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Background: The presence of vascular dysfunction is a well-recognized feature in youth with type 1 diabetes (T1D), accentuating their lifetime risk of cardiovascular events. Therapeutic strategies to mitigate vascular dysfunction are a high clinical priority. In the bromocriptine quick release T1D study (BCQR-T1D), we tested the hypothesis that BCQR would improve vascular health in youth with T1D. Methods: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating the cardiovascular and metabolic impact of BCQR in T1D. Adolescents in the BCQR-T1D study were randomized 1:1 to phase-1: 4 weeks of BCQR or placebo after which blood pressure and central aortic stiffness measurements by pulse wave velocity, relative area change, and distensibility from phase-contrast magnetic resonance imaging were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. Results: Thirty-four adolescents (mean age 15.9±2.6 years, hemoglobin A1c 8.6±1.1%, body mass index percentile 71.4±26.1, median T1D duration 5.8 years) with T1D were enrolled and had magnetic resonance imaging data available. Compared with placebo, BCQR therapy decreased systolic (∆=−5 mmHg [95% CI, −3 to −7]; P P =0.039). BCQR reduced ascending aortic pulse wave velocity (∆=−0.4 m/s; P =0.018) and increased relative area change (∆=−2.6%, P =0.083) and distensibility (∆=0.08%/mmHg; P =0.017). In the thoraco-abdominal aorta, BCQR decreased pulse wave velocity (∆=−0.2 m/s; P =0.007) and increased distensibility (∆=0.05 %/mmHg; P =0.013). Conclusions: BCQR improved blood pressure and central and peripheral aortic stiffness and pressure hemodynamics in adolescents with T1D over 4 weeks versus placebo. BCQR may improve aortic stiffness in youth with T1D, supporting future longer-term studies.

BACKGROUND Physical activity (PA) is a cornerstone of type 2 diabetes mellitus (T2DM) treatment. Sex differences in PA behavior or barriers/facilitators to PA among individuals with T2DM are unclear. PURPOSE To summarize the evidence related to sex differences in participation in PA and barriers/facilitators to PA among individuals with T2DM across the life span. DATA SOURCES Systematic searches (CRD42021254246) were conducted with Ovid MEDLINE, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), APA PsychInfo, and SPORTDiscus. STUDY SELECTION We included studies with assessment of PA, sedentary behaviors (SB), or barriers/facilitators to PA among individuals with T2DM by sex or gender. DATA EXTRACTION Participant characteristics, meeting PA guidelines, participation in PA and SB, and barriers/facilitators to PA were extracted by two independent reviewers. DATA SYNTHESIS A total of 53 articles (65,344 participants) were included in the systematic review and 21 articles in the meta-analysis. Sex differences were not observed in meeting of PA guidelines among adolescents (odds ratio 0.70 [95% CI 0.31, 1.59]), but males were more likely than females to meet PA guidelines among adults (1.65 [1.36, 2.01]) and older adults (1.63 [1.27, 2.09]). Males performed more moderate-to-vigorous PA (MVPA) than females across all age-groups. Common barriers to PA were lack of time (men) and lack of social support and motivation (women). LIMITATIONS Limitations include heterogeneity of measures used to assess PA and lack of stratification of data by sex. CONCLUSIONS Sex differences in meeting PA guidelines were not observed among adolescents but were apparent among adults and older adults with T2DM. Females consistently engaged in less MVPA than males across the life span.

To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes.Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8 mg to 1.6 mg to 3.2 mg, minimum dose 1.6 mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry.Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areas under the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR.Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.

Background. In cystic fibrosis-related diabetes (CFRD) screening, oral glucose tolerance test (OGTT) thresholds for detecting prediabetes and diabetes are defined by the 2-hour glucose (2 hG). Intermediate OGTT glucoses, between 0 and 2 hours, that are ≥200 mg/dL are deemed “indeterminate,” although lower 1-hour glucose (1 hG) thresholds identify those at increased risk of type 2 diabetes in other populations, and may also better predict clinical decline in CF. Studies of 1 hG thresholds 140 mg/dL. The average 1 hG was 267 mg/dL when 2 hG ≥ 200 mg/dL. In a subset with baseline 2 hG p = 0.036 ). Baseline 2 hG predicted decline in FEV1%predicted, but 1 hG did not. Conclusions. In youth with CF, 1 hG ≥ 140 mg/dl is an early indicator of CFRD risk. However, 2 hG, rather than 1 hG, predicted lung function decline.

