Insulin Area Under The Curve Research Articles

198-LB: Dynamic Behavior of Healthy People with Different Numbers of Autoantibodies

Background and aims: The risk of type 1 diabetes (T1D) can be assessed by the number of islet autoantibodies (Ab), genetic, and metabolic markers to predict the progression to diabetes. Prior OGTT-based work had suggested that β cell dysfunction exists prior to T1D diagnosis. Here, we test whether the frequently sampled glucose, insulin, and C-peptide responses to a mixed meal depend on the number of Ab. Methods: Sixty healthy relatives to T1D with mean±SD age of 23.7±10.7 years, HbA1c of 5.3±0.3%, and BMI of 23.8±5.6 kg/m2 with zero (N=21), one (N=18), and ≥2 (N=21) Ab, were enrolled in an ancillary study from the NIH-funded TrialNet Pathway to Prevention study. At 08:00, the participants consumed a 6ml/kg standardized liquid mixed meal (SLMM). To estimate the SLMM glycemic and hormonal behavior, 14 blood samples were collected from -30 (relative to the SLMM ingestion) to 120 minutes for insulin, C-peptide, and glucose. Glucose-Insulin-C-peptide features were extracted from the post-SLMM period to compare the different Ab groups. Results: Among all glycemia metrics, only two were different across the Ab groups: glucose incremental AUC for the “tail” (60 min- 120 min; during the decline, after glucose reaches its peak) and glucose at 90 min with p-value 0.036, and 0.025 respectively. Regarding the insulin features after the post-SLMM; the insulin AUC for the tail, insulin at 30 min, insulin at 120 min, and the baseline insulin were different across the Ab groups (p=0.043, 0.033, 0.029, and 0.019 respectively), with higher insulin values for those with 1 Ab. As well, the C-peptide features: C-peptide at SLMM time, max C-peptide, and C-peptide at 120 min were different across the different Ab groups (p=0.019, 0.038, and 0.041 respectively), with higher C-peptide values for those with 1 Ab. Conclusion: The study suggests that the progression to T1D may be marked by detectable simultaneous changes in glycemia, insulin, and C-peptide in the very early stages of the disease even before transitioning to the first stage of T1D. Disclosure E. Montaser: None. M. D. Breton: Consultant; Dexcom, Inc., Tandem Diabetes Care, Inc., Roche Diabetes Care, Sanofi, Arecor, Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc., Novo Nordisk. S. A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. M. D. Deboer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. A. L. Mccall: None. B. Kovatchev: Other Relationship; Dexcom, Inc., Johnson & Johnson Medical Devices Companies, Novo Nordisk, Sanofi, Research Support; Dexcom, Inc., Novo Nordisk, Tandem Diabetes Care, Inc., Speaker's Bureau; Tandem Diabetes Care, Inc. L. Farhy: Research Support; Dexcom, Inc., Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK106907); Commonwealth Research Commercialization Fund (MF20-007-LS); The Leona M. and Harry B. Helmsley Charitable Trust (2204-05134); JDRF (2-SRA-2022-1260-S-B)

1104-P: South Asian vs. White Adolescents Have Lower Insulin Sensitivity and Higher Insulin AUC

Background: T2D occurs at higher rates in South Asian (SA) adults, even at non-overweight/obese BMI. OGTT metrics were compared in SA vs White (W) adolescents to identify early contributors to increased T2D risk. Methods: Healthy SA and W adolescents, ages 12-21y, with BMI ≥80%ile (or ≥23kg/m2 if ≥18y) underwent 10-sample 180-min OGTT to determine incremental insulin AUC (iAUC), Oral Minimal Model insulin sensitivity (Si), and disposition index (DI: Si x insulin iAUC at 180min). Ancestry differences in OGTT outcomes were compared using linear regression adjusted for age, sex, and BMI. Results: For n=21, age [median (IQR) W: 20.1y (16.1, 21.3), SA: 21.0 (20.3, 21.6)], sex [W: 6F, SA: 4F], and BMI [W: 25.2kg/m2 (24.7, 31.4), SA: 24.6 (24.1, 27.9)] were not different for SA vs W. Fasting glucose [β=7.1, p=0.01; SA: 98.0mg/dL (92.0, 102.5), W: 89.0mg/dL (87.0, 93.5)], fasting insulin [β=7.0, p=0.005], insulin iAUC at 30min [β=1192, p=0.02], and log-transformed insulin iAUC at 180min [β=0.98, p=0.002] were higher, and log-transformed Si [β=-1.07, p=0.008] lower in SA than W. HbA1c, OGTT 1h and 2h glucose, and DI did not differ. Conclusions: Higher OGTT insulin in overweight SA adolescents contrast with reduced insulin found in SA adults and suggests reduced Si and insulin hyper-secretion are precursors to β-cell failure and T2D in SA adults. Understanding T2D mechanistic differences by ancestry may lead to improved T2D treatments. Disclosure T.A.Hitt: None. D.Stefanovski: None. S.Malina: None. C.X.D.Wang: None. B.S.Zemel: None. A.Kelly: None. S.N.Magge: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115648); National Institutes of Health (UL1TR001878, UL1TR001079)

