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Adipose tissue secretes an abundance of lipid and protein mediators, and this secretome is depot‐specific, with local and systemic effects on metabolic regulation. Intermuscular adipose tissue (IMAT) accumulates within the skeletal muscle compartment in obesity, and is associated with insulin resistance and metabolic disease. While the human IMAT secretome decreases insulin sensitivity in vitro, its composition is entirely unknown. The current study was conducted to investigate the composition of the human IMAT secretome, compared to that of the subcutaneous (SAT) and visceral adipose tissue (VAT) depots. IMAT, SAT, and VAT explants from individuals with obesity were used to generate conditioned media. Proteomics analysis of conditioned media was performed using multiplex proximity extension assays, and eicosanoid analysis using liquid chromatography–tandem mass spectrometry. Compared to SAT and/or VAT, IMAT secreted significantly more cytokines (IL2, IL5, IL10, IL13, IL27, FGF23, IFNγ and CSF1) and chemokines (MCP1, IL8, CCL11, CCL20, CCL25 and CCL27). Adipokines hepatocyte growth factor and resistin were secreted significantly more by IMAT than SAT or VAT. IMAT secreted significantly more eicosanoids (PGE2, TXB2, 5‐HETE, and 12‐HETE) compared to SAT and/or VAT. In the context of obesity, IMAT is a distinct adipose tissue with a highly immunogenic and inflammatory secretome, and given its proximity to skeletal muscle, may be critical to glucose regulation and insulin resistance. Intermuscular adipose tissue (IMAT) is interlaced within the muscle compartment and is negatively associated with the metabolic syndrome. This is the first report of the composition of the human IMAT secretome. In obesity, the IMAT secretome is highly immunogenic, secreting a distinct combination of cytokines, chemokines, adipokines and eicosanoids that are associated with insulin sensitivity. This study highlights the potential significance of crosstalk between IMAT and skeletal muscle in the development of type 2 diabetes.

Objective Adult women with polycystic ovary syndrome (PCOS) and obesity have an 8‐fold increased risk of developing type 2 diabetes (T2D). Our goal was to determine the incidence and risk factors for T2D in adolescents with PCOS and obesity. Research design and methods Retrospective chart review of girls aged 11–21 years with confirmed PCOS (oligomenorrhea and hyperandrogenism) diagnosis between July 2013 and Aug 2018 and at least one follow‐up visit and BMI >85%ile. T2D incidence, defined with an HbA1c ≥6.5%, was calculated. A nested case–control study with 1:3 matching by race, ethnicity, and BMI was performed to determine predictors of T2D diagnosis. Results Four hundred ninety‐three patients with PCOS (age 15.6 ± 1.9 years, BMI 36.2 ± 6.3 kg/m2) were identified with a follow‐up of 1018 person‐years. Twenty‐three developed T2D (incidence 22.6/1000 person‐years) with diagnosis a median of 1.8 years (2 months–5.5 years) after PCOS diagnosis. T2D risk was higher in girls with a prediabetes HbA1c (5.7%–6.4%) (HR 14.6 [4.8–44.5]) and among Hispanic girls with an elevated HbA1c and alanine aminotransferase (HR 19.0 [3.7–97.2]) at the time of PCOS diagnosis. In the 1:3 matched cohort, T2D risk was 18.7 times higher (OR 18.66 [2.27–153.24]) for every 0.1% increase in HbA1c at the time of PCOS diagnoses. Conclusions Girls with PCOS and obesity have an 18‐fold increase in T2D incidence compared to published rates in non‐PCOS youth. Hispanic girls with elevated HbA1c and ALT are at particular risk. Due to the morbidity associated with youth onset T2D, these findings argue for better screening and prevention approaches in this population.