Background: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. Methods: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. Results: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m 2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:−0.33, q = 0.01), histidine (r:−0.45, q < 0.001), methionine (r: −0.29, q = 0.02), phenylalanine (r: −0.29, q = 0.01), serine (r: −0.42, q < 0.001), threonine (r: −0.28, q = 0.02), citrate (r: −0.35, q = 0.003), fumarate (r: −0.24, q = 0.04), and malate (r: −0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: −0.28, q = 0.04), phenylalanine (r:−0.3, q = 0.03), fumarate (r: −0.29, q = 0.04), and malate (r: −0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: −0.28, q = 0.02) was correlated with higher mean ACR. Conclusions: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. Trial registration: ClinicalTrials.gov NCT03618420 and NCT03584217 Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information [Figure not available: see fulltext.]

Adolescents with polycystic ovary syndrome (PCOS) and obesity can have insulin resistance, dysglycemia, and hepatic steatosis. Excess pancreatic fat may disturb insulin secretion and relate to hepatic fat. Associations between pancreatic fat fraction (PFF) and metabolic measures in PCOS were unknown.This secondary analysis included 113 sedentary, nondiabetic adolescent girls (age = 15.4 [1.9] years), with or without PCOS and BMI ≥ 90th percentile. Participants underwent fasting labs, oral glucose tolerance tests, and magnetic resonance imaging for hepatic fat fraction (HFF) and PFF. Groups were categorized by PFF (above or below the median of 2.18%) and compared.Visceral fat and HFF were elevated in individuals with PCOS versus control individuals, but PFF was similar. PFF did not correlate with serum androgens. Higher and lower PFF groups had similar HFF, with no correlation between PFF and HFF, although hepatic steatosis was more common in those with higher PFF (≥5.0% HFF; 60% vs. 36%; p = 0.014). The higher PFF group had higher fasting insulin (p = 0.026), fasting insulin resistance (homeostatic model assessment of insulin resistance, p = 0.032; 1/fasting insulin, p = 0.028), free fatty acids (p = 0.034), and triglycerides (p = 0.004) compared with those with lower PFF. β-Cell function and insulin sensitivity were similar between groups.Neither PCOS status nor androgens related to PFF. However, fasting insulin and postprandial lipids were worse with higher PFF.

Objective: Glomerular injury is a recognized complication of diabetic ketoacidosis (DKA), yet the tubular lesions are poorly understood. The aim of this prospective study was to evaluate the presence and reversibility of tubular injury during DKA in children with type 1 diabetes (T1D). Research Design and Methods: Blood and urine samples were collected from 40 children with DKA (52% boys, mean age 11 ± 4 years, venous pH7.2 ± 0.1, glucose 451 ± 163 mg/dL) at three timepoints: 0–8 and 12–24 h after starting insulin, and 3 months after discharge. Mixed-effects models evaluated the changes in tubular injury markers over time (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1 [KIM-1], and interleukin 18 [IL-18]). We also evaluated the relationships among the tubular injury biomarkers, copeptin, a vasopressin surrogate, and serum uric acid (SUA). Results: Serum NGAL, KIM-1, and IL-18 were highest at 0–8h (306.5 ± 45.9ng/mL, 128.9 ± 10.1pg/mL, and 564.3 ± 39.2pg/mL, respectively) and significantly decreased over 3 months (p=0.03, p=0.01, and p < 0.001, respectively). There were strong relationships among increases in copeptin and SUA and rises in tubular injury biomarkers. At 0–8h, participants with acute kidney injury (AKI) [17%] showed significantly higher concentrations of tubular injury markers, copeptin, and SUA. Conclusions: DKA was characterized by tubular injury, and the degree of injury associated with elevated copeptin and SUA. Tubular injury biomarkers, copeptin and SUA may be able to predict AKI in DKA.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Background: Physical activity (PA) is a cornerstone of type 2 diabetes mellitus (T2DM) treatment. Sex differences in PA behavior or barriers/facilitators to PA among individuals with T2DM are unclear. Purpose: To summarize the evidence related to sex differences in participation in PA and barriers/facilitators to PA among individuals with T2DM across the lifespan. Data Source: Systematic searches (CRD42021254246) were conducted using Ovid Medline, EMBASE, Web of Science, CINAHL, AMED, PsychINFO, and SPORTDiscus. Study Selection: Studies assessing PA, sedentary behaviors (SB) or barriers/facilitators to PA among individuals with T2DM by sex or gender. Data Extraction: Participant characteristics, meeting PA guidelines, participation in PA and SB, and barriers/facilitators to PA were extracted by two independent reviewers. Data Synthesis: Fifty-three articles (65,344 participants) were included in the systematic review; 21 articles in the meta-analysis. Sex differences were not observed in meeting PA guidelines among adolescents (OR [95% CI], 0.70 [0.31, 1.59]), but males were more likely than females to meet PA guidelines among adults (1.65 [1.36, 2.01]) and older adults (1.63 [1.27, 2.09]). Males performed more moderate to vigorous PA (MVPA) than females across all age groups. Common barriers were lack of time (men) and lack of social support and motivation (women). Limitations: Limitations include heterogeneity of measures used to assess PA and lack of stratification of data by sex. Conclusions: Sex differences in meeting PA guidelines were not observed among adolescents, but were apparent among adults and older adults with T2DM. Females consistently engaged in less MVPA than males across the lifespan.

