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Background: The Allostatic load score (ALS) is a composite score that measures the cumulative physiological burden of sustained exposure to stress and biological dysregulation. ALS has markers capture risk in 4 domains (neuro-endocrine, metabolic, cardiovascular, and immunological). Higher ALS in adults predict cardiovascular disease (CVD), but it is unknown whether ALS is associated with CVD risk in youth and young adults (YA), and whether the risk and association would differ at such an early age. Aims: In youth and YA we compared 1) the total ALS; 2) the cardiovascular profile according to high and low ALS; and 3) the association of ALS with markers of CVD. Methods: Participants in the African PRospective study on the Early Detection and Identification of Cardiovascular disease and HyperTension (AfricanPREDICT) were 587 youth Results: ALS median range was 1-8, and a high ALS of >3 was observed in 35% of youth, and 47% YA. In youth with high ALS, ALS associated with narrower retinal arteries (Adj R 2 :0.16, β-coefficient, -1.73, (95%CI), -2.95, -0.94), P =0.052), greater pulse wave velocity (Adj R 2 :0.56, 0.75 (0.48, 1.98), P =0.021), increased left ventricular mass index (Adj R 2 :0.61, 2.21 (0.43, 8.46) P =0.048), lower left ventricular function (global longitudinal strain) (Adj R 2 :0.37, -0.45 (-1.06, -0.06) P =0.015). Similarly, in YA with high ALS, ALS associated with narrower retinal arteries (Adj R 2 :0.43, -4.54 (-6.58, -2.50), P 2 :0.44, 0.62 (0.09, 1.17), P =0.043), increased left ventricular mass index (Adj R 2 :0.53, 2.62 (1.52, 5.76) P =0.032), lower diastolic function (E/A ratio) (Adj R 2 :0.27, -0.11 (-0.18, -0.04) P =0.002). Conclusion: Youth and YA with high ALS had a more adverse CVD risk profile and greater association with markers of cardiovascular aging compared to their low ALS counterparts. ALS and allostatic dysregulation should be evaluated in youth and YA, when assessing current and future cardiovascular risk.

Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6-(2)H(2)]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance. NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

BACKGROUND: Hepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes. METHODS: Adolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging–proton density fat fraction. RESULTS: Hepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: –10.6% [95% CI: –19.1%, –2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532). CONCLUSION: Our results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD. TRIAL REGISTRY: ClinicalTrials.gov NCT02513121. FUNDING: The Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children’s Healthcare of Atlanta and Emory University’s Children’s Clinical and Translational Discovery Core, Children’s Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.

Context Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. Aim In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. Cases We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol 1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. Conclusion Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

Young adults with type 2 diabetes (T2D-Y) have increased risk of subclinical atherosclerotic cardiovascular disease (ASCVD) . Cardiac magnetic resonance imaging (MRI) may guide risk stratification by noninvasively quantifying coronary wall thickness (CWT, an indicator of ASCVD) and endothelial function (arterial dilation during isometric hand grip exercise, IHE) . The utility of these novel MRI biomarkers in T2D-Y is unknown. We hypothesized that T2D-Y would be associated with increased CWT and impaired endothelial function. In T2D-Y (6 male, age 19.8±1.6y, BMI 37±7kg/m2) and 12 healthy controls (5 male, age 22.7±2.9 y, BMI 24±5 kg/m2) we measured CWT and coronary and brachial dilation during IHE with a 3.0 Tesla MRI. T2D-Y had higher HbA1c (6.5 ± 0.8 vs. 5.1 ± 0.6%, P Disclosure A. Villalobos-Perez: None. J. Feeley: None. K.Z. Abd-Elmoniem: None. K.B. Dietsche: None. J.R. Matta: None. M.S. Stagliano: None. L. Mabundo: None. E.L. Shouppe: None. M. Walter: None. S.T. Chung: None. Funding NIDDK/NIH Intramural Research Program

Metformin is the first-line therapy for youth-onset type 2 diabetes mellitus (Y-T2D) but is suboptimal in up to 50% of youth. The reasons for increased failure rates are unknown. Metformin plasma concentration reflects total body distribution and kinetics but is not used clinically in adults because peak metformin concentration varies widely. Few studies, and none in youth, have measured trough therapeutic concentration as a potential biomarker of response. We hypothesized that trough metformin plasma concentrations after short-term therapy would be associated with treatment response. In this secondary analysis of a randomized trial of metformin alone vs. metformin and liraglutide (combo) therapy Y-T2D youth, we determined the relationship of metformin concentration with glycemia. Nineteen Y-T2D: age 15.4±2.1 (12-20y) mean±SD (range) , 61% female, Tanner Stage IV-V, BMI 40.0±8.0 (22.1-53.4 kg/m2) were randomized to 2000mg/day metformin (n=10) or 2000mg metformin+ 1.8mg liraglutide (combo, n=8) for 3 months after a 5-7 day drug-free run-in period. At baseline, youth on combo had higher HbA1c (7.1±0.7; 6.2±0.6%, P=0.006) but had similar BMI, fasting glucose, and 2hr glucose on OGTT. Metformin concentrations increased (combo:337±559 vs. metformin: 420±433 (1.6-1537 ng/mL) , P=0.7) and negatively correlated with change in 2hr glucose (combo: r=-0.9, P=0.002; metformin: r=-0.73, P=0.02) , fasting glucose (combo: r=-0.59, P=0.13; metformin: r=-0.64, P=0.06) , and change in HbA1c (combo: r=-0.89, P=0.01, metformin: r=0.31, P=0.4) . Metformin adherence measured by pill counts was 78% with no difference by group (combo: 80±20; metformin: 75±16%) . Metformin concentrations were not associated with percent adherence to medication or change in weight (P>0.10) . Overall, metformin concentrations were widely variable in Y-T2D but associated with improvements in glycemia after 3 months and should be explored as a viable biomarker for predicting treatment response in Y-T2D. Disclosure K.B. Dietsche: None. A. Zenno: None. S.A. Dixon: None. L. Mabundo: None. E.L. Shouppe: None. D.E. Estrada: None. F.R. Cogen: None. M. Walter: None. P. Walter: None. S.T. Chung: None. Funding NIDDK/NIH Intramural Research Program