Hepatic steatosis (HS) is common in adolescents with obesity and polycystic ovary syndrome (PCOS). Gut microbiota are altered in adults with obesity, HS, and PCOS, which may worsen metabolic outcomes, but similar data is lacking in youth. Thirty-four adolescents with PCOS and obesity underwent stool and fasting blood collection, oral glucose tolerance testing, and MRI for hepatic fat fraction (HFF). Fecal bacteria were profiled by high-throughput 16S rRNA gene sequencing. 50% had HS (N = 17, age 16.2±1.5 years, BMI 38±7 kg/m2, HFF 9.8[6.5, 20.7]%) and 50% did not (N = 17, age 15.8±2.2 years, BMI 35±4 kg/m2, HFF 3.8[2.6, 4.4]%). The groups showed no difference in bacterial α-diversity (richness p = 0.202; evenness p = 0.087; and diversity p = 0.069) or global difference in microbiota (β-diversity). Those with HS had lower % relative abundance (%RA) of Bacteroidetes (p = 0.013), Bacteroidaceae (p = 0.009), Porphyromonadaceae (p = 0.011), and Ruminococcaceae (p = 0.008), and higher Firmicutes:Bacteroidetes (F:B) ratio (47.8% vs. 4.3%, p = 0.018) and Streptococcaceae (p = 0.034). Bacterial taxa including phyla F:B ratio, Bacteroidetes, and family Bacteroidaceae, Ruminococcaceae and Porphyromonadaceae correlated with metabolic markers. Obese adolescents with PCOS and HS have differences in composition of gut microbiota, which correlate with metabolic markers, suggesting a modifying role of gut microbiota in HS and PCOS.

Objective Glycemic control deteriorates more rapidly in youth vs adults. We compared model‐derived measures of β‐cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a β‐cell defect differentiates these age groups. Methods This is a cross‐sectional analysis of baseline data from the Restoring Insulin Secretion (RISE) Study. Youth (54 Y‐IGT, 33 Y‐D) and adults (250 A‐IGT, 104 A‐D) underwent 3‐hour oral glucose tolerance tests for modeling of insulin secretion rates (ISRs), glucose sensitivity, and rate sensitivity. Insulin sensitivity was quantified as the glucose infusion rate/insulin (M/I) from a hyperglycemic clamp. Results Youth had lower insulin sensitivity despite similar body mass index. Analyses were adjusted for insulin sensitivity. Youth had higher basal ISRs (Y‐IGT 200 ± 161 vs A‐IGT 152 ± 74, P < .001; Y‐D 245 ± 2.5 vs A‐D 168 ± 115 pmol/min/m2, P = .007) and total ISRs (Y‐IGT 124 ± 86 vs A‐IGT 98 ± 39, P < .001; Y‐D 116 ± 110 vs A‐D 97 ± 62 nmol/m2, P = .002). Within IGT, glucose sensitivity (Y‐IGT 140 ± 153 vs A‐IGT 112 ± 70 pmol/min/m2/mM, P = .004) and rate sensitivity (median[interquartile range]:Y‐IGT 2271[1611, 3222] vs A‐IGT 1164[685, 1565] pmol/m2/mM, P < .001) were higher in youth, but not different by age group within diabetes. Conclusions Model‐derived measures of β‐cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and β‐cell secretion more responsive to glucose in youth relative to adults even after adjusting for differences in insulin sensitivity. It is unknown whether these findings in youth reflect β‐cells that are healthier or whether this is a defect that contributes to more rapid loss of function.

Background/objective Rates of dysglycemia are increasing in youth, secondary to obesity and decreased insulin sensitivity (IS) in puberty. The oral minimal model (OMM) has been developed in order to measure IS using an easy oral glucose load, such as an oral glucose tolerance test (OGTT), instead of an hyperinsulinemic‐euglycemic clamp (HE‐clamp), a more invasive and time‐consuming procedure. However, this model, following a standard 2 hour‐ OGTT has never been validated in youth, a population known for a different physiologic response to OGTT than adults. Thus, we compared IS measurements obtained from OMM following a 2‐hour OGTT to HE‐clamp and isotope tracer‐assessed tissue IS in adolescents. We also compared the liver/muscle‐specific IS from HE‐clamp with other liver/muscle‐specific IS surrogates following an OGTT previously validated in adults. Methods Secondary analysis of a cross‐sectional study. Adolescent girls with (n = 26) and without (n = 7) polycystic ovary syndrome (PCOS) (14.6 ± 1.7 years; BMI percentile 23.3%‐98.2%) underwent a 2‐hour 75 g OGTT and a 4‐phase HE‐clamp. OMM IS (Si), dynamic Si (Sid) and other OGTT‐derived muscle and liver IS indices were correlated with HE‐clamp tissue‐specific IS. Results OMM Si and Sid correlated with HE‐clamp‐measured peripheral IS (r = 0.64, P <.0001 and r = 0.73; P <.0001, respectively) and the correlation coefficient trended higher than the Matsuda index (r = 0.59; P =.003). The other tissue‐specific indices were poorly correlated with their HE‐clamp measurements. Conclusion In adolescent girls, the 2‐hour OMM provided the best estimate of peripheral IS. Additional surrogates for hepatic IS are needed for youth.