The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel anti-diabetic agents, diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate post-prandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of anti-hyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.

OBJECTIVE To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. RESEARCH DESIGN AND METHODS Glucagon was measured in three randomized, parallel, clinical studies: 1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). RESULTS No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P < 0.05 for all, except AGR at 12 months [P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. CONCLUSIONS Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions.

OBJECTIVETo identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study.RESEARCH DESIGN AND METHODSA total of 91 youth (10–19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline).RESULTSGlycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05–0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05).CONCLUSIONSGlycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Polycystic Ovary Syndrome (PCOS) is associated with metabolic diseases, including diabetes, and metformin is indicated if a1c is ≥5.7 demonstrating prediabetes/diabetes. To determine when to prescribe metformin, 2018 PCOS guidelines advise only an OGTT to screen, whereas ADA guidelines also include A1c. We sought to determine patterns of dysglycemia and metabolic disease in youth with PCOS and obesity. Data from girls (age 12-21 yrs, n=110) with obesity and untreated PCOS were examined. Metabolic assessments included fasting labs, 4-hour oral sugar tolerance test (OSTT, 75 g glucose, 25 g fructose) with Oral Minimal Modeling, liver fat assessment by MRI, and endogenous glucose release (Ra) with isotope tracers (N=31) . Data were divided by A1c ( Disclosure E.Finn: None. Y.Garcia reyes: None. A.E.Taylor: None. A.L.Garfield: None. C.A.Vivas: None. K.Fuller: None. B.C.Bergman: Research Support; Eli Lilly and Company. K.J.Nadeau: None. M.Cree-green: None. Funding National Institutes of Health (R01DK120612) , (K23DK107871) , (UL1 TR002535) , (P30 DK048520) , (K12HD057022) ;Doris Duke Foundation (CDSA) , (CDSA COVID extension) , (2015212) ; Childrens Hospital Colorado; Boettcher Web Waring Foundation

Objective: We examined changes in the excretion of various amino acids and in glycolysis and ketogenesis-related metabolites, during and after diabetic ketoacidosis (DKA) diagnosis, in youth with known or new onset type 1 diabetes (T1D). Methods: Urine samples were collected from 40 youth with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, blood glucose 451 ± 163 mg/dL) at 3 time points: 0–8 h and 12–24 h after starting an insulin infusion, and 3 months after hospital discharge. Mixed-effects models evaluated the changes in amino acids and other metabolites in the urine. Results: Concentrations of urine histidine, threonine, tryptophan, and leucine per creatinine were highest at 0–8 h (148.8 ± 23.5, 59.5 ± 12.3, 15.4 ± 1.4, and 24.5 ± 2.4% of urine creatinine, respectively), and significantly decreased over 3 months (p = 0.028, p = 0.027, p = 0.019, and p < 0.0001, respectively). Urine histidine, threonine, tryptophan, and leucine per urine creatinine decreased by 10.6 ± 19.2, 0.7 ± 0.9, 1.3 ± 0.9, and 0.5 ± 0.3-fold, respectively, between 0 and 8 h and 3 months. Conclusions: In our study, DKA was associated with profound aminoaciduria, suggestive of proximal tubular dysfunction analogous to Fanconi syndrome.