Metformin is the only first-line oral agent for youth with type 2 diabetes mellitus (Y-T2D) , but efficacy and adherence is complicated by gastrointestinal (GI) side effects. Prebiotic microbiome modulators (MM) may reduce side effects by shifting the microbial flora and promoting metabolism of short-chain fatty acid producing bacteria. The feasibility and tolerability of prebiotic use in Y-T2D is unknown. We hypothesized that a prebiotic MM would be safe, tolerable, and decrease GI symptoms in youth. We compared lower GI symptoms and glycemia in Y-T2D at initiation of daily metformin therapy in a 1-week, randomized, double-blind, crossover trial of a daily prebiotic MM versus placebo shake (Phase 1) followed by a 1 month open-labeled extension (Phase 2) . We assessed stool frequency, stool consistency (King’s Stool Chart) , and used principal component analysis to create a composite GI symptom score (urgency, bloating, flatulence, consistency) . Mixed effects models were used to compare continuous glucose monitor profiles and quality of life metrics (Pediatric Quality of Life Inventory™) . In six Y-T2D (17.2±1.7y (mean±SD) , 66% female, BMI 42±9 kg/m2, HbA1c 6.4±0.6%) stool frequency was assessed every 1-2 days. Stool frequency, stool composition, GI symptom score, and quality of life scores were not different by group or study phase. There were no severe adverse effects during the trial. One youth had increased bloating and discontinued the prebiotic in Phase 2. During phase 1, prebiotic MM tended to have lower average glucose (122±26 vs. 135±23 mg/dL, P=0.07) but this was not sustained in phase 2 (136±31 vs.135±23, P=0.8) . Time in range, standard deviation, and coefficient of variation of glucose were similar during the study. In summary, the prebiotic MM was well tolerated during short-term metformin therapy in Y-T2D, but was not associated with GI symptom, quality of life, or metabolic changes. Future studies should explore localized gut and systemic metabolic effects of prebiotics in youth. Disclosure K. Tuttle: None. L. Mabundo: None. M.S. Stagliano: None. K.B. Dietsche: None. A.B. Courville: None. D.E. Estrada: None. S.T. Chung: None. Funding NIDDK/NIH Intramural Research Program

The carbohydrate–insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m−2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal−1) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal−1) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d−1 less energy intake than the low-carbohydrate diet over 2 weeks (P

Background Metabolic and bariatric surgery (MBS) is currently the most effective weight loss treatment in adults and children with severe obesity. However, up to 50% of adolescents continue to have obesity three years post-MBS. Vertical sleeve gastrectomy (VSG), the most common MBS performed in adolescents, causes an increase in post-prandial glucagon-like peptide 1 (GLP-1) post-operatively, but the duration of this incretin hormone response is unclear. Liraglutide, a GLP-1 analogue, may supplement the physiological increase in GLP-1 following VSG and promote weight loss via appetite suppression. We hypothesized that daily liraglutide treatment would significantly reduce body weight in adolescents who had previously undergone VSG but who continued to have insufficient weight loss. This abstract reports interim data from our prospective clinical trial of liraglutide in adolescents with obesity after VSG (ClinicalTrials.gov Identifier: NCT04883346). Methods This trial is an active, open-label, phase II pilot study to investigate the efficacy of daily subcutaneous liraglutide to promote reduction of BMI in adolescents with persistent obesity 1 year or more after VSG. The primary objective is to determine the effect size for the change in BMI of liraglutide 3. 0 mg daily at 16 weeks in study participants to calculate the sample size of a subsequent randomized controlled trial. Inclusion criteria are age 12 to 20.99 years, good general health, BMI≥30 kg/m2, and a personal history of VSG ≥1-year prior. Exclusion criteria include major medical illnesses, use of medications associated with weight gain, or use of weight-loss medications within the last 3 months of screening. Liraglutide is initiated at 0.6 mg daily and escalated by 0.6mg weekly to 3 mg/d for the last 12 weeks of treatment. Participants receive monthly nutrition counseling throughout the study. Results At time of interim analysis (3/24/22), 26 participants (baseline age 18±1.9y, mean±SD; 65% female; 55% black; baseline BMI 42. 0±7. 0 kg/m2) were screened and 20 started liraglutide. Among 17 participants who reached 8 weeks of treatment, mean absolute change in weight was -3.9±2.6 kg, percent change in weight was -3.6±2.6%, absolute change in BMI was -1.4±0.9 kg/m2, and percent change in BMI was -3.6±2.6%. There were no serious treatment-emergent adverse events (TEAEs) reported; 16/20 participants reported non-serious TEAEs including low energy (40%), nausea (40%), and vomiting (20%). In this interim analysis of an open-label phase II pilot study, the mean weight change from baseline was -3.6% after 8 weeks of liraglutide treatment in adolescents with persistent obesity after VSG. No new TEAEs were identified. Completion of this study will help determine if weight reduction with liraglutide suggests value to carry out a randomized placebo controlled study using liraglutide. Presentation: No date and time listed

For over 100 years, the oral glucose tolerance test (OGTT) has been the cornerstone for detecting prediabetes and type 2 diabetes (T2DM). In recent decades, controversies have arisen identifying internationally acceptable cut points using fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and/or HbA1c for defining intermediate hyperglycemia (prediabetes). Despite this, there has been a steadfast global consensus of the 2-h PG for defining dysglycemic states during the OGTT. This article reviews the history of the OGTT and recent advances in its application, including the glucose challenge test and mathematical modeling for determining the shape of the glucose curve. Pitfalls of the FPG, 2-h PG during the OGTT, and HbA1c are considered as well. Finally, the associations between the 30-minute and 1-hour plasma glucose (1-h PG) levels derived from the OGTT and incidence of diabetes and its complications will be reviewed. The considerable evidence base supports modifying current screening and diagnostic recommendations with the use of the 1-h PG. Measurement of the 1-h PG level could increase the likelihood of identifying high-risk individuals when the pancreatic s-cell function is substantially more intact with the added practical advantage of potentially replacing the conventional 2-h OGTT making it more acceptable in the clinical setting.

OBJECTIVE In African-born Blacks living in America, we determined by BMI category 1) prevalence of abnormal glucose tolerance (Abnl-GT) and 2) diagnostic value and reproducibility of hemoglobin A1c (HbA1c), fructosamine, and glycated albumin (GA). RESEARCH DESIGN AND METHODS Participants (n = 416; male, 66%; BMI 27.7 ± 4.5 kg/m2 [mean ± SD]) had an oral glucose tolerance test with HbA1c, GA, and fructosamine assayed. These glycemic markers were repeated 11 ± 7 days later. Abnl-GT diagnosis required 0 h ≥5.6 mmol/L (≥100 mg/dL) and/or 2 h ≥7.8 mmol/L (≥140 mg/dL). Thresholds for HbA1c, GA, and fructosamine were the values at the 75th percentile for the population (39 mmol/mol [5.7%], 14.2%, and 234 μmol/L, respectively). RESULTS Abnl-GT prevalence in the nonobese was 34% versus 42% in the obese (P = 0.124). Reproducibility was excellent for HbA1c and GA (both κ ≥ 0.8), but moderate for fructosamine (κ = 0.6). Focusing on HbA1c and GA in the nonobese, we found as single tests the sensitivities of HbA1c and GA were 36% versus 37% (P = 0.529). Combining HbA1c and GA, sensitivity increased to 58% because GA identified 37% of Africans with Abnl-GT not detected by HbA1c (P value for both tests vs. HbA1c alone was CONCLUSIONS Adding GA to HbA1c improves detection of Abnl-GT in nonobese Africans.

