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Context The oral minimal model is a widely accepted noninvasive tool to quantify both β-cell responsiveness and insulin sensitivity (SI) from glucose, C-peptide, and insulin concentrations during a 3-hour 9-point oral glucose tolerance test (OGTT). Objective Here, we aimed to validate a 2-hour 7-point protocol against the 3-hour OGTT and to test how variation in early sampling frequency impacts estimates of β-cell responsiveness and SI. Methods We conducted a secondary analysis on 15 lean youth with stage 1 type 1 diabetes (T1D; ≥ 2 islet autoantibodies with no dysglycemia) who underwent a 3-hour 9-point OGTT. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI = φtotal × SI). Seven- and 5-point 2-hour OGTT protocols were tested against the 3-hour 9-point gold standard to determine agreement between estimates of φtotal and its dynamic and static components, SI, and DI across different sampling strategies. Results The 2-hour estimates for the disposition index exhibited a strong correlation with 3-hour measures (r = 0.975; P < .001) with similar results for β-cell responsiveness and SI (r = 0.997 and r = 0.982; P < .001, respectively). The agreement of the 3 estimates between the 7-point 2-hour and 9-point 3-hour protocols fell within the 95% CI on the Bland-Altman grid with a median difference of 16.9% (−35.3 to 32.5), 0.2% (−0.6 to 1.3), and 14.9% (−1.4 to 28.3) for DI, φtotal, and SI. Conversely, the 5-point protocol did not provide reliable estimates of φ dynamic and static components. Conclusion The 2-hour 7-point OGTT is reliable in individuals with stage 1 T1D for assessment of β-cell responsiveness, SI, and DI. Incorporation of these analyses into current 2-hour diabetes staging and monitoring OGTTs offers the potential to more accurately quantify risk of progression in the early stages of T1D.

Context The “carbohydrate-insulin model” claims that adipose tissue insulin sensitivity explains development of obesity via adipocyte energy storage and/or low postprandial metabolic fuel levels. Objective We tested whether adipose tissue insulin sensitivity predicts changes in the degree of obesity over time. Methods This secondary analysis of an observational study of youth with obesity included 213 youths at a pediatric weight management clinic. Adipose tissue insulin sensitivity/resistance and whole-body insulin sensitivity were evaluated using oral glucose tolerance test (OGTT)-derived surrogates in the face of changes in the degree of obesity over time. The main outcome measure was change in body mass index (BMI) z score. Results Mean BMI z change was 0.05 ± 0.28 (range, −1.15 to 1.19), representing a broad distribution of changes in the degree of obesity over a follow-up period of 1.88 ± 1.27 years. Adipose tissue insulin resistance was not associated with changes in the degree of obesity in univariate or multivariate analyses (adjusted for baseline age, BMI z score, sex, ethnicity, and time of follow-up). Low postprandial free fatty acid concentrations or their suppression during the OGTT were not associated with changes in the degree of obesity in univariate or multivariate analyses. Whole-body insulin sensitivity was not associated with changes in the degree of obesity in univariate or multivariate analyses. Conclusion In this secondary analysis, in youth with obesity, adipose tissue insulin resistance is not protective from increases of the degree of obesity and skeletal muscle insulin resistance is not associated with increases of the degree of obesity. The analysis was performed using data derived from NCT00000112 and NCT00536250.

To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth.Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging.Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of β-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and β-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, β-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and β-cell function.We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D).This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion ofA total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion ofAlthough the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of