TG concentrations across lipoprotein subclasses associate with diabetic kidney disease (DKD) in adults with T1D, but little is known about this relationship in youth with T1D. We evaluated cross-sectional relationships among TG concentrations across lipoprotein subclasses, intraglomerular hemodynamics, and renal oxygen availability (RO2) in youth with T1D. Glomerular filtration rate (GFR) , RO2, renal plasma flow (RPF) , afferent arteriolar resistance (RA) , efferent arteriolar resistance (RE) , intraglomerular pressure (PGLO) , and urine albumin-to-creatinine ratio (UACR) were assessed. Concentrations of lipid constituents from lipoprotein subclasses were quantified via targeted nuclear magnetic resonance spectroscopy (Nightingale Health Ltd., Helsinki, Finland) . Particle sizes for VLDL, LDL, intermediate-density lipoprotein, and HDL were measured. Fifty youth with T1D (age 16.0 ± 3.0 years, 50% female, HbA1c 8.7 ± 1.3%, T1D duration 5.7 ± 2.6 years) and 20 without T1D were included. VLDL-TG concentrations and small LDL-TG correlated with intraglomerular hemodynamic function parameters and RO2. To conclude, strong relationships were found among renal function markers and TG concentrations across lipoprotein subclasses in adolescents with T1D. Disclosure M.E.Pauley: None. K.L.Tommerdahl: None. C.Vinovskis: None. L.Pyle: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. Funding MEP supported by NIH (T32DK063687) ; KLT supported by NIH (K23 HL159292) , Children’s Hospital Colorado Research Institute Research Scholar Award, University of Colorado Diabetes Research Center (P30 DK116073) , Ludeman Family Center for Women’s Health Research at the University of Colorado, and Dept of Pediatrics, Section of Endocrinology at University of Colorado School of Medicine; PB supported by NIDDK (RDK129211, R21 DK129720, K23 DK116720, UC DK114886, and P30 DK116073) , JDRF (2-SRA-2019-845-S-B, 3-SRA-2017-424-M-B, 3-SRA-2022-1097-M-B) , Boettcher Foundation, American Heart Association (20IPA35260142) , Ludeman Family Center for Women’s Health Research at the University of Colorado, Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine

Our objective was to compare renal hemodynamic function between obese youth with and without type 2 diabetes (T2D) and relate these measures to adipose insulin resistance (IR) . We assessed insulin sensitivity and kidney function in obese youth with (n=31, 15.8 ± 1.8 years, BMI 35.6 ± 6.6 kg/m2) , and without (n=20, 15.3 ± 2.1 years, BMI 38.2 ± 7.4 kg/m2) T2D. A hyperglycemic clamp was performed with 20% dextrose to maintain mild hyperglycemia for 240 minutes. Free fatty acids (FFA) were measured at baseline and every minutes during the steady state. FFA suppression (baseline FFA subtracted from steady state FFA) was used to estimate adipose IR. Iohexol and p-aminohippurate clearances were used to measure GFR and renal plasma flow, respectively. Renal hemodynamic parameters were calculated using Gomez equations. FFA suppression was attenuated in youth with T2D compared to obese controls (55.6% vs. 92.1%, p Youth with T2D had impaired FFA suppression compared to obese controls, indicating adipose IR. Impaired FFA suppression was associated with perturbed renal hemodynamics, indicating a potential role for adipose IR in the development of early diabetic kidney disease. Disclosure C.Platnick: None. P.V.Prasad: None. L.Li: None. L.Pyle: None. R.G.Nelson: None. D.Van raalte: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.

T2D is a global epidemic leading to excess cardiovascular (CV) mortality including heart failure (HF) . Strategies are emerging to prevent HF progression, so early detection is needed. We have identified preclinical cardiac dysfunction associated with central arterial stiffness and decreased cardiorespiratory fitness. We hypothesized that cardiac magnetic resonance (CMR) would identify changes in diabetes. Methods: Age and BMI-similar premenopausal women and men with (n=24) and without (n=30) uncomplicated T2D were studied. CMR for cardiac function, regionally resolved pulse wave velocity (PWV) via 2D phase-contrast MRI assessed proximal arterial stiffness, and carotid to femoral applanation tonometry PWV (C-F PWV) using SphygmoCor assessed global arterial stiffness. The vascular territories covered by SphygmoCor does not include the ascending aorta. Results: CMR showed significant changes consistent with cardiac dysfunction in T2D (Table 1) . PWV was significantly greater with T2D in the ascending and proximal descending aorta (p Conclusions: CMR detects early arterial stiffening in people with uncomplicated T2D and mild cardiac dysfunction. These findings support the use of CMR for detecting central arterial stiffness and incipient CV complications. Disclosure D.Enge: None. M.O.Whipple: None. K.S.Hunter: None. K.J.Nadeau: None. J.G.Regensteiner: None. A.J.Barker: None. J.Reusch: Advisory Panel; Medtronic. M.Schäfer: None. T.Fujiwara: None. E.Clark: None. E.Englund: None. R.L.Scalzo: None. D.Rafferty: None. I.E.Schauer: None. L.Abushamat: None. Funding National Institutes of Health (CX001532) University of Colorado Denver (NCT03419195) National Institutes of Health (R01-DK-124344) National Institutes of Health (K25HL119608)