163-LB: Youth with Delayed Sleep Phase Have Reduced Insulin Sensitivity

Background: U.S. adolescents have short and delayed sleep, which may have metabolic consequences. We hypothesized that shorter sleep duration and later sleep phase are associated with decreased insulin sensitivity (SI) and worse glucose tolerance in overweight youth. Methods: We enrolled healthy youth aged 12-21y with BMI ≥80%ile (or ≥23kg/m2 if ≥18y). We obtained 14 days of wrist actigraphy (ActiGraph GT3XP-BTLE), a frequently-sampled 180 min OGTT (fsOGTT) with 10 samples, and administered validated questionnaires to estimate obstructive sleep apnea (OSA) risk. From actigraphy, we derived average sleep duration (SLD), mid-sleep time (MST), and sleep onset (SO). From the fsOGTT, we estimated SI using the OGTT Minimal Model and the disposition index (DI = SI x incremental insulin AUC 180min). We used multivariable linear regression to examine associations between sleep patterns and glycemic outcomes adjusting for confounders. Results: To date, we enrolled 24 youth (13F) with a median (IQR) age of 20.6y (19.2, 21.5), BMI of 25.2kg/m2 (24.3, 28.9), and fsOGTT glucoses of: fasting 91mg/dL (86, 95), 1h 141mg/dL (113, 179), and 2h 117mg/dL (78, 144). Participants had a median SLD of 7.3h (6.8, 8.1) per night, with SO of 1:13am (12:27am, 2:09am) and MST of 4:48am (4:23am, 6:01am). Age, race, and sex were not associated with sleep outcomes and not included in regressions. We found that (1) later MST [β=10.3, p=0.01] and SO [β=11.4, p=0.01] were each associated with higher fsOGTT 2h glucose, (2) later SO was associated with lower log-transformed SI [β= -0.27, p=0.04], and (3) later MST trended towards lower log-transformed DI [β= -0.1, p=0.055] adjusting for BMI and OSA risk. SLD was not related to any fsOGTT variables. Conclusions: To our knowledge, this is the first study in overweight youth to show that delayed sleep phase (SO and MST), but not short SLD, was associated with lower SI using the rigorous OGTT minimal model. Further studies are needed to examine if delayed sleep is a modifiable risk factor for diabetes prevention in youth. Disclosure T. A. Hitt: None. D. Stefanovski: None. A. Kelly: None. S. Malina: None. C. X. D. Wang: None. F. P. Sgambati: None. B. S. Zemel: None. J. Jun: None. S. N. Magge: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115648); National Institutes of Health (UL1TR001878, UL1TR001079)

0198 Effects of a 1-hour nightly weeklong sleep extension pilot study in undergraduates on health

Abstract Introduction Sleep restriction impairs health, but less is known about the potential health benefits of extending sleep in undergraduate students with habitual short sleep. This study examined the effects of a 1-week, 1-hour per night sleep extension on cardiometabolic health, hydration status, sedentary behavior, and physical activity in undergraduate students. Methods Twelve healthy undergraduate students (83% female; mean±SD age 20.2±1.5; range 18-23 years) obtaining fewer than 7 hours of average nightly sleep completed a two-week study. The first week consisted of sleeping typically ("Habitual"), followed by a peer-delivered intervention to extend time in bed by ≥1 hour/night during the second week ("Extension"). Sleep and physical activity actigraphy were collected throughout. Following each week, participants completed in-person cardiometabolic assessments, including a standardized meal response procedure and blood pressure measurement. Blood samples for measurement of glucose and insulin were collected before, during, and following a standardized breakfast. Urine samples yielded markers of hydration (specific gravity and osmolality). Mixed-effects regression models with random intercepts for individuals compared outcomes after the Extension week to Habitual outcomes. Results Compared to Habitual sleep, average sleep duration across the Extension week increased (b±SEM, +42.6±.3 minutes; p=.005). After the breakfast meal, glucose area under the curve (AUC; −26.5±10.2 mg/dL*h; p=.025) and time to return to baseline levels (−83.0±46.4 minutes; p=.031) decreased following Extension. There was no change in insulin AUC. Systolic blood pressure decreased (−6.6±2.8 mmHg; p=.037) after Extension. Average time spent in sedentary behavior (−44.3±15.7 minutes; p=.018) and percentage of wake spent in moderate-to-vigorous physical activity (−1%±.4%; p=.030) decreased across the Extension week. Participants who increased average sleep duration ≥15 minutes (n=9) were better hydrated according to urine osmolality (−187.0±68.4 mOsm/kg; p=.026) and specific gravity (−.01±.002 g/mL; p=.012) and had lowered odds of dehydration according to urine osmolality (≥800 mOsm/kg; −67%; OR=.03; p=.035). Conclusion This pilot study provided evidence that sleep extension may improve cardiometabolic health and hydration and reduce both sedentary behavior and moderate-to-vigorous physical activity. Future research in randomized controlled trials should examine if such findings extrapolate to larger samples and older populations. Support (if any) CRC/CTSI: UL1-TR002014; pilot grant to AMC from the Department of Biobehavioral Health, Pennsylvania State University