Introduction: Youth with obesity and abnormal glucose tolerance (AGT) have an atherogenic lipoprotein (Lp) profile (small dense HDL and small LDL) and an increased risk for atherosclerotic disease, but the relative contributions of hyperglycemia and insulin resistance to the development of subclinical atherosclerosis in youth are not well defined. Hypothesis: Atherogenic Lp concentrations (ApoB, small LDLp, small HDLp) are associated with lower insulin sensitivity (Si) and greater carotid intimal thickness (cIMT), irrespective of glycemic status. Methods: In 155 youth with obesity (14.5±1.4y (mean±SD), 50% female; 42 lean (LC: BMI 25-85%ile), 44 insulin sensitive (OIS, fasting insulin ≤20μM/mL, BMI≥95%ile), 35 insulin resistant (OIR; fasting insulin>20μM/mL, BMI≥95%ile) and 34 with AGT (23 prediabetes, 11 type 2 diabetes) we compared a standard lipid panel and Lp size and number. Linear regressions were used to test the associations between lipids/ NMR-derived Lp with Si index derived from a minimal model during an intravenous glucose test. cIMT was determined by ultrasonography. In a subset of 56 youth (21 LC, 19 OIS, 10 OIR, and 7 AGT) we explored the change in Si with the change in Lp and cIMT after 2 years. Results: OIR and AGT had higher triglycerides and lower HDL compared to LC, P P P Conclusions: Among youth with obesity, insulin resistance was associated with atherogenic lipoproteins and cIMT, regardless of glucose tolerance status. Alterations in HDL particle number and size were distinct early manifestations that were observed in youth with AGT compared to their peers.

Context Youth with obesity and abnormal glucose tolerance have an increased risk for atherosclerosis but the relative contributions of insulin resistance and hyperglycemia to dyslipidemia and the development of subclinical atherosclerosis are unknown. Objective This work aims to determine the association between insulin resistance, dyslipidemia, and carotid intimal thickness (cIMT) in adolescents with normal and abnormal glucose tolerance. Methods An observational cohort study in 155 youth: 44 obese insulin sensitive (OIS; fasting insulin ≤ 20 µM/mL, body mass index [BMI] ≥ 95th percentile), 35 obese insulin resistant (OIR; fasting insulin > 20 µM/mL, BMI ≥ 95th percentile), 34 obese abnormal glucose tolerant (AGT; BMI ≥ 95th percentile), and 42 Lean (BMI 5th-85th percentile). Lipids, lipoprotein particle size and concentration (-P), insulin sensitivity (SI an intravenous glucose test), and CMIT were compared using linear models adjusted for age, race/ethnicity, biological sex, and Tanner stage. Lipid/lipoprotein profile and CMIT were reevaluated in a subset after 2 years. Results Compared to OIS and Lean, OIR and AGT had elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) but similar total cholesterol and low-density lipoprotein cholesterol (LDL-C). Among OIS, OIR, AGT, lower SI was associated with atherogenic lipids (higher triglycerides, LDL-C, non–HDL-C, and lower HDL-C) and lipoproteins (higher total LDL-P and small HDL-P, and lower large HDL-P). There was a steeper decline in the association of SI with HDL-C and large HDL-P in AGT compared with OIR and OIS. cIMT was comparable across groups and inversely correlated with SI, with no change after 2 years. Conclusion Among youth with obesity, insulin resistance was associated with an atherogenic lipoprotein/lipid profile and cIMT, regardless of glucose tolerance status. Insulin resistance in AGT youth was associated with a shift to smaller HDL-P compared to normoglycemic youth with obesity. Alterations in HDL-P metabolism may be early adverse manifestations of hyperglycemia in youth with obesity.

IntroductionThe transition from paediatric to adult diabetes care in youth-onset diabetes (type 1 diabetes mellitus, Y-T1DM and type 2 diabetes mellitus, Y-T2DM) is associated with worsening glycaemic control, missed clinical visits, decreased medication adherence and the emergence of cardiometabolic complications. The socio-ecological challenges that influence transitioning to adult diabetes care may be distinct between Y-T1DM and Y-T2DM. The goal of this scoping review is to map the state of the literature on transitioning care in Y-T2DM compared with Y-T1DM and to identify the main sources and types of evidence available. The objectives are : (1) to identify the factors within the socio-ecological framework (individual, relationship, community, societal) associated with transitioning to adult care in Y-T2DM compared with Y- T1DM, and (2) to identify knowledge gaps related to transitioning to adult care.MethodsThe scoping review protocol and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews guidelines. A systematic search of scientific databases (PubMed, Embase, Cumulative Index to Nursing and Allied Health, Scopus and APA PsycNet will be undertaken for articles between 1 January 1990 and 30 September 2022. Study designs will include peer-reviewed experimental and quasi-experimental published studies without language or country-specific restrictions. We will exclude articles on other diabetes subtypes and will exclude non-peer reviewed articles such as opinion papers, anecdotal reports or supplementary commentaries.AnalysisReferences will be collated, sorted and extracted using Covidence. Factors associated with transition from paediatric to adult diabetes care in Y-T1DM and Y-T2DM will be identified using the socio-ecological framework and results will be presented in narrative format, tables, and summary graphs.Ethics and disseminationEthical approval will not be applicable for this review.Trial registration numberhttps://osf.io/k2pwc.

Youth with type 2 diabetes (T2D-Y) have severe insulin resistance (IR) and increased risk for atherosclerotic cardiovascular disease (ASCVD). High levels of remnant triglyceride-rich lipoproteins (TRLp), the sum of small very low-density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) particles, may mediate this additional risk. Yet, the relationship of remnant TRLp with IR and inflammation in at-risk youth is unknown. We compared lipoprotein particles in 48 youth: 33 T2D-Y and 15 age/BMI matched peers without diabetes (age 15.5 ± 2.6 y, Tanner Stage IV-V, BMI 38.6 ± 7.4 kg/m2) and determined the relationship of remnant TRLp with IR and GlycA, a composite marker of inflammation. Fasting lipoprotein particle size and number, apolipoprotein B (apoB) and GlycA were derived from the NMR LipoProfile®. Insulin sensitivity was determined by the Matsuda index during a multi-sample 75g OGTT. T2D-Y had higher A1c (7.0 ± 1.2 vs. 5.6 ± 0.3%, P Disclosure A. Villalobos-perez: None. S. T. Chung: None. A. Zenno: None. C. K. Cravalho: None. S. Matta: None. A. B. Courville: None. L. Mabundo: None. V. R. Sharma: None. J. M. Dawson: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