Background Hyperglycemia has traditionally been considered a major contributor to insulin resistance (IR) in type 1 diabetes (T1D), yet studies examining the relationship between HbA1c and IR are conflicting. Glucose measures captured by continuous glucose monitoring (CGM) (eg, peak glucose, standard deviation, hypoglycemia) in youth have not been explored as predictors of insulin sensitivity (IS). Objective Assess the relationship between IS and glycemia in youth with T1D and type 2 diabetes (T2D). Methods Sedentary 12‐19 year olds with diabetes had peripheral IS measured by hyperinsulinemic‐euglycemic clamp. HbA1c and 3 days of CGM data were also collected. Spearman correlation coefficients were calculated to examine the association between variables. Results Participants included 100 youth with T1D [46% male, median body mass index (BMI) 74 percentile, HbA1c 8.5%] and 42 with T2D (26% male, BMI 99 percentile, HbA1c 6.9%). Nineteen with T1D and 13 with T2D also wore CGM. In T2D youth, higher HbA1c, average sensor glucose, area under the CGM curve, and metabolic syndrome characteristics correlated with lower IS. In T1D youth, higher BMI percentile, waist circumference, triglycerides, and LDL cholesterol, but not HbA1c, correlated with lower IS. Moreover, higher CGM overnight means glucose correlated with greater IS, and CGM hypoglycemia correlated with lower IS. Conclusions Markers of metabolic syndrome and hyperglycemia predicted decreased IS in T2D youth. Paradoxically, hypoglycemia predicted decreased IS in T1D youth and hyperglycemia, particularly overnight, predicted improved IS. These preliminary results imply different mechanisms underlying IR in T1D vs T2D and suggest a role for non‐insulin therapies in T1D to improve IR.

Background Polycystic ovarian syndrome (PCOS) includes insulin resistance (IR) and impaired glucose tolerance (IGT) in youth, and a greatly elevated risk of type 2 diabetes in adulthood. Identifying IR is challenging and documenting IGT requires an oral glucose tolerance test (OGTT). Objective Identify easily applied surrogate measures for IR and IGT in girls with PCOS. Methods We studied 28 girls with PCOS (body mass index [BMI] percentile 98 (83.99); 15.5 (14.5,16.6) years of age) and 20 with normal menses [BMI percentile (97 (88.99); 15.5 (13.3,16.1) years]. Hyperinsulinemic‐euglycemic clamps (insulin dose of 80 μU/ml/min) to determine glucose infusion rate (GIR) and a 75 g OGTT were performed. Surrogates for IR including fasting insulin, homeostatic model assessment‐insulin resistant (HOMA‐IR), Matsuda index, and estimate of insulin sensitivity (e‐IS) were compared to IGT status and GIR. Spearman correlations were performed between surrogates and GIR or IGT, and receiver operator curve (ROC) analysis to predict GIR below the median or IGT status. Results GIR was lower in PCOS (12.9 ± 4.6 vs 17.1 ± 5.1 mg/kg fat‐free mass·min; P = 0.01). Within PCOS, HOMA‐IR (r = −0.78, P < 0.0001), e‐IS (r = 0.70, P < 0.001), and Matsuda (r = 0.533, P < 0.001) correlated with GIR. e‐IS provided a good sensitivity (100%) and specificity (71%) to identify IR (e‐IS cutoff: <6.3, ROC‐area under curve = 0.898). Fasting insulin >22 IU/mL had the best sensitivity (88%), specificity (78%), and ROC (0.760) for IGT status. Conclusions Girls with PCOS have significant IR, and IGT is common. Both e‐IS and fasting insulin are obtainable without an OGTT or clamp and could be used clinically to guide treatment in PCOS.