Background: Global vascular dysfunction is well-recognized in youth with type 1 diabetes (T1D) , accentuating lifetime cardiovascular event risk and making therapeutic strategies to mitigate vascular dysfunction a high priority. In the BCQR-T1D study, we tested the hypothesis that BCQR, a medication used in obese adults with type 2 diabetes, would improve vascular health in T1D youth. Methods: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating cardiovascular and metabolic impacts of BCQR in T1D. Youth were randomized 1:1 to phase-1: 4-weeks of BCQR or placebo after which blood pressure (BP) , peripheral vascular stiffness by brachial artery distensibility (BrachD) , and central aortic stiffness by pulse wave velocity (PWV) , relative area change (RAC) and distensibility from phase-contrast MRI, were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. Results: Forty-two adolescents (mean age 15.9 years, HbA1c 8.6%, BMI %ile 71.4, T1D duration 5.8 years) with T1D were enrolled. Compared to placebo, BCQR therapy decreased systolic (∆ = -5 mmHg, p Conclusions: BCQR improved BP, central and peripheral aortic stiffness and pressure hemodynamics in T1D adolescents over 4 weeks vs. placebo, even if normal weight, supporting future longer-term studies. Disclosure M.Schäfer: None. I.E.Schauer: None. K.J.Nadeau: None. L.Browne: None. U.Truong: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. A.Baumgartner: None. K.S.Hunter: None. J.Reusch: Advisory Panel; Medtronic. A.J.Barker: None. Funding JDRF BROM QR THERP3-SRA-2015-125-M-R

BACKGROUND: Little is known regarding obstructive sleep apnea’s (OSA’s) prevalence or the factors related to OSA remission post–metabolic bariatric surgery (MBS) in adolescents. OBJECTIVES: To identify the baseline OSA prevalence in adolescents with severe obesity and examine factors associated with post-MBS OSA remission. SETTING: Tertiary-care children’s hospital. METHODS: We conducted a retrospective chart review of 81 patients pre-MBS with OSA assessments done between June 2017 to September 2020 to collect demographic characteristics; co-morbidities; polysomnography (PSG) results, if indicated; and weight data. Chi-square or Mann-Whitney tests compared baseline characteristics and surgical outcomes by pre-MBS OSA status. McNemar’s test or t tests assessed differences in baseline characteristics, stratified by remission versus no remission of OSA. RESULTS: The patients were 71% female, had an average age of 16.9 ± 2.0 years, and had a mean body mass index (BMI) of 47.9 ± 7.3 kg/m(2). Half (50%) of the patients were Hispanic and 20% had type 2 diabetes. The OSA prevalence, defined as an Obstructive Apnea Hypopnea Index (OAHI) score ≥5, was 54% pre-MBS (n = 44), with 43% having severe OSA (OAHI > 30). Those with OSA were older (17.3 versus 16.4 yr, respectively; P = .05), more likely to be male (79% versus 42%, respectively; P = .022), and had higher baseline weights (142.0 versus 126.4 kg, respectively; P = .001) than those without OSA. Of the 23 patients with a post-MBS PSG result (average 5 mo post MBS), 15 (66%) had remission of OSA. Patients with OSA remission had a lower average pre-MBS BMI (46.0 versus 57.7 kg/m(2), respectively; P < .001) and weight (132.9 versus 172.6 kg, respectively; P = .002) but no significant differences in percentage weight loss through 12 months post MBS versus those with continued OSA. CONCLUSION: The OSA prevalence in an adolescent MBS population was higher than that in the general adolescent population with severe obesity. Remission of OSA was correlated with lower pre-MBS BMI and weight, but not weight loss within the first year post-MBS. (Surg Obes Relat Dis 2021;17:711–717.)