To formulate precision nutrition prescriptions, it is essential to understand the relationship between dietary assessment, ethnicity and cardiometabolic disease. Erythrocyte (RBC) fatty acid (FA) profiles reflect long-term dietary fat intake but have not been rigorously compared with short-term FA intake in women of African ancestry who have paradoxically low triglycerides with high fat intake. We compared the type of dietary fat consumed (proportion of total fat) using food records with fasting RBC FA (mol%) determined by gas chromatography in 130 female, healthy, federal employees without diabetes (12% African Immigrants (AI), 47% African Americans (AA), 41% White Americans (WA)); mean age 43+10 y and BMI 30 + 6 kg/m2). Diet quality and home prepared meals were similar across ethnicities. AI reported the lowest energy intake. Regardless of absolute energy intake, macronutrient distributions were similar. Fat intake differed by ethnicity; WA had the highest saturated FA (SFA) and lowest eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and omega-3 index (EPA + DHA), while AI and AA had similar SFA, EPA and DHA intake. AI women had the highest RBC DHA and omega-3 index. Associations between FA intake and RBC profiles were significant for DHA (r=0.3, p Disclosure A. B. Courville: None. S. T. Chung: None. S. Yang: None. L. Mabundo: None. C. K. Cravalho: None. S. Matta: None. A. Villalobos-perez: None. J. M. Dawson: None. A. H. Lichtenstein: None. A. E. Sumner: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

Metformin is the only approved oral therapy in youth with type 2 diabetes (T2D-Y) but its molecular mechanisms remain controversial. Recent data links metformin-induced weight loss with increased levels of a peptide hormone, growth differentiation factor 15 (GDF15). Yet high GDF15 is linked to high stress and lipolysis and its value in T2D-Y is known. We compared fasting GDF15 in 32 T2D-Y not on metformin to 15 matched peers without diabetes and determined the change in GDF15 in 19 T2D-Y after 3 months of metformin (metformin only, n=13 and metformin + liraglutide, n=6). Youth were 15.5 ± 2.6 years (mean ± SD), 64% female, 78% African American with similar BMI 39 ± 7 kg/m2). T2D-Y had higher HbA1c (6.9 ± 1.1 vs. 5.6 ± 0.3%, P 0.2). GDF15 increased ≥2-fold in 6 of 18 T2D-Y (Figure). Overall, GDF15 correlated with age (r=0.4, P=0.01) but the change in GDF15 did not correlate with changes in glucose, weight, blood pressure, inflammatory markers, sex or treatment group. GDF15 was highly variable and not associated with cardiometabolic markers in youth. GDF15 markedly increased in a small subset of youth, but the determinants and implications of this change remain to be elucidated. Changes in GDF15 may have no association with metformin action. Disclosure S. Matta: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. S. T. Chung: None. C. K. Cravalho: None. A. Villalobos-perez: None. L. Mabundo: None. V. R. Sharma: None. M. Walter: None. J. M. Dawson: None. A. Zenno: None. A. B. Courville: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are “by products” of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = −0.4, BCAA: r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA: r ≥ 0.3 and glycine: r = −0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth.Clinical Trial RegistrationClinicaltrials.gov, identifier NCT:02960659

Background: Insulin resistance is a pathophysiological condition associated with diabetes and cardiometabolic diseases that is characterized by a diminished tissue response to insulin action. Our understanding of this complex phenomenon and its role in the pathogenesis of cardiometabolic diseases is rooted in the discovery of insulin, its isolation and purification, and the challenges encountered with its therapeutic use. Summary: In this historical perspective, we explore the evolution of the term “insulin resistance” and demonstrate how advances in insulin and glucose analytics contributed to the recognition and validation of this metabolic entity. We identify primary discoveries which were pivotal in expanding our knowledge of insulin resistance, the challenges in measurement and interpretation, contemporary techniques, and areas of future exploration. Key Message: Measurements of insulin resistance are important tools for defining and treating cardiometabolic diseases. Accurate quantification of this pathophysiological entity requires careful consideration of the assumptions and pitfalls of the methodological techniques and the historical and clinical context when interpreting and applying the results.

Genetic differences in desaturase genes and consequently fatty acid metabolism have been reported. The aims were to examine ethnic differences in serum fatty acid composition and desaturase indices, and assess the ethnic-specific associations with insulin sensitivity (IS) and liver fat in black and white South African (SA) women.In this cross-sectional study including 92 premenopausal black (n = 46) and white (n = 46) SA women, serum fatty acid composition was measured in cholesteryl ester (CE) and nonesterified fatty acid (NEFA) fractions. Desaturase activities were estimated as product-to-precursor ratios: stearoyl-CoA desaturase-1 (SCD1-16, 16:1n-7/16:0); δ-5 desaturase (D5D, 20:4n-6/20:3n-6), and δ-6 desaturase (D6D, 18:3n-6/18:2n-6). Whole-body IS was estimated from an oral glucose tolerance test using the Matsuda index. In a subsample (n = 30), liver fat and hepatic IS were measured by 1H-magnetic resonance spectroscopy and hyperinsulinemic euglycemic clamp, respectively.Despite lower whole-body IS (P = .006), black women had higher CE D5D and lower D6D and SCD1-16 indices than white women (P .01). CE D6D index was associated with lower IS in white women only (r = -0.31, P = .045), whereas D5D index was associated with higher IS in black women only (r = 0.31, P = .041). In the subsample, D6D and SCD1-16 indices were positively and D5D was negatively associated with liver fat (P .05). Conversely, CE SCD1-16 was negatively associated with hepatic IS (P .05), but not independently of liver fat.Ethnic differences in fatty acid-derived desaturation indices were observed, with insulin-resistant black SA women paradoxically showing a fatty acid pattern typical for higher insulin sensitivity in European populations.

For over 100 years, the oral glucose tolerance test (OGTT) has been the cornerstone for detecting prediabetes and type 2 diabetes (T2DM). In recent decades, controversies have arisen identifying internationally acceptable cut points using fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and/or HbA1c for defining intermediate hyperglycemia (prediabetes). Despite this, there has been a steadfast global consensus of the 2-h PG for defining dysglycemic states during the OGTT. This article reviews the history of the OGTT and recent advances in its application, including the glucose challenge test and mathematical modeling for determining the shape of the glucose curve. Pitfalls of the FPG, 2-h PG during the OGTT, and HbA1c are considered as well. Finally, the associations between the 30-minute and 1-hour plasma glucose (1-h PG) levels derived from the OGTT and incidence of diabetes and its complications will be reviewed. The considerable evidence base supports modifying current screening and diagnostic recommendations with the use of the 1‐h PG. Measurement of the 1‐h PG level could increase the likelihood of identifying high-risk individuals when the pancreatic ß-cell function is substantially more intact with the added practical advantage of potentially replacing the conventional 2‐h OGTT making it more acceptable in the clinical setting.