17 Can a yeast-derived prebiotic improve insulin response in aged horses?

Research has shown aged horses to be disproportionately affected by insulin dysregulation. Therefore, the objective of this study was to test the hypothesis that feeding ActivAge® (AA), a unique yeast-derived prebiotic purported to improve metabolic health, would lower insulin response in aged horses. Ten Quarter Horse geldings (19 ± 0.6 yr; 587.5 ± 22 kg) were utilized in a randomized design, with a 42d feeding period, followed by a 28d washout, then a crossover 42d feeding period. All horses received 0.36 kg/45.5 kg BW/d Purina® Equine Senior® (ES) paired with either 0.45 kg/d of a pelleted supplement containing AA (TRT) or no supplement (CON). All horses were offered 1.25% BW/d Timothy hay. All hay and concentrate feedings were split into 2 equal feedings at 0700 and 1430. Horses were housed in stalls with individual drylot turnouts. The glucose-insulin response to feeding (GIRF) was recorded on d28, and horses underwent a combined glucose-insulin tolerance test (CGIT) on d35 in each feeding period. For both tests, horses were catheterized for blood samples and no hay was fed before or during the sampling periods. For GIRF, horses were offered their AM meal and serial (every 30 min) blood samples were obtained from −30 through 360 min. For the CGIT, horses were administered IV dextrose (150mg/kg) and insulin (0.1U/kg) and serial blood samples were taken at −30, 0, 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, and 120 min. Serum was analyzedfor glucose and plasma was analyzed for insulin via colorimetric ELISA (Mercodia). Additionally, serum samples were collected via venipuncture every 2 wk, 2 h post AM meal, and analyzed for glucagon-like protein 1 (GLP-1) via an equine specific ELISA (MyBioSource). Data were analyzed via ANOVA using the MIXED procedure (SAS 9.4). Horses in both CON and TRT had similar glucose responses to feeding. No differences were observed in peak glucose response or area under the curve (AUC) for glucose. The insulin response during the GIRF was impacted by treatment with a trend for TRT having a lower insulin level (P = 0.07) and a decreased AUC (P = 0.02) compared with CON. For the CGIT, CON and TRT had similar glucose curves during the test, however there was a trend for the AUC for insulin in TRT to be lower compared with CON (P = 0.10). Horses in both the CON and TRT had similar starting levels of GLP-1 at d 0 but with time, GLP-1 levels rose in CON while they stayed lower in TRT over each 42-d feeding period (P < 0.001). In conclusion, feeding horses ActivAge® appears to affect insulin, but not glucose response, in standardized testing. Changes to GLP-1 secretion by enterocytes may be a mechanism behind this phenomenon.

370 Epicardial adipose tissue and cardiometabolic health in youth-onset type 2 diabetes undergoing vertical sleeve gastrectomy

OBJECTIVES/GOALS: The goal of this study is to investigate the potential independent relationship between epicardial adipose tissue (EAT) and cardiometabolic health in youth-onset type 2 diabetes (T2D) and explore changes in EAT as a potential mediator of changes in cardiometabolic health in response to vertical sleeve gastrectomy (VSG). METHODS/STUDY POPULATION: We will assess glycemic control, insulin sensitivity and secretion in youth with T2D before and 3 months after VSG. Fasting labs, anthropometrics, and a 4-hour, frequently sampled liquid mixed meal tolerance test (45g carbohydrates, 14g fat, and 14g protein) were performed. Calculations included glucose, insulin, and GLP-1 area under the curve (AUC), Matsuda Index, HOMA-IR, and oral disposition index (DI). These cardiometabolic outcomes will then be assessed for associations between total EAT volume, measured from cardiac MRI. RESULTS/ANTICIPATED RESULTS: Previous studies have shown that individuals with obesity have higher EAT than lean controls, and adults with T2D have even higher EAT than obese controls. Therefore, we anticipate that our participants will have higher volume of EAT than what has been reported in the literature and that they will have worsening cardiometabolic outcomes without MBS. Our anticipated results will include: Weight and BMI, hemoglobin A1c, diabetes medications, Matsuda Index, HOMA-IR, DI, and glucose and insulin AUC during an MMTT. Cardiac MRI's are being analyzed and will give total EAT volume and will be analyzed for correlations with the cardiometabolic outcomes of body composition, aortic stiffness, blood pressure, cardiac structure and function, as well as lipid panel and insulin sensitivity. DISCUSSION/SIGNIFICANCE: This study is the first to specifically assess EAT in adolescents with T2D. The assessment of EAT will be done with gold-standard MRI and correlated with cardiometabolic health assessed by gold-standard methods. Together, the results will give insight into EAT as a potential independent cardiometabolic risk factor in adolescents undergoing VSG.

Associations of atrial natriuretic peptide with measures of insulin and adipose depots.

Low concentrations of natriuretic peptides (NPs) have been associated with greater risk for Type 2 diabetes (T2D). African American individuals (AA) have lower NP levels and are disproportionately burdened by T2D. The purpose of this study was to test the hypothesis that higher post-challenge insulin in AA adults is associated with lower plasma N-terminal pro-atrial natriuretic peptide (NT-proANP). A secondary purpose was to explore associations between NT-proANP and adipose depots. Participants were 112 AA and European American (EA) adult men and women. Measures of insulin were obtained from an oral glucose tolerance test and hyperinsulinemic-euglycemic glucose clamp. Total and regional adipose depots were measured from DXA and MRI. Multiple linear regression analysis was used to assess associations of NT-proANP with measures of insulin and adipose depots. Lower NT-proANP concentrations in AA participants was not independent of 30-min insulin area under the curve (AUC). NT-proANP was inversely associated with 30-min insulin AUC in AA participants, and with fasting insulin and HOMA-IR in EA participants. Thigh subcutaneous adipose tissue and perimuscular adipose tissue were positively associated with NT-proANP in EA participants. Higher post-challenge insulin may contribute to lower ANP concentrations in AA adults.