Purpose: Up to 1.8% of youth identify as transgender; many will be treated with a gonadotropin-releasing hormone agonist (GnRHa). The impact of GnRHa on insulin sensitivity and body composition in transgender youth is understudied. We aimed to evaluate differences in insulin sensitivity and body composition in transgender youth on GnRHa therapy compared with cisgender youth. Methods: Transgender participants were matched to cisgender participants on age, body mass index, and sex assigned at birth. Transgender males (n=9, ages 10.1–16.0 years) on GnRHa (mean±standard deviation duration of exposure: 20.9±19.8 months) were compared with cisgender females (n=14, ages 10.6–16.2). Transgender females (n=8, ages 12.6–16.1) on GnRHa (11.3±7 months) were compared with cisgender males (n=17, ages 12.5–15.5). Differences in insulin sensitivity (1/[fasting insulin], homeostatic model of insulin resistance [HOMA-IR]), glycemia (hemoglobin A1C [HbA1c], fasting glucose), and body composition (dual-energy X-ray absorptiometry) were evaluated using a mixed linear regression model. Results: Transgender males had lower 1/fasting insulin and higher HOMA-IR (p=0.031, p=0.01, respectively), fasting glucose (89±4 vs. 79±13 mg/dL, p=0.012), HbA1c (5.4±0.2 vs. 5.2±0.2%, p=0.039), and percent body fat (36±7 vs. 32±5%, p=0.042) than matched cisgender females. Transgender females had lower 1/fasting insulin and higher HOMA-IR (p=0.028, p=0.035), HbA1c (5.4±0.1% vs. 5.1±0.2%, p=0.007), percent body fat (31±9 vs. 24±10%, p=0.002), and lower percent lean mass (66±8 vs. 74±10%, p

Context Youth-onset type 2 diabetes is a disease of pubertal onset, associated with additional burden of pubertal insulin resistance on the β-cell. Objective Evaluate the impact of metformin treatment during puberty, a critical window of cardiometabolic change, on insulin sensitivity (Si) and compensatory β-cell response in youth with obesity. Setting Pediatric academic hospital clinical translational research center. Participants Healthy youth in early puberty [Tanner stage (T) 2-3] with normoglycemia and obesity (n = 44). Intervention Double-blinded placebo-control trial of metformin during puberty (until T5). Main Outcome Measures Insulin sensitivity (Si), insulin response [acute insulin response to glucose (AIRg)], and disposition index (DI), estimated from frequently sampled intravenous glucose tolerance testing; body fat (dual X-ray absorptiometry); and other laboratory parameters, collected at baseline, T4, and T5. Placebo-subtracted treatment effect was calculated using linear mixed models. Results At T5, metformin treatment, adjusting for sex, race, and baseline value, was associated with improved BMI z-score (−0.44 ± 0.16, P = 0.02), percentage body fat (%body fat; −3.4 ± 1.2%, P = 0.06), and waist circumference (−11.3 ± 3.2cm, P = 0.003). There were no significant treatment effects at T5 on Si or secretion: Si (0.85 ± 0.87 × 10−4/min−1/μIU/mL, P = 0.34), AIRg (−259 ± 386 μIU/mL, P = 0.51), or DI (508 ± 802 × 10−4/min−1, P = 0.53). High baseline DI predicted longitudinal decline in DI. Conclusions Two years of metformin treatment in obese youth during puberty improved BMI and body fat, but not Si or β-cell function. Of note, high DI in early puberty may be predictive of later decline in DI. Further studies are needed to develop strategies for preservation of β-cell function in youth at risk for type 2 diabetes.

OBJECTIVE Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND METHODS Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. RESULTS Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or CONCLUSIONS In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.

OBJECTIVE We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS This was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp–measured IS and βCF at baseline and the change in glucose response curves 12 months after randomization were assessed. RESULTS At randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher βCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect. CONCLUSIONS Despite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve.

OBJECTIVE Insulin resistance and obesity are independently associated with type 1 diabetes (T1D) and are known risk factors for cardiovascular and kidney diseases, the leading causes of death in T1D. We evaluated the effect of BMI on cardiovascular and kidney outcomes in youth with T1D versus control youth with normal weight or obesity and youth with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Pubertal youth (n = 284) aged 12–21 years underwent assessments of resting heart rate (RHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), leptin, hs-CRP, adiponectin, ratio of urine albumin to creatinine, and estimated glomerular filtration rate. Participants with T1D underwent bicycle ergometry for VO2peak, monitoring for peripheral brachial artery distensibility (BAD), endothelial function testing for reactive hyperemic index, and aortic MRI for central arterial stiffness or shear. RESULTS In adolescents with T1D, RHR, SBP, DBP, mean arterial pressure, leptin, hs-CRP, and hypertension prevalence were significantly higher, and BAD, descending aorta pulse wave velocity, and VO2peak lower with an obese versus normal BMI. Although hypertension prevalence and RHR were highest in obese adolescents with T1D and adiponectin lowest in youth with T2D, other measures were similar between obese adolescents with T1D and those with T2D. CONCLUSIONS Obesity, now increasingly prevalent in people with T1D, correlates with a less favorable cardiovascular and kidney risk profile, nearly approximating the phenotype of youth with T2D. Focused lifestyle management in youth-onset T1D is critically needed to reduce cardiovascular risk.