Background The main purpose of the study is to assess the association between obstructive sleep apnea (OSA) and insulin secretion in children with obesity. Methods We enrolled children and adolescents who attended our pediatric clinic because of obesity and OSA. Glucose homeostasis was assessed through standard 2-h oral glucose tolerance test (OGTT). Nocturnal cardio-respiratory polygraphy was performed for OSA diagnosis. Twenty-two patients underwent a 3-h OGTT to investigate insulin secretion and sensitivity through the oral-minimal model. Results seventy-seven children and adolescents were included in the study. Based on OSA severity, the cohort was divided into three groups (29 mild, 29 moderate, and 19 severe OSA). The group with mild OSA showed lower levels of 30-min glucose (p = 0.01) and 60-min glucose (p = 0.03), and lower prevalence of elevated 1-h glucose (10.4% versus 44.8% in moderate and 31.6% in severe OSA, p = 0.01). The odds for elevated 1-h plasma glucose was 6.2-fold (95%CI 1.6–23.4) higher in subjects with moderate and severe OSA compared to mild OSA (p = 0.007) independent of confounders. Spearman correlation test revealed a positive correlation between 30-min plasma glucose and apnea-hypopnea index (AHI, r = 0.31, p = 0.01), oxygen desaturation index (ODI, r = 0.31, p = 0.009), and mean desaturation (r = 0.25, p = 0.04). The 3-h OGTT study included 22 participants (7 mild, 9 moderate, and 6 severe OSA). The group with mild OSA showed a higher dynamic, static, and total insulin secretion compared to those with moderate and severe OSA (p p = 0.007, p = 0.007, respectively). AHI was significantly correlated to dynamic insulin secretion (r = −0.48, p = 0.02). Conclusions OSA might impair beta-cell function reducing the pool of promptly releasable insulin in children and adolescents with obesity, in the absence of an effect on insulin sensitivity.

The oral minimal model is a widely accepted noninvasive tool to quantify both β-cell responsiveness and insulin sensitivity from glucose, C-peptide and insulin concentrations during a 3-h 9-point oral glucose tolerance test (OGTT). Here, we aimed to validate a 2-h 7-point protocol against the 3-h OGTT and to test how variation in early sampling frequency impacts estimates of β-cell responsiveness and insulin sensitivity.We conducted a secondary analysis on 15 lean youth with stage 1 T1D (≥2islet autoantibodies with no dysglycemia) who underwent a 3-h 9-point OGTT. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI=φtotal × SI). Seven- and 5-point 2-h OGTT protocols were tested against the 3-h 9-point gold standard to determine agreement between estimates of φtotal and its dynamic and static components, SI, and DI across different sampling strategies.The 2-h estimates for the disposition index exhibited a strong correlation with 3-h measures (r = 0.975, p 0.001) with similar results for β-cell responsiveness and insulin sensitivity (r = 0.997 and r = 0.982, p 0.001, respectively). The agreement of the three estimates between the 7-point 2-h and 9-point 3-h protocols fell within the 95% CI on the Bland-Altman grid with a median difference of 16.9%(-35.3, 32.5), 0.2%(-0.6, 1.3) and 14.9%(-1.4, 28.3) for DI, φtotal and SI. Conversely, the 5-point protocol did not provide reliable estimates of φ dynamic and static components.The 2-h 7-point OGTT is reliable in subjects with Stage 1 T1D for assessment of β-cell responsiveness, insulin sensitivity, and disposition index. Incorporation of these analyses into current 2-h diabetes staging and monitoring OGTTs offers the potential to more accurately quantify risk of progression in the early stages of T1D.

Background: We assessed the longitudinal trajectory of beta-cell function with respect to baseline incretin effect in youth with obesity. Methods: At baseline and two years, youth with obesity and 2-h glucose ≥ 120mg/dL underwent a 3-hour OGTT and isoglycemic intravenous glucose infusion (to quantify the incretin effect) . Participants were stratified into three tertiles based on the baseline incretin effect. The oral minimal model quantified beta cell function (oDI) and insulin sensitivity (SI) . Results: Thirty participants completed the assessments [follow-up: age 18.6±2.4y, 19F; BMI 38.6±7.4 kg/m2, NGT/IGT/T2D 12/17/1]. At 2 years, 2-h glucose improved in the high incretin group (p=0.047) , but was stable in the middle- and low- incretin groups (panel G) . At 2 years, the baseline high-incretin group exhibited a lower 60-min glucose (p=0.026) than the low-incretin group, with similar 120-min glucose (p=0.696) , despite the low-incretin cohort’s relative increase in early insulin secretion (panel D, F) . The low-incretin tertile also exhibited a reduced β cell function (oDI) at follow-up (panel I) (p=0.044) mainly due to lower insulin sensitivity (panel H) (p=0.013) . Conclusion: Low incretin effect is associated with a longitudinal decline of beta cell function and decreased insulin sensitivity, despite greater first-phase insulin secretion. Disclosure A.Galderisi: None. J.O.Lat: None. S.Samuels: None. B.Pierpont: None. M.A.Van name: Research Support; Provention Bio, Inc. N.Santoro: None. S.Caprio: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS (16-004945)