Reproducibility and determinants of the metabolic responses during a mixed-meal tolerance test.

The aim of this study was to assess the reproducibility and physiological determinants of mixed-meal tolerance tests (MMTTs) on glucose and insulin responses. While inpatients on a weight-maintaining diet, 894 individuals (574 with normal and 267 with impaired glucose regulation and 53 with type 2 diabetes [T2D]) underwent 9-hour MMTTs (breakfast and lunch; 30% weight-maintaining diet each; 40% carbohydrate, 40% fat, and 20% protein). Total/incremental areas under the curve (AUC/iAUC) were calculated from MMTT plasma glucose/insulin concentrations. Acute insulin response (AIR) was quantified by intravenous glucose tolerance test and insulin action (M) via hyperinsulinemic-euglycemic clamp. A subset had repeat MMTTs (median follow-up=1.4 years). In individuals without T2D, for breakfast-versus-lunch reproducibility of glucose, AUCs were moderate (intraclass correlation coefficients [ICCs]: 0.44-0.61), and iAUCs were poor (ICCs < 0.15). For repeated MMTTs, reproducibility of AUC/iAUCs was low (ICCs: 0.11-0.36). For insulin, AUC reproducibility was high (ICCs > 0.70), and iAUCs were moderate (ICCs: 0.64-0.71). For repeated MMTTs, ICC AUC/iAUCs were 0.34 to 0.54. In those with T2D, ICC glucose AUC/iAUCs were >0.80 and >0.50, respectively, and for insulin were <0.40. For repeated MMTTs, ICC glucose/insulin AUC/iAUCs were moderate. Glucose AUCs associated with M/AIR (partial Rs < -0.25), and insulin AUCs negatively/positively associated with M/AIR (partial Rs=-0.51/0.24). Reproducibility of glucose/insulin responses to MMTTs varied by subtraction of fasting values, glucose status, and time. Insulin secretion and action explained ~20% of MMTT responses. The substantial variability in MMTT response requires consideration in studies using MMTT outcomes.

The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.

Standard procedures for blood withdrawal in conscious male rats induce stress and profoundly affect glucose tolerance and secretion of glucoregulatory hormones

ObjectiveA fundamental difference between physiological and pharmacological studies in rats and humans is that withdrawal of blood from conscious rats necessitates restraint which inevitably inflicts a higher level of stress. We investigated the impact of handling on acute glucose regulation and secretion of glucoregulatory hormones in rats. MethodsFasted male Sprague Dawley rats (375–400 g, n = 11) were given an oral glucose tolerance test (OGTT) by gavage (2 g/kg). Blood was sampled frequently until 90 min after challenge by handheld sampling (HS) or by automated sampling (AS). In the HS experiment, blood was withdrawn by restraint and sublingual vein puncture; two weeks later, samples were obtained by AS through an implanted catheter in a carotid artery, allowing sampling without disturbing the animals. ResultsOn the day of HS, post challenge glucose AUCs were ∼17% higher (P < 0.0001), despite gastric emptying (AUC) being reduced by ∼30% (P < 0.0001). Plasma insulin AUC was 3.5-fold lower (P < 0.001), and glucose-dependent insulinotropic peptide (GIP) AUC was reduced by ∼36% but glucagon-like peptide-1 concentrations were not affected. Glucagon concentrations were higher both before and after challenge (fold difference in AUCs = 3.3). Adrenocorticotropin (ACTH) and corticosterone AUCs were 2.4-fold and 3.6-fold higher (P < 0.001), respectively. Discussion and conclusionOur study highlights that sampling of blood from conscious rats by sublingual vein puncture inflicts stress which reduces glucose absorption and glucose tolerance and blunts secretion of insulin and GIP. As blood sampling in humans are less stressful, standard procedures of conducting OGTT's in rats by HS presumably introduce an interspecies difference that may have negative consequences for translatability of test results.

Beneficial effects of premeal almond load on glucose profile on oral glucose tolerance and continuous glucose monitoring: randomized crossover trials in Asian Indians with prediabetes

BackgroundRapid conversion from prediabetes to diabetes and frequent postprandial hyperglycemia (PPHG) is seen in Asian Indians. These should be the target of dietary strategies.ObjectivesWe hypothesized that dietary intervention of preloading major meals with almonds in participants with prediabetes will decrease overall glycemia and PPHG.DesignThe study included two phases: (1) an oral glucose tolerance test (OGTT)-based crossover randomized control study, the effect of a single premeal almond load (20 g) given before OGTT was evaluated (n = 60, 30 each period). (2) The continuous glucose monitoring system (CGMS)-based study for 3 days including premeal almond load before three major meals was a free-living, open-labeled, crossover randomized control trial, where control and premeal almond load diets were compared for glycaemic control (n = 60, 30 in each period). The study was registered at clinicaltrials.gov (registration no. NCT04769726).ResultsIn the OGTT-based study phase, the overall AUC for blood glucose, serum insulin, C-peptide, and plasma glucagon post-75 g oral glucose load was significantly lower for treatment vs. control diet (p < 0.001). Specifically, with the former diet, PPHG was significantly lower (18.05% in AUC on OGTT, 24.8% at 1-h, 28.9% at 2-h post OGTT, and 10.07% during CGMS). The CGMS data showed that premeal almond load significantly improved 24-glucose variability; SD of mean glucose concentration and mean of daily differences. Daily glycaemic control improved significantly as per the following: mean 24-h blood glucose concentration (M), time spent above 7.8 mmol/L of blood glucose, together with the corresponding AUC values. Premeal almond load significantly decreased following: overall hyperglycemia (glucose AUC), PPHG, peak 24-h glycaemia, and minimum glucose level during night.ConclusionIncorporation of 20 g of almonds, 30 min before each major meal led to a significant decrease in PPHG (as revealed in OGTT-based study phase) and also improved insulin, C-peptide, glucagon levels, and improved glucose variability and glycemic parameters on CGMS in participants with prediabetes.Clinical trial registryThe study was registered at clinicaltrials.gov (registration no. NCT04769726).