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.

Youth with obesity have increased risk for cardiometabolic (CM) disease but identifying those at highest risk remains a challenge. 4 potential biomarkers are “byproducts” of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance (IR) and type 2 diabetes (T2D) in adults (glycine inversely), but their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 184 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT and 54 obese with abnormal glucose tolerance (AGT; 20 with T2D and 34 with prediabetes) and determined their relationships with HOMA-IR (homeostatic model of IR) and hemoglobin A1c (HbA1c). Compared to lean and obese NGT, AGT youth had higher systolic blood pressure and HbA1c (Table). All 4 biomarkers were higher in youth with obesity vs. lean, while only LPIR was higher in AGT youth vs. obese NGT (Table). While all 4 were correlated with HOMA-IR, LPIR had the strongest correlation (LPIR: r=0.6; GlycA: r=0.4, glycine: r=-0.4, BCAA: r=0.2, all P Disclosure S.T. Chung: None. S. Matta: None. A. Meyers: None. C.K. Cravalho: None. A. Villalobos-Perez: None. L. Mabundo: None. A.B. Courville: None. M.L. Sampson: None. J.D. Otvos: Employee; Self; LabCorp. S.N. Magge: None. Funding National Institutes of Health (to S.T.C., L.M., A.B.C.)

The dyslipidemia of insulin resistance (IR), characterized by high triglyceride-rich lipoproteins (TRLP) and low high-density lipoproteins (HDL), is associated with systemic inflammation, small low-density lipoproteins (LDL) and are important risk factors for atherosclerotic disease (ASCVD) in adults. Yet, in youth with type 2 diabetes (T2D) the natural history of ASCVD and the role of low-grade inflammation is still emerging. We compared lipoprotein profiles and inflammatory markers in 21 youth with T2D, within 5 years of diagnosis, to 10 age/BMI matched control youth with normal glucose tolerance (age: 15.8±2.5 (10-23 y) mean±SD (range), Tanner Stage IV-V, BMI: 38.9±6.9 (27.1-57.8 kg/m2). Fasting lipoprotein particle size and number, apolipoprotein B (apoB), and GlycA, a composite marker of inflammation, were derived from the NMR LipoProfile®. Pro-inflammatory markers were measured with multi-plex ELISA assays (C-Reactive Protein (hsCRP), IL-6, IL-8, IL-1β, TNF-alpha). IR was calculated by the Matsuda index during a multi-sample 75g OGTT. Youth with T2D, had higher A1c (7.2±1.3 vs. 5.4±0.3%, P Disclosure A. Villalobos-Perez: None. C.K. Cravalho: None. S. Matta: None. A. Meyers: None. L. Mabundo: None. M.L. Sampson: None. M. Walter: None. A.B. Courville: None. S.T. Chung: None. Funding National Institutes of Health (to S.T.C., L.M., A.B.C.)

Branched chain amino acids (BCAA) are important signaling molecules that are strongly related to type 2 diabetes (T2D), but the data linking BCAAs to reduced insulin sensitivity (IS) in youth is conflicting. This complex relationship of BCAAs with IS and glycemia may be further confounded by metformin that potentially alters BCAA synthesis and transport via gut mechanisms. Therefore, we compared: (1) BCAAs in 20 youth with T2D pre-metformin to 10 normal glucose tolerant (NGT) age/BMI-matched controls and (2) the change in BCAAs after 3 months of metformin in 8 youth with T2D. Fasting BCAAs were measured with nuclear magnetic resonance spectroscopy and IS and oral disposition index (oDI) calculated during a multi-sample 75g OGTT. Compared to NGT, youth with T2D had higher BCAAs and hemoglobin A1c (HbA1c) but lower IS and oDI (Table). Higher total BCAAs pre-metformin correlated with HbA1c (r=0.6, P0.2). Metformin decreased HbA1c and increased leucine and isoleucine (Table), but there was no change in BMI, IS or valine (all P>0.05). In youth, higher BCAAs were related to lower β-cell function relative to IS and worse glycemia. Although metformin improved glycemia, BCAAs were paradoxically increased suggesting that BCAAs may not be a useful treatment biomarker or indicator of changes in metabolic status. Disclosure A. Meyers: None. C.K. Cravalho: None. A. Villalobos-Perez: None. S. Matta: None. L. Mabundo: None. A.B. Courville: None. M.L. Sampson: None. J.D. Otvos: Employee; Self; LabCorp. S.T. Chung: None. Funding National Institutes of Health (to S.T.C., L.M., A.B.C.)

The data relating branched chain amino acids (BCAAs) with obesity and type 2 diabetes is conflicting but may be further clarified by examining its relationship to race/ethnicity and menopause. Therefore, we determined the relationship of BCAA with markers of insulin sensitivity (SI) in 122 federally employed women (49 White, 73 Black: 58 African American and 15 African Immigrant, age 44±10 (mean±SD) (range 24-62y); BMI 30.2±5.7 (range 20.3-45.2 kg/m2); 33% menopausal) using linear regression models adjusted for race and menopause. Fasting BCAAs were measured by nuclear magnetic resonance (NMR) spectroscopy, whole-body SI derived from the minimal model, basal hepatic insulin sensitivity (HISI) using [6,62H2]glucose, and hepatic and visceral adipose tissue (VAT) by proton NMR. BCAAs were similar in black and white women (leucine:104±30 vs. 114±37, valine:196±40 vs. 204±34, isoleucine:41±12 vs. 38±12 μmol/L, all P≥0.1) and did not differ by menopause (P>0.5). Total and individual BCAAs were associated with lower whole-body SI (Figure), weakly associated with VAT (AdjR2=0.1, P=0.01), liver fat (AdjR2=0.01, P=0.01), and there was no association with HISI (P>0.2). Overall, plasma BCAAs were not robust markers of insulin resistance in women of white or African ancestry and higher levels in women with insulin resistance may reflect a composite effect of dietary and metabolic processes. Disclosure S. Matta: None. C.K. Cravalho: None. A. Villalobos-Perez: None. A. Meyers: None. L. Mabundo: None. A.B. Courville: None. M.L. Sampson: None. A.E. Sumner: None. S.T. Chung: None. Funding National Institutes of Health (to S.T.C., L.M., A.B.C.)