Youth with type 1 diabetes (T1D) demonstrate insulin resistance, independently of glycaemia, when compared to normoglycaemic peers. Insulin resistance increases the risk of cardiovascular disease and diabetic kidney disease, factors also associated with systemic inflammation. We evaluated the effect of metformin on markers of inflammation and diabetic kidney disease in adolescents with T1D. EMERALD, a double-blind, randomized, placebo-controlled trial of 3 months of metformin in 48 participants aged 12-21 years with T1D, included baseline and follow-up assessments of serum creatinine and cystatin C to estimate glomerular filtration rate (eGFR), aspartate aminotransferase, alanine aminotransferase, high-sensitivity C-reactive protein, white blood count, platelets, adiponectin, leptin, and urine albumin: creatinine ratio (UACR). Metformin was associated with a 13.9 mL/min/1.73 m2 (95% confidence interval 4.7-23.1 mL/min/1.73 m2 ) increase in estimated GFR by serum creatinine versus placebo (P ≤ 0.01), with a significant difference remaining after multivariable adjustments (P = 0.03). Whereas eGFR measured by serum creatinine increased significantly after metformin treatment, no differences were observed in cystatin C, UACR, or systemic inflammatory markers. Additional studies with directly measured GFR in response to metformin in T1D are needed.

The extent to which weight loss contributes to increases in insulin sensitivity (IS) and β-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes.The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and β-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time.BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of β-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on β-cell function.Reducing demand on the β-cell by improving IS through weight loss does not reverse β-cell dysfunction. L + M was the only treatment that enhanced β-cell function.

Background: Early identification of youth with type 1 diabetes (T1D) at risk for diabetic kidney disease may improve clinical outcomes. We examined the cross-sectional relationship between kidney biomarkers neutrophil gelatinase–associated lipocalin (NGAL), copeptin, interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), chitinase-3-like protein-1 (YKL-40), and monocyte chemoattractant protein-1 (MCP-1) and intrarenal hemodynamic function in adolescents with T1D. Methods: Urine albumin-to-creatinine ratio (UACR), renal vascular resistance (RVR), glomerular filtration rate (GFR), intraglomerular pressure (P GLO), efferent arteriole resistance (R E), afferent arteriolar resistance (R A), and renal plasma flow (RPF), and the above indicated biomarkers were assessed in youth aged 12–21 years with and without T1D of < 10 years duration. Results: Fifty adolescents with T1D (16.1 ± 3.0 years, HbA1c 8.6 ± 1.2%) and 20 adolescents of comparable BMI without T1D (16.1 ± 2.9 years, HbA1c 5.2 ± 0.2%) were enrolled. Adolescents with T1D demonstrated significantly higher GFR, RPF, R E, and P GLO than controls (39%, 33%, 74%, and 29%, respectively, all p < 0.0001). Adolescents with T1D also exhibited significantly lower RVR and R A than controls (25% and 155%, respectively, both p < 0.0001). YKL-40 and KIM-1 concentrations, respectively, were positively associated with GFR (r: 0.43, p = 0.002; r: 0.41, p = 0.003), RPF (r: 0.29, p = 0.08; r: 0.34, p = 0.04), UACR (r: 0.33, p = 0.02; r: 0.50, p = 0.0002), and P GLO (r: 0.45, p = 0.006; r: 0.52, p = 0.001) in adolescents with T1D. Conclusions: Higher concentrations of biomarkers YKL-40 and KIM-1 may help define the risk for intraglomerular hemodynamic dysfunction in youth with T1D. Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information. [Figure not available: see fulltext.]

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/m(2), 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/m(2), P = .002). Within IGT, glucose sensitivity (Y-IGT 140 ± 153 vs A-IGT 112 ± 70 pmol/min/m(2)/mM, P = .004) and rate sensitivity (median[interquartile range]:Y-IGT 2271[1611, 3222] vs A-IGT 1164[685, 1565] pmol/m(2)/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.