Determination of skeletal muscle mass by aspartate aminotransferase / alanine aminotransferase ratio, insulin and FSH in Chinese women with sarcopenia

Background:Sarcopenia is an age-related skeletal muscle disorder that involves a loss of muscle mass or strength and physiological function. Skeletal muscle deteriorates in both quantity and quality. The endocrine system is an important regulator of muscle metabolism. Therefore, we aimed to explore the relationship between biochemical markers and muscle mass in sarcopenia.Methods:We used the AWGS 2014 as the diagnostic criteria for sarcopenia, considering both the loss in muscle mass, muscle strength and physical performance. A total of 2837 elderly female participants over 50 years of age from the West China Health and Aging Trend (WCHAT) study were included. Insulin, glucose, 25(OH)VD, procalcitonin, alanine aminotransferase, aspartate aminotransferase, total protein, prealbumin, albumin, thyroid-stimulating hormone, free triiodothyronine, free tetraiodothyronine, triglycerides, cholesterol, high-density lipoprotein, very low-density lipoprotein, cortisol, and follicle-stimulating hormone were measured. Based on the findings of univariate analysis, multivariate regression and receiver operating characteristic (ROC) curves were established.Results:Participants with sarcopenia had significantly lower free triiodothyronine, insulin, total protein, albumin, prealbumin, albumin/prealbumin ratio (A/G), alanine aminotransferase, triglycerides, and very low-density lipoprotein concentrations (P < 0.05). Compared with those without sarcopenia, those with sarcopenia had significantly higher free tetraiodothyronine, cortisol, follicle-stimulating hormone (FSH), aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT), and high-density lipoprotein concentrations (P < 0.05). Insulin (OR = 0.854), FSH (OR = 1.016), and the AST/ALT ratio (OR = 1.819) were independent risk factors for low muscle mass (P < 0.001). The AUC of insulin was the highest, followed by the AST/ALT ratio and FSH (0.691, 0.671, and 0.634, respectively), and the AUC of the mixture of the above three reached 0.736.Conclusion:In this cross-sectional study of elderly Chinese females aged over 50 years from the WCHAT, FSH, insulin, and AST/ALT ratio were associated with sarcopenia and risk factors for low muscle mass.

Pilot Trial on the Effect of 5-Aminolevulinic Acid on Glucose Tolerance in Patients with Maternally Inherited Diabetes and Deafness.

The amino acid 5-aminolevulinic acid (5-ALA) is the first heme biosynthetic precursor. The combination of 5-ALA with sodium ferrous citrate (SFC) enhances heme production, leading to increased adenosine triphosphate (ATP) production in mitochondria. We investigated whether administering 5-ALA/SFC improves glucose tolerance with an increase in insulin secretion in patients with maternally inherited diabetes and deafness (MIDD), which is characterized by an insulin secretory disorder due to impaired mitochondrial ATP production. This was a single-arm, open-label, interventional study. We prospectively administered the oral glucose tolerance test (OGTT) twice in five patients with MIDD who had received intensive insulin therapy: before and 24weeks after an administration of 5-ALA/SFC (200/232mg per day). We measured the concentrations of glucose, insulin, C-peptide, and proinsulin at fasting, and 30, 60, and 120min after glucose load in each OGTT. The primary endpoint was the changes in the area under the curve (AUC) of serum insulin from 0 to 120min during OGTT from baseline to 24weeks. The serum insulin AUC (µU/mL) during the 120-min OGTT tended to increase from baseline to 24weeks but not significantly (17.1 ± 13.7 versus 22.3 ± 13.4, p = 0.077). The plasma glucose AUC (mg/dL) during the 120-min OGTT at 24weeks was not significantly decreased; the late phase of glucose excursion from 60 to 120min was significantly decreased compared with baseline (357 ± 42 versus 391 ± 50, p = 0.041). The mean level of glycated hemoglobin (HbA1c) decreased from 8.3 ± 1.2% at baseline to 7.9 ± 0.3% at 24weeks (p = 0.36) without increasing the daily dose of insulin injections. The 24-week administration of 5-ALA/SFC did not demonstrate a significant improvement in insulin secretion in patients with MIDD. Further investigations with a larger number of patients and a placebo control group are required to clarify the potential efficacy of 5-ALA/SFC for ameliorating mitochondrial dysfunctions in MIDD. UMIN-CTR000040581 and jRCT071200025.