OBJECTIVE The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. RESEARCH DESIGN AND METHODS Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT − AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. RESULTS The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [−7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. CONCLUSIONS A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.

Background: The objective of this study was to assess the safety and performance of the Omnipod® personalized model predictive control (MPC) algorithm in adults, adolescents, and children aged ≥6 years with type 1 diabetes (T1D) under free-living conditions using an investigational device. Materials and Methods: A 96-h hybrid closed-loop (HCL) study was conducted in a supervised hotel/rental home setting following a 7-day outpatient standard therapy (ST) phase. Eligible participants were aged 6–65 years with A1C

Background Intraperitoneal insulin delivery has proven to safely overcome a major limit of subcutaneous delivery—meal announcement—and has been able to optimize glycemic control in adults under controlled experimental conditions. In addition, intraperitoneal delivery avoids peripheral hyperinsulinemia resulting from the subcutaneous route and restores a physiological liver gradient. Methods Relying on a unique data set of intraperitoneal closed-loop insulin delivery obtained with a Model Predictive Controller (MPC), we develop a compartmental model of intraperitoneal insulin kinetics, which, once included in the UVa/Padova T1D simulator, will facilitate the investigation of various control strategies, for example, the simpler Proportional Integral Derivative controller versus MPC. Results Intraperitoneal insulin kinetics can be described with a 2-compartment model including liver and plasma. Conclusion Intraperitoneal insulin transit is fast enough to render irrelevant the addition of a peritoneal compartment, proving the peritoneum being a virtual—not actual—transit space for insulin delivery.

OBJECTIVE The carbohydrate-insulin model (CIM) claims that chronic exposure to hyperinsulinemia induced by dietary carbohydrates explains development of obesity via direct effects of insulin and/or low postprandial metabolic fuel levels. We aimed at testing whether indices of hyperinsulinemia and postprandial glucose levels can predict increases in the degree of obesity over time. RESEARCH DESIGN AND METHODS Children and adolescents with obesity attending a pediatric obesity clinic performed oral glucose tolerance tests (OGTTs) and received standard obesity management. Indices of hyperinsulinemia and insulin secretion were derived from the OGTT and evaluated in the face of changes in the degree of obesity over time. RESULTS A total of 591 children (217 males and 374 females) participated, and the mean follow-up was 1.86 ± 1.29 years. OGTT-derived area under the curve of insulin, peak insulin, fasting insulin, the insulinogenic index, or insulin at 30 min were not associated with greater changes in the degree of obesity in univariate or multivariate analyses (adjusted for baseline age, BMI z score, sex, and ethnicity). Low postprandial glucose 4 years, none of these parameters was associated with greater increases in the degree of obesity. CONCLUSIONS In children and adolescents with obesity, exposure to hyperinsulinemia, greater insulin secretion, or low postprandial glucose is not associated with greater increases in the degree of obesity over 2–4 years. The CIM should be evaluated in children with lower BMI and for longer follow-up periods.