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10–17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1–5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.

BackgroundExcess gestational weight gain (GWG) in pregnant adolescents is a major public health concern. Excess GWG increases risk of pregnancy complications as well as postpartum and offspring obesity and cardiometabolic disease. Prevention interventions for pregnant adults that target lifestyle modification (i.e., healthy eating/physical activity) show insufficient effectiveness. Pregnant adolescents have distinct social-emotional needs, which may contribute to excess GWG. From an interpersonal theoretical framework, conflict and low social support increase negative emotions, which in turn promote excess GWG through mechanisms such as overeating and physical inactivity.MethodsThe current manuscript describes the design of a pilot randomized controlled feasibility trial of adolescent interpersonal psychotherapy (IPT) to address social-emotional needs and prevent excess GWG. Up to 50 pregnant, healthy adolescents 13-19y, 12-18 weeks gestation are recruited from an interdisciplinary adolescent maternity hospital clinic and randomized to IPT + usual care or usual care alone. IPT involves 6 individual 60-minute sessions delivered by a trained behavioral health clinician during 12-30 weeks gestation. Sessions include relationship psychoeducation, emotion identification and expression, and teaching/role-playing communication skills. Between sessions, adolescents are instructed to complete a daily journal and to have conversations to work on relationship goals. Outcomes are assessed at baseline, mid-program, post-program, and 3-months postpartum. Primary outcomes are feasibility and acceptability based upon rate of recruitment, session attendance, program acceptability ratings, and follow-up retention. Secondary outcomes are perinatal social functioning, stress, depression, and eating behaviors assessed with validated surveys and interviews; perinatal physical activity and sleep measured via accelerometer; GWG from measured weights; and at 3-months postpartum only, maternal adiposity by dual energy x-ray absorptiometry, maternal insulin sensitivity derived from 2-hour oral glucose tolerance testing, and infant adiposity by air displacement plethysmography.DiscussionThis pilot trial will address a key gap in extant understanding of excess GWG prevention for a high-risk population of adolescents. If feasible and acceptable, brief psychotherapy to address social-emotional needs should be tested for its effectiveness to address excess GWG and postpartum maternal/infant health. If effective, such an approach has potential to interrupt an adverse, intergenerational cycle of social-emotional distress, obesity, and cardiometabolic disease among young mothers and their offspring.Trial registrationClinicalTrials.govNCT03086161, retrospectively registered

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 (Si) 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 Si, insulin response (acute insulin response to glucose, AIRg) and disposition index (DI) by intravenous glucose tolerance test at baseline (T2-T3), T4, and T5 Results Youth with obesity had significantly lower Si and higher AIRg at each time point (P Conclusions Obesity significantly impacts Si during puberty, even at the earliest stages. However, in general, obese youth have adequate β-cell compensation for the significantly reduced Si of puberty. Future studies are needed to better predict the subset of youth who fail to maintain β-cell compensation during puberty.

Context Cardiovascular disease (CVD) is a major cause of mortality in adults with type 1 diabetes. Objective We prospectively evaluated CVD risk factors in a large, contemporary cohort of adults with type 1 diabetes living in the United States. Design Observational study of CVD and CVD risk factors over a median of 5.3 years. Setting The T1D Exchange clinic network. Patients Adults (age ≥ 18 years) with type 1 diabetes and without known CVD diagnosed before or at enrollment. Main Outcome Measure Associations between CVD risk factors and incident CVD were assessed by multivariable logistic regression. Results The study included 8,727 participants (53% female, 88% non-Hispanic white, median age 33 years [interquartile ratio {IQR} = 21, 48], type 1 diabetes duration 16 years [IQR = 9, 26]). At enrollment, median HbA1c was 7.6% (66 mmol/mol) (IQR = 6.9 [52], 8.6 [70]), 33% used a statin, and 37% used blood pressure medication. Over a mean follow-up of 4.6 years, 325 (3.7%) participants developed incident CVD. Ischemic heart disease was the most common CVD event. Increasing age, body mass index, HbA1c, presence of hypertension and dyslipidemia, increasing duration of diabetes, and diabetic nephropathy were associated with increased risk for CVD. There were no significant gender differences in CVD risk. Conclusion HbA1c, hypertension, dyslipidemia and diabetic nephropathy are important risk factors for CVD in adults with type 1 diabetes. A longer follow-up is likely required to assess the impact of other traditional CVD risk factors on incident CVD in the current era.