In nonwhite populations the prevalence of abnormal glucose tolerance (Abnl-GT) is increasing in the nonobese. However, the prevalence of Abnl-GT in African-born blacks is unknown. As BMI correlates positively with A1C and negatively with glycated albumin (GA) and fructosamine (FA), BMI may influence the diagnostic sensitivity of nonfasting markers of glycemia. Working with Africans, our goals were to determine: a) by BMI category the prevalence of Abnl-GT; and b) the diagnostic value of nonfasting markers of glycemia, individually and combined. In 416 African-born blacks living in America (male: 66%; age: 39±10 (mean±SD), range 20 to 65y, BMI: 27.7±4.5, range 18.2-42.4 kg/m2) OGTT were performed. A1C, GA and FA levels were measured. A1C, GA and FA levels were repeated 11±7 days later in 136 participants. Abnl-GT was defined by glucose: 0h ≥100 and/or 2h ≥140 mg/dL. Thresholds for A1C, GA and FA were defined by the cut-off at the upper quartile for the population (5.7%, 14.2%, 234 µM/L, resp). Analytic tools were κ-statistic, Spearman correlations and the McNemar test. In short, Abnl-GT occurred in 36% (152/416). Of the individuals with Abnl-GT, 68% (104/152) were nonobese. Reproducibility of A1C and GA were excellent (both κ≥0.8) but only moderate for FA (κ=0.6). For this reason, results focus on A1C and GA. BMI positively correlated with A1C (r= 0.18) and negatively with GA (r=-0.18) (both P Disclosure A.E. Sumner: None. A.F. Hobabagabo: None. E.M. Shoup: None. T. Hormenu: None. N.H. Osei-Tutu: None. C. DuBose: None. L. Mabundo: None. S.T. Chung: None. D.B. Sacks: Other Relationship; Self; Sebia, Trinity Biotech plc.

Obesity and insulin resistance are the hallmarks of abnormal glucose tolerance (Abnl-GT) in African Americans and African Caribbeans. In contrast, prevalence, phenotype and etiology of Abnl-GT in African-born blacks are unknown. Working with African-born blacks living in America, we determined (a) the prevalence of Abnl-GT, and (b) the etiology of Abnl-GT by BMI category (i.e., primary β-cell failure vs. insulin resistance). OGTT was performed in 461 African-born blacks (male: 66%; age: 39±10 (mean±SD), range: 20-65y; BMI: 27.6±4.5, range: 18.4-42.4 kg/m2). Abnl-GT was diagnosed by glycemia: 0h glucose≥100 or 2h glucose≥140 mg/dL. Insulin resistance was defined by the cutoff at the lowest quartile of the Matsuda Index for the population (≤2.97). Primary β-cell failure was diagnosed if Abnl-GT was present and Matsuda Index was >2.97. Obesity occurred in 27% (123/461). Abnl-GT occurred in 38% (173/461). By BMI category, Abnl-GT occurred in 35% (117/338) of the nonobese and 46% (56/123) of the obese. Overall, β-cell failure occurred in 61% (105/173) of participants with Abnl-GT (Figure). Yet, the odds of primary β-cell failure as the cause of Abnl-GT were 4 times higher in the nonobese than the obese (OR: 4.2; 95% CI: 2.2, 8.3). In short, the prevalence of Abnl-GT was high in both nonobese and obese African-born blacks. However, in nonobese Africans with Abnl-GT, primary β-cell failure was more common than insulin resistance. Disclosure A.F. Hobabagabo: None. T. Hormenu: None. E.M. Shoup: None. N.H. Osei-Tutu: None. C. DuBose: None. L. Mabundo: None. S.T. Chung: None. A.E. Sumner: None.

The high prevalence of undiagnosed diabetes (DM) in Africa calls for the identification of effective, efficient, and feasible screening tests. Emerging data suggests that random plasma glucose≥100 mg/dL (RPG≥100) may be a valuable screening tool and equivalent to or better than standard ADA criteria, which requires fasting blood samples, knowledge of family history, anthropometrics and blood pressure. Since RPG≥100 as a screening tool for DM has not been tested in Africans, our goals were twofold: first, to compare the diagnostic performance of RPG≥100 to ADA criteria; second, to determine for RPG≥100 the number needed to screen to find a single case of DM. Hence, African-born blacks who self-identified as healthy and were living in America (n=469, 66% male, age: 38±10y (mean±SD), BMI: 27.6±4.5 kg/m2) had random plasma glucose levels measured. One week later, an OGTT was performed. Glucose criteria for the OGTT was used to diagnose DM. Area under the receiver operating characteristic curve (AROC) was used to assess the performance of RPG≥100 and ADA criteria (age≥45y, BMI≥25 kg/m2, HDL250mg/dL, SBP≥140mmHg, DBP≥90mmHg, and family history of DM). The number of people needed to screen to correctly identify one case of undiagnosed DM was calculated by the formula: 1/(proportion correctly diagnosed - proportion incorrectly diagnosed). DM was identified in 7% (31/469) of the participants; whereas RPG≥100 occurred in 15% (68/469). For the prediction of DM, RPG≥100 tended to be superior to the ADA criteria (AROC 0.80 vs. 0.68, P=0.09). RPG≥100 was 71% sensitive and 89% specific. ADA criteria was 90% sensitive and 37% specific. For RPG≥100, the number needed to screen to correctly identify a single case of DM was two. Overall, RPG≥100 as a screening tool for DM is effective, more cost-efficient, and less time-consuming than ADA criteria. In short, RPG≥100 may be an important way forward for the detection of DM in Africans and further study is warranted. Disclosure E.M. Shoup: None. N.H. Osei-Tutu: None. T. Hormenu: None. A.F. Hobabagabo: None. C. DuBose: None. L. Mabundo: None. S.T. Chung: None. M.F. Horlyck-Romanovsky: None. A.E. Sumner: None.

Whether stress-related behaviors or social factors are associated with diabetes (DM) in African-born blacks living in the United States is unknown. Thus, African immigrants who identified as healthy underwent OGTT and had extensive questioning about lifestyle and socioeconomic status. Neither participants nor investigators knew the outcome of the OGTT at the time surveys were administered. The participants were 470 African-born blacks living in Washington, DC (male: 66%, age 38±10y, range 20-65y, BMI 27.6±4.5, range 19.5-39.9). DM was diagnosed by glucose criteria for the OGTT or A1C≥6.5%. DM was identified in 9% (40/470) of participants. Age, BMI and years in the United States were higher in the group with DM (age: 44±10 vs. 38±10y; BMI: 29.8±4.9 vs. 27.4±4.4; Years in U.S.:16±10 vs. 12±10y, all P0.5). Overall, undiagnosed DM was associated with stress-related behaviors such as alcohol intake, smoking and diet. Whereas, difficult to address social characteristics such as education, income and health insurance did not differ by DM status. Combining DM screening with counseling on stress may lead to improved health for African immigrants. Disclosure N.H. Osei-Tutu: None. T. Hormenu: None. E.M. Shoup: None. A.F. Hobabagabo: None. C. DuBose: None. S.T. Chung: None. L. Mabundo: None. A.E. Sumner: None.