Insulin-resistant diabetes in Rabson–Mendenhall syndrome (RMS) is relatively unresponsive to first-line antidiabetic treatments, including metformin and insulin. We report 2 patients with RMS treated with 2 different sodium-glucose cotransporter inhibitors 2: empagliflozin in an 11-year-old boy and dapagliflozin in a 12-year-old girl. In the first patient, we began empagliflozin at 2.5 mg/day and increased the dose to 10 mg/day over 3 months. During treatment with empagliflozin, the amount of time during which the patient maintained serum glucose in the 70 to 180 mg/dL target range increased by 2 hours per day. Hemoglobin A1C dropped from >14% to 11.9%, urinary calcium increased almost twofold, and β-hydroxybutyrate remained 50%. In 2 patients with RMS, empagliflozin and dapagliflozin were well tolerated and improved glycemic control without significantly increasing ketonemia. Renal calcium excretion should be carefully monitored.

OBJECTIVE In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling. RESULTS Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity. CONCLUSIONS We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.

The objective of this study is to assess the effect of neonatal procedures on glucose variability in very preterm infants. Preterm infants (≤ 32 weeks gestation and/or birthweight ≤ 1500 g) were started on continuous glucose monitoring (CGM) on day 2 of birth and monitored for 5 days. Minimally invasive (heel stick, venipunctures) and non-invasive (nappy change, parental presence) procedures were recorded. CGM data were analyzed 30 min before and after each procedure. The primary outcome was the coefficient of glucose variation (CV = SD/mean) before and after the procedure; SD and median glucose were also evaluated. We analyzed 496 procedures in 22 neonates (GA 30.5 weeks [29–31]; birthweight 1300 g [950–1476]). Median glucose did not change before and after each procedure, while CV and SD increased after heel prick (p = 0.017 and 0.030), venipuncture (p = 0.010 and 0.030), and nappy change (p Conclusions: Non-invasive and minimally invasive procedures increase glucose variability in the absence of changes of mean glucose. What is Known:• Minimally invasive procedures - including nappy change - may increase neonatal stress in preterm infants. What is New:• Continuous glucose monitoring provides a quantitative measure of neonatal stress during neonatal care procedures demonstrating an increase of glucose variability.

BACKGROUND: Preterm infants are susceptible to hyperglycemia and hypoglycemia, conditions which may lead to adverse neurodevelopment. The use of continuous glucose monitoring devices (CGM) might help keeping glucose levels in the normal range, and reduce the need for blood sampling. However, the use of CGM might be associated with harms in the preterm infant. OBJECTIVES: Objective one: to assess the benefits and harms of CGM alone versus standard method of glycemic measure in preterm infants. Objective two: to assess the benefits and harms of CGM with automated algorithm versus standard method of glycemic measure in preterm infants. Objective three: to assess the benefits and harms of CGM with automated algorithm versus CGM without automated algorithm in preterm infants. SEARCH METHODS: We adopted the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9), in the Cochrane Library; MEDLINE via PubMed (1966 to 25 September 2020); Embase (1980 to 25 September 2020); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 25 September 2020). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomized controlled trials and quasi‐randomized trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi‐RCTs in preterm infants comparing: 1) the use of CGM versus intermittent modalities to measure glycemia (comparison 1); or CGM associated with prespecified interventions to correct hypoglycemia or hyperglycemia versus CGM without such prespecified interventions (comparison 2). DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of included trials using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria (assessing randomization, blinding, loss to follow‐up, and handling of outcome data). We evaluated treatment effects using a fixed‐effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: Four trials enrolling 138 infants met our inclusion criteria. Investigators in three trials (118 infants) compared the use of CGM to intermittent modalities (comparison one); however one of these trials was analyzed separately because CGM was used as a standalone device, without being coupled to a control algorithm like in the other trials. A fourth trial (20 infants) assessed CGM with an automated algorithm versus CGM with a manual algorithm. None of the four included trials reported the neurodevelopmental outcome, i.e. the primary outcome of this review. Within comparison one, the certainty of the evidence on the use of CGM on mortality during hospitalization is very uncertain (typical RR 3.00, 95% CI 0.13 to 70.30; typical RD 0.04, 95% CI ‐0.06 to 0.14; 50 participants; 1 study; very low certainty). The number of hypoglycemic episodes was reported in two studies with conflicting data. The number of hyperglycemic episodes was reported in one study (typical MD ‐1.40, 95% CI ‐2.84 to 0.04; 50 participants; 1 study). The certainty of the evidence was very low for all outcomes because of limitations in study design, and imprecision of estimates. Three studies are ongoing. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if CGM improves preterm infant mortality or morbidities. Long‐term outcomes were not reported. Clinical trials are required to determine the most effective CGM and glycemic management regimens in preterm infants before larger studies can be performed to assess the efficacy of CGM for reducing mortality, morbidity and long‐term neurodevelopmental impairments. The absence of CGM labelled for neonatal use is still a major limit in its use as well as the absence of dedicated neonatal devices.