Objective Most youth with type 1 diabetes do not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for hemoglobin A1c (HbA1c), blood pressure (BP), lipids, and body mass index (BMI). We hypothesized that ISPAD/ADA goal achievement would be associated with better insulin sensitivity (IS) and cardiopulmonary fitness. Methods IS was quantified as glucose infusion rate (GIR) from a hyperinsulinemic‐euglycemic clamp in youth with type 1 diabetes from the RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) (n = 86) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) (n = 41) cohorts (n = 127; age 15.7 ± 2.2 years, 52% girls). Cardiopulmonary fitness was measured as peak oxygen consumption (VO2peak/kg) during upright (RESISTANT) or supine (EMERALD) cycle ergometry and were stratified by cycle type. Goal achievement was defined as HbA1c < 7.5%, BP < 90th percentile, LDL‐cholesterol < 100 mg/dL, HDL‐cholesterol > 35 mg/dL, triglycerides < 150 mg/dL and BMI < 85th percentile. Participants were stratified into 3 groups: achieving 0‐3 goals (n = 52), 4 goals (n = 48), and 5‐6 goals (n = 27). Differences between groups were examined with generalized linear models. Results IS was lower in youth who met 0‐3 goals (5.2 ± 3.4 mg/kg/min) vs those who met 4 goals (7.4 ± 4.1 mg/kg/min, P = .04) and those who met 5‐6 goals (8.5 ± 4.3 mg/kg/min, P = .003), and remained significant after adjustments for sex and diabetes duration. Upright VO2peak was lower in youth who met 0‐3 goals (25.8 ± 4.6 mL/kg/min) vs those who met 4 goals (33.0 ± 7.8 mL/kg/min, P = .01) and those who met 5‐6 goals (33.2 ± 4.4 mL/kg/min, P = .004). Similar and significant relationships were observed in EMERALD participants for supine VO2peak. Conclusions ADA/ISPAD goal achievement was associated with greater IS and cardiopulmonary fitness.

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.

OBJECTIVES/GOALS: Intermuscular adipose tissue (IMAT) has been associated with insulin resistance and type 2 diabetes, yet mechanistic studies addressing the functional role of IMAT are lacking. The aim of this work was to identify novel mechanisms by which IMAT may directly impact skeletal muscle metabolism. METHODS/STUDY POPULATION: We quantified the secretome of IMAT, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) to determine if there are differences between depots in the secretion of cytokines, eicosanoids, FFAs and proteins that influence metabolic function. SAT and VAT biopsies from patients undergoing laparoscopic bariatric surgery and IMAT extracted from vastus lateralis biopsies of individuals with Obesity were cultured for 48 hours in DMEM, and the conditioned media was analyzed using nanoflow HPLC-MS, multiplex ELISAs and LC/MS/MS for proteins, cytokines and eicosanoids/FFA, respectively. RESULTS/ANTICIPATED RESULTS: IMAT secretion of various extracellular matrix proteins (fibrinogen-β, collagenV1a3, fibronectin) was significantly different than VAT and SAT. Pro-inflammatory cytokine secretion of IFNg, TNFa, IL-8 and IL-13 from IMAT was higher than VAT and significantly higher than SAT (p < 0.05). IMAT secretes significantly more pro-inflammatory eicosanoids TXB 2 and PGE 2 than VAT (p = 0.02, 0.05) and SAT (p = 0.01, 0.04). IMAT and VAT have significantly greater basal lipolysis assessed by FFA release rates compared to SAT (p = 0.01, 0.04). DISCUSSION/SIGNIFICANCE OF IMPACT: These data begin to characterize the disparate secretory properties of SAT, VAT and IMAT and suggest a metabolically adverse secretome of IMAT, that due to its proximity to skeletal muscle may play an important functional role in the pathogenesis of insulin resistance and type 2 diabetes.