index and the area under the curve of plasma glucose (AUC-glucose) and insulin (AUC-insulin) concentration following an oral glucose tolerance test were measured, together with daily plasma cortisol (8 a.m., 3 p.m. and 12 a.m.; AUC-cortisol) and 8 a.m. cortisol after 1 mg overnight dexamethasone suppression test (DST). IGT was present in 27% of patients who were older and had higher BMI, plasma triglycerides and uric acid, AUC-cortisol and DST-cortisol, and lower HDL-cholesterol. Frequency of IGT increased progressively across tertiles of DST-cortisol, together with levels of glycated hemoglobin, fasting insulin and C-peptide, HOMA-index, AUC-glucose, and AUC-insulin. AUC-cortisol and DST-cortisol were directly correlated with insulin, C-peptide, HOMA-index, AUC-glucose, and AUC-insulin. Multivariate regression analysis showed that DST-cortisol was directly and independently correlated with HOMA index, AUC-glucose, and AUC-insulin. In a logistic regression model, both AUC-cortisol and DST-cortisol independently predicted IGT. Daily cortisol and cortisol response to DST are independent determinants of IGT and insulin resistance in nondiabetic patients with hypertension, suggesting that even subtle differences in regulation of cortisol secretion might increase the risk of these patients to develop diabetes.

OR34-04 Defective FGFR1 Signaling Disrupts Glucose Regulation In Humans: Evidence From Patients With Isolated Hypogonadotropic Hypogonadism Harboring FGFR1 Mutations

Abstract Disclosure: M. Stamou: None. C.J. Chiu: None. S. Jadhav: None. K. Salnikov: None. L. Plummer: None. S.B. Seminara: None. R. Balasubramanian: None. Introduction: Recent studies have shown that antibody-mediated activation of FGFR1 receptor improves metabolic health in rodents, nonhuman primates, and humans. Hence, disruption of the FGFR1 receptor may lead to glucose dysregulation. FGFR1 mutations contribute to 12% of the genetic background of subjects with isolated hypogonadotropic hypogonadism (IHH), a rare Mendelian disease caused by GnRH deficiency. In this study, we examined glucose effectiveness and insulin sensitivity in IHH subjects with rare FGFR1 variants and hypothesized that these subjects will display defective glucose metabolism compared healthy non-carrier controls. Methods: Nine subjects with IHH (7 males and 2 females) with heterozygous rare FGFR1 variants were enrolled [7 subjects with protein truncating variants: p.Q680*, p.R622*, p.Q52*, p.I347Nfs*61, p.R576Pfs*77, p.Q309*, c.1553-2A&amp;gt;G and 2 subjects with deleterious missense variants: p.G97S &amp; p.Y701C. Thirty healthy controls (17 males and 13 females) with no FGFR1 variants were enrolled from the Mass General Brigham Biobank. Medical history, physical exam, laboratory evaluation, a bone density scan, and an intravenous glucose tolerance test (IVGTT) were performed. The area under the curve (AUC) for glucose, insulin, and C-peptide response to 50% dextrose (0.3g/kg, t=0min) and an insulin bolus (0.03u/kg, t=20 min) were estimated for each subject. The glucose effectiveness (Sg), insulin sensitivity (SI), acute insulin response to glucose (AIR), and the disposition index (DI= AIRG*SI) were calculated using the Minimal Model Analysis. Statistical comparisons were performed with t-test and non-parametric Wilcoxon rank sum test. A linear regression model was used to adjust the t-test outcomes for potential confounders. Results: Despite similar BMIs (28 vs. 26.5, p=0.29), IHH FGFR1 positive subjects demonstrated higher % fat mass compared to controls (38 vs. 31, p=0.02). IHH patients were supplemented with sex-steroids at the time of the study. Male patients demonstrated similar testosterone levels compared to controls (385 vs. 451 ng/dL, p=0.52). IHH FGFR1 positive subjects demonstrated a higher AUC for C-peptide compared to controls (167 vs. 92, p=0.001), that remained significant after adjusting for age, gender, BMI, and % fat mass. Non-parametric test showed higher AUC for glucose, insulin, and C-peptide (p 0.01, 0.01 &amp; 0.005 respectively) as well as lower SI (p=0.01) and higher AIRg (p=0.037) in the IHH FGFR1 positive group compared to non-carrier controls. Discussion: This is the first study to evaluate glucose metabolism in humans with naturally occurring FGFR1 variants. IHH FGFR1 positive subjects showed higher insulin response to glucose and lower insulin sensitivity during an IVGTT test compared to the healthy non-carrier controls. These findings confirm that FGFR1 signaling is a key regulator of insulin secretion and action in humans. Presentation: Sunday, June 18, 2023