Long-term survivors of bronchopulmonary dysplasia develop chronic obstructive lung disease. Herein we report in vivo histopathology from bronchial biopsies of 3 adolescent survivors of severe bronchopulmonary dysplasia. Thickened basement membranes with lymphocytic infiltrates and signs of immature neoangiogenesis in the absence of T-helper lymphocytes or eosinophils suggest the presence of an ongoing active airway process.

Background: Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoimmunity with normal glucose tolerance (Stage 1 T1D), followed by dysglycemia (Stage 2). The metabolic phenotypes of beta-cell function and insulin sensitivity were explored in normoglycemic youth with stage 1 T1D and compared to healthy non-related peers during a 3-h oral glucose tolerance test (OGTT). Methods: Participants were recruited from TrialNet (cases) and Yale University (controls). Twenty-eight lean youth with at least two islet autoantibody (cases) and 32 healthy controls underwent a 3-hour 9-point OGTT with measurement of glucose, C-peptide and insulin. The oral minimal model was used to quantitate beta-cell responsivity (Phitotal) and insulin sensitivity (SI), allowing assessment of beta-cell function by the disposition index, DI=Phitotal x SI. Subjects with impaired fasting glucose, impaired glucose tolerance or any OGTT glucose concentration >200mg/dL were excluded. Results: Cases (10.5y[8, 15]) exhibited reduced DI (p Conclusion: Pre-symptomatic stage 1 T1D is associated with both reduced insulin sensitivity and lower beta cell responsiveness in youth. Disclosure A. Galderisi: None. A. Moran: Advisory Panel; Self; Dompe, Novo Nordisk, Research Support; Self; Abbott Diabetes, Intrexon, Provention Bio, Inc. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. M. Martino: None. N. Santoro: None. S. Caprio: None. C. Cobelli: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD40787, R01DK111038, R01HD28016, R01DK114504); National Center for Research Resources (UL1RR0249139); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK111038); Diabetes Research Center (P30DK045735, R01DK114504-01A, K12AWDA10768, GR103182); National Institutes of Health (U01DK085476, UL1TR002494, U01DK085505); Fondazione Cassa di Risparmio di Padova e Rovigo (2018); European Commission (EU951933)

Studies suggest that Indian Americans (IA) living in US have higher basal insulin resistance than other ethnic groups thereby increasing risk for T2DM. To characterize glucose metabolism between IA to Indians (I) living in India, we studied thirty-one Indians recruited at the Chellaram Hospital in Pune, India and twenty Indian Americans at Mayo Clinic, MN. All underwent a 3-hour 9-point OGTT with analyses of glucose, insulin and C-peptide. The oral minimal model was used to estimate β-cell function (φtotal) and insulin sensitivity (SI), with assessment of β-cell responsivity (Disposition Index: DI). Insulin clearance was calculated as AUC of insulin secretion rate over insulin concentrations. Both I and IA were similar with respect to age (33±7 vs. 39±13y), BMI (25.0±1.8 vs. 24.7± 3.2kg/m2) and sex (13F and 9F) respectively. Results are in fig 1. Fasting and iAUC glucose did not differ between groups (p=0.478), while integrated C-peptide and Insulin concentrations were higher in I than IA (p Disclosure V. Purandare: None. A. Galderisi: None. M. Maertino: None. A. Basu: None. C. Cobelli: None. A. Unnikrishnan: Advisory Panel; Self; Sanofi-Aventis, Other Relationship; Self; Novo Nordisk A/S, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.)