PSUN138 Demonstration of Progressive Beta-Cell Failure in Familial Partial Lipodystrophy

Abstract Background Familial Partial Lipodystrophy Type 2 (FPLD2) is an autosomal dominant disorder caused by inherited mutations on the LMNA gene, typically on exon 8 and 11. Insulin resistance and diabetes mellitus are common clinical manifestations in patients with partial lipodystrophy. Despite aggressive treatment aiming reduction in insulin resistance, patients usually require insulin treatment, highlighting the presence of insulin secretion defects. The sequence of events to develop metabolic derangement is not well studied. This study aims to compare the metabolic changes and insulin secretion in two generations of patients with FPLD2. Methods In a longitudinal study, we are studying the metabolic and morphometric changes in younger patients carrying the mutation who have not fully expressed the phenotype and comparing their findings to their affected older relatives. In the first year of the study, six affected young patients (age: 17±4 years, 4F/2M) and four affected older relatives (age: 46±7 years, all-female) have completed a 5-hour OGTT with 75g of glucose to determine the metabolic parameters at 30-minute intervals as well as the area under the curve (AUC) for these parameters. Results Patients in the younger group did not have a clinical diagnosis of diabetes (mean HbA1c of 5.3±0.3%), while all patients in the older generation had the diagnosis of diabetes mellitus with higher HbA1c (7.9±3.1%, p=0.05). Younger patients showed a lower AUC for glucose (28703±12037 mg/dL/min), triglycerides (38820±15305 mg/dL/min, p&amp;lt;0.05)) and free fatty acids (FFA) (78±29mmol/L/min) compared to older affected patients (glucose AUC: 67563±39089 mg/dL/min; triglycerides AUC: 96461±39989 mg/dL/min; FFA AUC: 159±125 mmol/L/min). However, insulin and C-peptide AUC were higher in the younger group compared to the older generation (insulin AUC: 60664±66802 vs. 29331±23341 mcU/mL/min; C-peptide AUC: 3466±1646 vs. 2548±1391 mg/L/min). The change in C-Peptide in the first 30 min post glucose was significantly higher in the younger group compared to the older group (12±1.8 vs. 5±4 mg/L; p&amp;lt;0.05). Insulin secretion during the first 30 min of the test was numerically higher in the younger group versus the older group (213±90 vs. 90±115 mcU/mL). Conclusion Our data (albeit limited) show that the clinical manifestation of diabetes mellitus in older patients with FPLD2 is associated with impairments in insulin secretion, therefore highlighting the importance of beta-cell failure in the development of diabetes mellitus in this population. These data draw attention to the need for further investigation of the pancreatic endocrine dysfunction to treat and better understand diabetes mellitus in this population. Strategies to address just insulin resistance may not be sufficient to prevent the development of diabetes in the long run. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP424 Postprandial Adipose Insulin Resistance in Adolescent Girls with PCOS and Obesity

Abstract Background Polycystic ovary syndrome (PCOS) is common and associated with metabolic disease, in particular glucose abnormalities and insulin resistance (IR). Fat metabolism is linked with IR, manifesting as decreased suppression of lipolysis following meals, inflammation, and ectopic fat accumulation. Our previous work demonstrated adipose IR during a hyperinsulinemic-euglycemic clamp and increased hepatic fat in adolescents with PCOS. We hypothesized that postprandial fat metabolism would be altered compared to controls with obesity. Design/Methodology Data from 133 girls aged 13-21 years with obesity (BMI &amp;gt;90th%ile) enrolled in 1 of 4 cross-sectional metabolic studies were included in this secondary analysis. PCOS was determined per NIH diagnostic standards. Controls had regular menses and were &amp;gt;1-year post-menarche. Metabolic assessments were identical across studies and included fasting labs (lipid panel, inflammatory markers, androgens, insulin sensitivity indices), 4-hour oral sugar tolerance test (OSTT, 75 grams glucose, 25 grams fructose), liver fat by MRI, and body composition by DXA. Glycerol production (Ra) D5 glycerol infusion to measure lipolysis was evaluated in a subset. Metrics of glucose, insulin, glycerol, free fatty acid (FFA), and glucagon during the OSTT were calculated including AUC, fasting, nadir, and peak. Adipo IR (fasting FAA x fasting insulin) was determined. Data between controls and girls with PCOS were compared by Student's t-tests with Welch correction. Spearman's correlations were used within groups to evaluate associations. Results Participants included 110 girls with PCOS (age 16.4±1.6 years; BMI 35.9±5.8 kg/m2) and 23 without PCOS (15.9±1.6; 34.6±6.7). Per design, markers of androgen excess including total testosterone (p&amp;lt;0.001), free testosterone (p&amp;lt;0.001), degree of hirsutism (p=0.004), and severity of acne (p&amp;lt;0.001) were worse in girls with PCOS. Consistent with previous work, girls with PCOS had worse markers of glycemia including higher HbA1c (p&amp;lt;0.001), fasting glucose (p=0.027), 2-hour glucose (p=0.008), glucose AUC (p=0.033), and insulin AUC (p=0.034). They also had higher liver (p&amp;lt;0.001) and visceral fat (p=0.007), total (p=0.007) and LDL cholesterol (p=0.006), and triglycerides (p=0.005). Regarding adipose IR, fasting FFA (699±175 µmol/L vs. 593±163, p=0.007), FFA nadir (68±26 vs. 51±16, p=0.003), FFA AUC (114210 vs. 92518, p = 0.018), glycerol AUC (13815 vs. 8393, p&amp;lt;0.0001), and Adipo IR (p=0.034) were significantly higher while fasting glycerol Ra (p=0.571) did not differ. There were no differences between groups in markers of inflammation. Within the PCOS group, higher glycerol AUC correlated with higher HbA1c (p=0.001) and highly-sensitive C-reactive protein (hsCRP) (p=0.029), while increased FFA AUC correlated with increased hsCRP (p=0.043) and AST (p=0.037), but not markers of insulin resistance or dysglycemia. Conclusions Adolescents with PCOS and obesity have increased adipose IR. Future focus and treatment of adipose IR may be a promising avenue to delay onset of metabolic syndrome complications in girls with PCOS and obesity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF10 | PMON215 Greater changes in metabolic hormones are associated with a smaller decrease in pulsatile LH secretion in response to short term moderate energy restriction in healthy, young women