OBJECTIVES: To investigate differences in ad libitum energy intake when inpatient adults were exposed to diets with equal calories and protein but varied widely in the ratio of carbohydrate to fat. METHODS: 16 adults without diabetes were admitted to the Metabolic Clinical Research Unit in the NIH Clinical Center for four continuous weeks and were randomized to receive either a plant-based, low-fat (LF) diet or an animal-based, low-carbohydrate (LC) diet for two weeks, followed by the alternate diet for two weeks. The LF diet was ∼75% carbohydrate and ∼10% fat, whereas the LC was ∼10% carbohydrate and ∼75% fat. The LF diet had ∼4-fold more fiber and was ∼60% of the energy density of the LC diet. Both diets were matched for protein and the presented calories were double each subject's maintenance energy requirements, as calculated from their measured resting energy expenditure multiplied by 1.6. Participants received three daily meals, had continuous access to snacks, and were instructed to eat as much or as little as they wanted. Leftovers were weighed to determine food intake. ProNutra software was used to calculate energy and nutrient intake. RESULTS: The study enrolled 9 men and 7 women with an age (mean ± SE) of 29 ± 1.7 years and body mass index (BMI) of 27.5 ± 1.5. During exposure to the LF diet, participants consumed 726 ± 84 kcal/d less than during the LC diet (P

OBJECTIVES: To explore postprandial responses to isocaloric meals after ∼2 weeks on an ad libitum Low Carbohydrate (LC) diet vs. a Low Fat (LF) diet. METHODS: 16 healthy volunteers without diabetes were admitted to the NIH Clinical Center and randomized to consume a LC or LF diet for 2 weeks immediately followed by 2 weeks of the alternate diet. The LC diet was composed of ∼75% fat, ∼10% carbohydrate, and ∼15% protein; the LF diet was ∼75% carbohydrate, ∼10% fat, and ∼15% protein. Daily meals and snacks were matched for presented calories and participants were instructed to consume as much or as little as desired. On day 13 of each diet after an 8 hour fast, participants consumed a liquid meal containing 30% of energy requirements with a macronutrient composition corresponding to the prevailing diet. Blood was drawn at 0, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes post meal consumption. Plasma concentrations of glucose, lactate, insulin, c-peptide, free fatty acids, and triglycerides were measured. RESULTS: 7 females and 9 males with an age of (mean ± SE) 28.7 ±1.7 y and BMI of 27.5 ± 1.5 kg/m(2) completed the study. During the LC diet, baseline levels of triglycerides and lactate were significantly lower (−33.5 ± 9.1 mg/dl; P = 0.003, −0.18 ± 0.05 mM; P = 0.002, respectively) and glucose, insulin, and c-peptide also tended to be lower (−3.7 ± 2.0 mg/dl; P = 0.09, −2.2 ± 1.2 µU/ml; P = 0.08, −0.35 ± 0.17 ng/ml; P = 0.06, respectively) whereas free fatty acids were significantly higher (0.28 ± 0.06 mM; P = 0.0005) compared to the LF diet. Average postprandial levels of glucose, lactate, insulin, and c-peptide were significantly lower following the LC meal (−11 ± 3 mg/dl; P = 0.003, −0.88 ± 0.06 mM; P

OBJECTIVE: In African-born Blacks living in America, we determined by BMI category 1) prevalence of abnormal glucose tolerance (Abnl-GT) and 2) diagnostic value and reproducibility of hemoglobin A(1c) (HbA(1c)), fructosamine, and glycated albumin (GA). RESEARCH DESIGN AND METHODS: Participants (n = 416; male, 66%; BMI 27.7 ± 4.5 kg/m(2) [mean ± SD]) had an oral glucose tolerance test with HbA(1c), GA, and fructosamine assayed. These glycemic markers were repeated 11 ± 7 days later. Abnl-GT diagnosis required 0 h ≥5.6 mmol/L (≥100 mg/dL) and/or 2 h ≥7.8 mmol/L (≥140 mg/dL). Thresholds for HbA(1c), GA, and fructosamine were the values at the 75th percentile for the population (39 mmol/mol [5.7%], 14.2%, and 234 μmol/L, respectively). RESULTS: Abnl-GT prevalence in the nonobese was 34% versus 42% in the obese (P = 0.124). Reproducibility was excellent for HbA(1c) and GA (both κ ≥ 0.8), but moderate for fructosamine (κ = 0.6). Focusing on HbA(1c) and GA in the nonobese, we found as single tests the sensitivities of HbA(1c) and GA were 36% versus 37% (P = 0.529). Combining HbA(1c) and GA, sensitivity increased to 58% because GA identified 37% of Africans with Abnl-GT not detected by HbA(1c) (P value for both tests vs. HbA(1c) alone was

Competing models of obesity and its treatment often contrast the relative roles of dietary fat versus carbohydrate. Advocates of low-carbohydrate diets posit that intake of high glycemic carbohydrates leads to elevated postprandial insulin thereby promoting body fat accumulation while increasing hunger and energy intake according to the carbohydrate-insulin model of obesity. Alternatively, proponents of low-fat diets argue that high fat intake promotes body fat storage due to passive overconsumption of energy resulting from the high energy density of dietary fat. To test these competing models, 20 adults without diabetes aged (mean±SE) 29.9±1.4 y with BMI=27.8±1.3 kg/m2 were admitted as inpatients to the NIH Clinical Center and randomized to consume ad libitum either a plant-based, low-fat (PBLF) diet (75.2% carbohydrate, 10.3% fat, non-beverage energy density = 1.1 kcal/g) or an animal-based, ketogenic, low-carbohydrate (ABLC) diet (75.8% fat,10.0% carbohydrate, non-beverage energy density = 2.2 kcal/g) for two weeks followed immediately by the alternate diet for two weeks. Three daily meals plus snacks amounting to twice each subject’s estimated energy requirements were provided and subjects were instructed to eat as much or as little as desired. The PBLF diet resulted in substantially greater glucose and insulin levels whereas the ABLC diet led to increased blood ketones of ~3 mM which is thought to suppress appetite. However, ad libitum energy intake was 689±73 kcal/d lower during the PBLF diet as compared to the ABLC diet (p