While there is clear evidence of an association between psoriasis and type 2 diabetes mellitus1 , limited information is available on the prevalence of psoriasis in children and adolescents with type 1 diabetes mellitus (T1D).2.

Childhood obesity is associated with later development of significant renal morbidity. We evaluated the impact of the degree of insulin sensitivity on estimated glomerular filtration rate (eGFR) and determined the factors associated with eGFR in obese children. We further tested the relation of eGFR to clinical outcomes such as blood pressure and microalbuminuria. We evaluated the relation of whole body insulin sensitivity and estimated glomerular filtration rate (eGFR) across the spectrum of obesity in children and adolescents. eGFR was calculated using the iCARE formula, which has been validated in obese children with varying glucose tolerance. 1080 children and adolescents with overweight and obesity (701 females and 379 males) participated. Insulin sensitivity was a strongly negatively associated with (B = −2.72, p

Background. The risk genotype for the common variant rs7903146 of the transcription factor-7-like-2 gene (TCF7L2) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. Methods Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m2) were genotyped for the rs7903146 of TCF7L2 and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100*(AUC-SROGTT – AUC-SRiso-IVGTT)/AUC-SROGTT [AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype. Results The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p Conclusion A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal.

In the aftermath of the SARS-CoV-2 pandemic, we revised the cost-effectiveness of the exploited interventions in neonatal intensive care unit, to redefine future strategies for hospital management. Costs were revised with respect to the lockdown R0 or under different R0 scenarios to estimate the cost-effectiveness of the screening program adopted. Weekly nasopharyngeal swabs for parents, neonates, and personnel were the major cost during the pandemic, although they effectively reduced the number of cases in our unit. Conclusion: Parents and healthcare personnel testing appears to be an effective strategy due to the high number of contact they have within the hospital environment and outside, able to minimize the cases within our unit.What is Known:• Costs of universal COVID-19 tests for parents, neonates, and NICU personnel have not been evaluated during the COVID-19 pandemic in neonatal intensive care unit in Europe.What is New:• Weekly nasopharyngeal swabs for parents, neonates, and personnel were the major cost during the COVID-19 pandemic in NICU.• Parents and healthcare personnel testing was effective to reduce costs related to COVID-19 due to the high number of contact they have within the hospital environment and outside. Supplementary Information The online version contains supplementary material available at 10.1007/s00431-020-03884-1.

Psoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3–10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance.Conclusion: Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known:• Psoriasis in adults is strongly associated with metabolic disease and insulin resistance.• Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis. What is New:• This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance.• In children with psoriasis metabolic syndrome risk factors should be assessed.

E-cigarettes (e-cigs) have been initially proposed as an aid to smoke cessation in adults, whereas they turned into a paradoxical preferential gateway to tobacco and nicotine initiation for adolescents naive to tobacco. More than 25% of US school-age students is an e-cigs user with a steep rise over the past years. A marketing strategy on media and social network targeting youths, in the absence of rules to protect the pediatric users, resulted in an unprecedented trend up in tobacco consumption among adolescents and gave rise to a new generation of nicotine-addicted teenagers. Flavored e-cigs liquids and aerosols contain airway irritants and toxicants, that, in turn, produced an increase in asthma prevalence and its exacerbations among adolescents. In addition, since August 2019 an outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) has been described. In view of this, e-cigs must no longer be considered harmless, especially in adolescents never used a tobacco product before. This is a call-for-action to establish effective rules and campaigns targeting youths aimed to limit their access to e-cigs, thereby preserving the potential benefit in quitting tobacco addiction described in adults. Behavioral and educational actions, out of the conventional primary care setting, have been described as a model for a youth-centered campaign. We call for stricter regulations on e-cigs products, with respect to their marketing to the youngest ones, along with public health and primary care interventions that could curb the spread of this "vaping" epidemic.