Abstract Background Energy restriction may result in hypothalamic amenorrhea by inhibiting GnRH secretion and downstream pulsatile LH secretion. Energy restriction also leads to adaptive changes in metabolic hormones. We sought to determine whether metabolic changes in response to energy restriction predict or mitigate inhibition of GnRH secretion. Methods Nineteen healthy women, (mean age ± SD; 23.36 ± 2.08 yrs) with regular ovulatory cycles and no evidence of energy restriction or excessive exercise, underwent two 5-day dietary interventions with identical exercise in the early follicular phase of two menstrual cycles. A neutral energy availability (NEA; 45 kCal/kg*LBM/d) was followed by a deficient energy availability (DEA; 20 kCal/kg*LBM/d) diet. On day five of each intervention, body composition was analyzed (BodPod®), and blood was sampled between 0800 —1600 hours for LH, TSH and GH, every 10 min, cortisol every 30 min, T3, reverse T3 (rT3) and T4 every 60 min, free T3 (FT3), free T4 (FT4) and TBG at 0800 h and 1600 h. We correlated means of pulsatile LH pulse frequency (LHPF) with integrated metabolic hormone changes across the day in the subset of women with reduced or unchanged LHPF after DEA (n=10) using linear regression. Results In ∼50% of healthy young women, LHPF decreased or was unchanged in response to short-term moderate energy deprivation. BMI and bodyweight declined after DEA in both groups while % fat mass was unchanged. TSH, T3, leptin, insulin declined, and T4 increased from NEA to DEA while glucose, cortisol and GH were unchanged. In subjects with reduced/unchanged LHPF, % delta T3 correlated inversely with delta LHPF (r=-0.727, p=0.017). Similarly, non-fasting delta TSH correlated inversely with % delta LHPF (r=-0.643, p=0.045), and % delta AUC TSH (r=-0.642, p=0.045) correlated inversely with DEA LHPF. Percent delta insulin (r= -0.722, p=0.018) and % delta insulin AUC (r= – 0.688, p=0.028) correlated inversely with delta LHPF. Percent delta insulin-glucose ratio (r=-0.772, p=0.009) and % change in AUC insulin-glucose ratio (r=-0.759, p=0.011) also correlated inversely with delta LHPF. This inverse relationship was preserved when insulin was normalized for caloric intake (n-insulin) was correlated with % delta LHPF (r=-0.722, p=0.018) and % delta AUC n-insulin correlated with delta LHPF (r= -0.631 and p= 0.050). Delta AUC leptin (r=-0.684, p=0.029) and % delta AUC leptin (r=-0.670, p=0.034) also correlated inversely with delta LHPF. Mean cortisol at NEA correlated inversely with LHPF during DEA (r=-0.816, p=0.007), implying that higher baseline cortisol levels may predict a greater relative fall in LHPF. Cortisol AUC in DEA also correlated inversely with LHPF in DEA (r=-0.722, p=0.028). Conclusion Our data suggest that greater changes in metabolic hormones may protect against the inhibitory effect of moderate energy deprivation on GnRH secretion in healthy young women with normal reproductive function. Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PSUN304 CRN04777 an Oral, Nonpeptide SST5-selective Somatostatin Agonist Dose Dependently Suppresses Basal and Stimulated Insulin Secretion

Abstract Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants, and children, and is caused by genetic mutations in the insulin secretion pathway in pancreatic beta-cells. Current medical and surgical treatments are often highly burdensome, only partially effective, and associated with significant morbidity. CRN04777 is a potent orally bioavailable SST5 agonist (EC50=0.41 nM) that is &amp;gt;1300 fold selective over other SST receptor subtypes. CRN04777 has been shown to suppress both glucose- and sulfonylurea (SU)-induced insulin secretion in rats. The latter is a model for the most common known monogenic form of human congenital HI. We report initial results from a randomized, double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04777 in 74 healthy volunteers. Endogenous insulin secretion was stimulated using intravenous glucose tolerance tests (IVGTT) or SU challenges in separate cohorts of volunteers. In the IVGTT cohorts, single doses of CRN04777 (0.5-120 mg) were administered after an overnight fast and 1 hour prior to an IV bolus of 300 mg/kg glucose, followed by serial measurements of blood glucose and insulin over 180 minutes. The SU-challenge cohorts received single doses of CRN04777 (30 and 60 mg) one hour after SU administration (5 mg of glibenclamide/glyburide), followed by measurement of the IV glucose infusion rate (GIR) over 8 hours under automated euglycemic clamp conditions (ClampArt®). CRN04777 was orally absorbed (Tmax 1-3 hours) and demonstrated a dose dependent increase in systemic exposures with an apparent terminal elimination t1/2 of approximately 40 hours. Basal insulin secretion was reduced dose-dependently, with a 73% reduction following 120 mg of CRN04777. Likewise, glucose stimulated insulin secretion during the IVGTT (plasma insulin AUC) was reduced dose-dependently by approximately 50% with a parallel doubling of plasma glucose AUC following 120 mg of CRN04777. CRN04777 resulted in dose-dependent reversal of SU-induced insulin secretion, with 79% and 90% reductions in insulin AUC5-180min, respectively, at 30 and 60 mg doses. At the 60 mg dose of CRN04777, no exogenous glucose infusion was needed to prevent SU-induced hypoglycemia. CRN04777 was well tolerated across the dose range evaluated. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that the selective SST5 agonist CRN04777 is well tolerated after oral administration in healthy volunteers, is suitable for once daily dosing and suppresses insulin secretion under basal and stimulated conditions, including in a pharmacologic model of congenital HI. Multiple ascending dose evaluations in healthy volunteers are underway to support future studies in congenital HI patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Exploring interindividual differences in fasting and postprandial insulin sensitivity adaptations in response to sprint interval exercise training