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). In rodent models of both health and lipodystrophy (LD), leptin decreases DNL. In human patients with LD, reduced adipose tissue results in adipokine deficiencies, including lower plasma leptin, which contributes to insulin resistance, dyslipidemia and ectopic accumulation of triglycerides (TG). The mechanisms by which leptin regulates serum and hepatic-TG are not well elucidated. Studying patients with LD before and after leptin therapy provides an important clinical model for understanding leptin’s effect on DNL. We hypothesized that leptin treatment in lipodystrophic patients would decrease DNL by decreasing insulin resistance and glycemia, resulting in reduced circulating and hepatic-TG. Leptin-naïve patients with LD (n=11) were treated with recombinant leptin (metreleptin) for 6 months. All measurements were performed after an 8–12 hr fast. The % of TG in TG-rich lipoproteins (TRLP-TG) derived from DNL (% DNL) was measured using body water labeling (oral D2O) of TG and mass spectrometry analysis. Absolute DNL was calculated as the product of TRLP-TG and % DNL. HbA1c and serum-TG were measured biochemically, hepatic-TG by MRI, and total body and hepatic insulin sensitivity measured during a hyperinsulinemic-euglycemic clamp. DNL decreased after metreleptin: % DNL from 22.8±6.8 to 9.1±5.1% (p=0.0008) and absolute DNL from 54.2±32.1 to 8.6±6.5 mg/dl (p=0.003). TRLP-TG decreased from (median [interquartile range]) 160 [107, 280] to 98 [66, 147] mg/dl (p=0.01). Total body and hepatic insulin sensitivity increased from 3.7 [3.0, 7.3] to 8.4 [5.1,10.6] mg/kgFFM/min (p=0.03) and from 61.0 [48.5, 69.3] to 84.7 [75.2, 107.6] % (p =0.01), respectively. HbA1c decreased from 8.6±1.8 to 7.1±1.4% (p=0.04), hepatic-TG decreased from 17.6±11.9 to 10.3±9.1% (p=0.02), and serum-TG from 386 [216, 686] to 223 [118, 497] mg/dl (p=0.06). DNL correlated negatively with insulin sensitivity both before (r=-0.73, p=0.03) and after (r=-0.85, p=0.004) metreleptin. DNL correlated positively with hepatic-TG before (r=0.70 p=0.03) and tended to correlate after metreleptin (r=0.65, p=0.06). The change in DNL correlated with change in serum-TG (r=0.77, p=0.04) but not the change in hepatic-TG (p=0.80). We show here for the first time that 6 months of metreleptin treatment in humans with LD decreased DNL by 84% and was associated with reductions in glycemia and improved peripheral and hepatic insulin sensitivity. These data indicate a strong link between metreleptin’s effects to increase clearance of blood glucose by peripheral tissues and reduce hepatic carbohydrate flux, resulting in DNL reductions. This led to lowered hepatic steatosis and dyslipidemia and suggests treatments that target multi-organ insulin resistance may lead to decreased NAFLD and cardiovascular risk.

Metformin is the only approved oral agent for youth with type 2 diabetes but its mechanism of action remains controversial. Recent data in adults suggest a primary role for the enteroinsular pathway, but there are no data in youth, in whom metformin efficacy is only ~50%. Our objectives were to compare incretin concentrations and rates of glucose production and gluconeogenesis in youth with type 2 diabetes before and after short-term metformin therapy compared with peers with normal glucose tolerance (NGT). This is a case–control observational study in youth with type 2 diabetes who were not on metformin (n = 18) compared with youth with NGT (n = 10) who were evaluated with a 2 day protocol. A 75 g OGTT was administered to measure intact glucagon-like 1 peptide (iGLP-1), gastric inhibitory polypeptide (GIP) and peptide YY (PYY). Insulinogenic index (IGI) and whole-body insulin sensitivity were calculated using glucose and insulin levels from the OGTT. Basal rates of gluconeogenesis (2H2O), glucose production ([6,6-2H2]glucose) and whole-body lipolysis ([2H5]glycerol) were measured after an overnight fast on study day 2. Youth with type 2 diabetes (n = 9) were subsequently evaluated with an identical 2 day protocol after 3 months on the metformin study. Compared with individuals with NGT, those with type 2 diabetes had higher fasting (7.8 ± 2.5 vs 5.1 ± 0.3 mmol/l, mean ± SD p = 0.002) and 2 h glucose concentrations (13.8 ± 4.5 vs 5.9 ± 0.9 mmol/l, p = 0.001), higher rates of absolute gluconeogenesis (10.0 ± 1.7 vs 7.2 ± 1.1 μmol [kg fat-free mass (FFM)]−1 min−1, p

IntroductionRisk of insulin resistance, dyslipidemia, diabetes and cardiac death is increased in Asians and Europeans with normal glucose tolerance (NGT) and 1-hour glucose ≥8.6 mmol/L. As African descent populations often have insulin resistance but a normal lipid profile, the implications for Africans with NGT and glucose ≥8.6 mmol/L (NGT-1-hour-high) are unknown.ObjectiveWe performed oral glucose tolerance tests (OGTTs) in 434 African born-blacks living in Washington, DC (male: 66%, age 38±10 years (mean±SD)) and determined in the NGT group if either glucometabolic or lipid profiles varied according to a 1-hour-glucose threshold of 8.6 mmol/L.MethodsGlucose tolerance category was defined by OGTT criteria. NGT was subdivided into NGT-1-hour-high (glucose ≥8.6 mmol/L) and NGT-1-hour-normal (glucose ResultsOne-hour-glucose ≥8.6 mmol/L occurred in 17% (47/272) with NGT, 72% (97/134) with pre-diabetes and in 96% (27/28) with diabetes. Both insulin resistance and beta-cell function were worse in NGT-1-hour-high than in NGT-1-hour-normal. Dyslipidemia occurred in both the diabetes and pre-diabetes groups but not in either NGT group. One-hour glucose concentration ≥8.6 mmol/L showed substantial agreement for the two OGTTs (к=0.628).ConclusionsAlthough dyslipidemia did not occur in either NGT group, insulin resistance and beta-cell compromise were worse in NGT-1 hour-high. Subdividing the NGT group at a 1-hour glucose threshold of 8.6 mmol/L may stratify risk for diabetes in Africans.

CONTEXT: Physiologic changes in glucose metabolism are well-described to occur during puberty. However, there are important gaps in understanding the interaction between obesity and the normal physiologic changes during puberty, as well as how these changes could contribute to the increased risk of comorbidities, such as type 2 diabetes and dyslipidemia, in youth with obesity. OBJECTIVE: The objective of this study was to compare longitudinal changes in insulin sensitivity (S(i)) and secretion during pubertal progression in youth with obesity versus those with normal weight. DESIGN: Longitudinal observational study evaluating youth from early puberty (Tanner [T]2-T3) until puberty completion (T5). SETTING: Pediatric academic hospital Clinical Translational Research Center. PARTICIPANTS: Pubertal youth with normal weight (n = 47; 22 female, 25 male) and obesity (n = 37; 23 female, 14 male) MAIN OUTCOME MEASURES: S(i), insulin response (acute insulin response to glucose, AIR(g)) and disposition index (DI) by intravenous glucose tolerance test at baseline (T2-T3), T4, and T5 RESULTS: Youth with obesity had significantly lower S(i) and higher AIR(g) at each time point (P

BACKGROUND: Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis. METHODS: Cross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured. RESULTS: Lipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%–0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%–17.1%], P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation. CONCLUSION: These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.