Customization of glucose targets in hybrid closed-loop (HCL) systems is important to enable tailored glucose management and safe onboarding across a wide range of users. The safety and performance of the Omnipod HCL personalized model predictive control (MPC) algorithm were assessed with a lower target of 110mg/dL for the first time in children aged 2-12y with type 1 diabetes (T1D) using an investigational device. Participants with A1C Participants (n=12) were (mean±SD): age 6.8±3.1y, T1D duration 3.7±2.9y, and A1C 7.1±0.7%. Despite 1-2 missed meal bolus challenges (mean 43g, range 18-88g CHO), percent time 70-180mg/dL was 76.6±7.2% and 80.4±9.9% with targets of 110mg/dL and 120mg/dL respectively. Outcomes were similar between the targets for mean glucose and time in glycemic ranges (Table). There were no serious adverse events. The Omnipod personalized MPC algorithm performed well and was safe in children aged 2-12y with T1D when tested at a target of 110mg/dL, even when stress-tested under challenging conditions. This algorithm is being evaluated in an at-home pivotal study with targets 110-150mg/dL. Disclosure J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Cecelia Health. Consultant; Self; Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi, T1D Exchange. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. G.P. Forlenza: Advisory Panel; Self; Medtronic. Consultant; Self; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. A. Galderisi: None. L. Ekhlaspour: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company, Medtronic. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, MannKind Corporation, Medtronic, Novo Nordisk Inc., Tandem Diabetes Care. M. Zgorski: None. R.S. Kingman: None. C. Berget: None. J. Lee: Employee; Self; Insulet Corporation. J.B. OConnor: None. B. Dumais: Employee; Self; Insulet Corporation. T. Vienneau: Employee; Self; Insulet Corporation. Stock/Shareholder; Self; Insulet Corporation. L.M. Huyett: Employee; Self; Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation. Funding Insulet Corporation

Prediabetes and type 2 diabetes in obese youths are associated with a reduced incretin effect. Herein, we investigated the metabolic and genetic determinants of incretin effect in obese youths with normal and impaired glucose tolerance. We studied 35 obese youth (15.8±2.4y, BMI 39.9±6.1kg/m2, NGT/IGT 18/17, F/M 18/17). All participants were genotyped for the TCF7L2 rs7903146 variant and underwent: A) 180-minutes OGTT and a matched iso-glycemic intravenous glucose tolerance test (iso-IVGTT) to estimate the incretin effect, by modelling of C-peptide secretion (SR), and insulin sensitivity (SI) by the oral minimal model; B) a hyperglycemic clamp with arginine stimulation to estimate insulin secretion independently from the oral phase. Incretin effect was measured as (SROGTT-SRiso-IVGTT)/SROGTT. Insulin clearance (CL) was computed as SROGTT-[Vx insulin]/AUCInsulin-OGTT. Determinants of the Incretin effect were assessed by multivariate logistic regression.Insulin clearance (p=0.004), T allele for TCF7L2 (p=0.018) and 2-h glucose (p=0.035) were independent determinants of the incretin effect (Figure A), with an increase in insulin clearance associated with greater incretin effect (Figure B). Lower insulin clearance, higher 2-h glucose and the risk-genotype of TCF7L2 rs7903146 are associated with a lower incretin effect in obese adolescents with prediabetes. Disclosure A. Galderisi: None. S. Samuels: None. B. Pierpont: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. N. Santoro: None. S. Caprio: None. Funding National Institutes of Health (R01DK111038); Patterson Foundation

OBJECTIVE: The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. RESEARCH DESIGN AND METHODS: Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m(2)) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SR(OGTT) − AUC-SR(iso-IVGTT)) / AUC-SR(OGTT), where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. RESULTS: The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [−7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. CONCLUSIONS: A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.