ABSTRACT Previous studies have concluded that wide variance in changes in insulin sensitivity markers following exercise training demonstrates heterogeneity in individual trainability. However, these studies frequently don’t account for technical, biological, and random within-subject measurement error. We used the standard deviation of individual responses (SDIR) to determine whether interindividual variability in trainability exists for fasting and postprandial insulin sensitivity outcomes following low-volume sprint interval training (SIT). We pooled data from 63 untrained participants who completed 6 weeks of SIT (n = 49; VO2max: 35 (7) mL⋅kg−1⋅min−1) or acted as no-intervention controls (n = 14; VO2max: 34 (6) mL⋅kg−1⋅min−1). Fasting and oral glucose tolerance test (OGTT)-derived measures of insulin sensitivity were measured pre- and post-intervention. SDIR values were positive and exceeded a small effect size threshold for changes in fasting glucose (SDIR = 0.27 [95%CI 0.07,0.38] mmol⋅L−1), 2-h OGTT glucose (SDIR = 0.89 [0.22,1.23] mmol⋅L−1), glucose area-under-the-curve (SDIR = 66.4 [−81.5,124.3] mmol⋅L−1⋅120min−1) and The Cederholm Index (SDIR = 7.2 [−16.0,19.0] mg⋅l2⋅mmol−1⋅mU−1⋅min−1), suggesting meaningful individual responses to SIT, whilst SDIR values were negative for fasting insulin, fasting insulin resistance and insulin AUC. For all variables, the 95% CIs were wide and/or crossed zero, highlighting uncertainty about the existence of true interindividual differences in exercise trainability. Only 2–22% of participants could be classified as responders or non-responders with more than 95% certainty. Our findings demonstrate it cannot be assumed that variation in changes in insulin sensitivity following SIT is attributable to inherent differences in trainability, and reiterate the importance of accounting for technical, biological, and random error when examining heterogeneity in health-related training adaptations. Highlights This study tested whether true interindividual variability exists for changes in insulin sensitivity and glyceamic control following 6-weeks of low volume sprint interval training (SIT). The high level of technical, biological, and random error associated with repeated measurements of insulin sensitivity and glycaemic control, means we can neither confidently conclude that there is evidence of true interindividual differences in the trainability of these outcomes following SIT, nor confidently identify responders or non-responders for such parameters. Researchers contrasting responders vs. non-responders for a given parameter, either to understand mechanisms of adaptation and/or develop physiological/genetic/epigenetic predictors of response, need to be aware that identification of responders and non-responders with sufficient certainty may not be achievable for parameters with a high level of technical, biological, and random error.

Corosolic acid improves glucose and insulin responses in middle-aged men with impaired fasting glucose: A randomized, double-blinded, placebo-controlled crossover trial

• Corosolic acid (CA) improved glucose tolerance in healthy, hyperglycemic individuals. • CA intake (1 mg/d) for 2 weeks improved postprandial glucose and insulin sensitivity. • CA improved the liver insulin sensitivity index after glucose loading. • CA intake did not alter gastrointestinal hormone levels or appetite measures. Corosolic acid (CA) improves glucose metabolism in diabetics and prediabetics, but its effects in healthy subjects with borderline hyperglycemia are unclear. Non-diabetic middle-aged men (n = 14) with impaired fasting glucose tolerance (mean ± SD; age, 51.7 ± 9.0 years; fasting blood glucose, 6.0 ± 0.4 mmol/L) underwent an oral glucose tolerance test (OGTT) after taking 1 mg/d CA or placebo for 2 weeks in a randomized double-blind crossover trial. In the 13 subjects who completed the study, the incremental area under the curve (iAUC) of plasma glucose after the OGTT was significantly lower in the CA condition than in the placebo condition (p = 0.028). The AUC and iAUC of the serum insulin and C-peptide concentrations, and liver insulin sensitivity values were also significantly lower in the CA condition. Glucagon, glucagon-like peptide-1, gastric inhibitory peptide, and non-esterified fatty acid levels did not differ significantly between conditions. CA may improve glucose tolerance in both healthy and prediabetic subjects. Trial registration: UMIN-CTR; http://www.umin.ac.jp/ ; Registration No. UMIN000034130.

β-Cell Function, Hepatic Insulin Clearance, and Insulin Sensitivity in South Asian and Nordic Women After Gestational Diabetes Mellitus.

South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, β-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25-40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized.