Achieving ADA/ISPAD clinical guideline goals is associated with higher insulin sensitivity and cardiopulmonary fitness in adolescents with type 1 diabetes: Results from RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) Studies.

OBJECTIVE: Most youth with type 1 diabetes do not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for hemoglobin A1c (HbA1c), blood pressure (BP), lipids, and body mass index (BMI). We hypothesized that ISPAD/ADA goal achievement would be associated with better insulin sensitivity (IS) and cardiopulmonary fitness. METHODS: IS was quantified as glucose infusion rate (GIR) from a hyperinsulinemic-euglycemic clamp in youth with type 1 diabetes from the RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) (n = 86) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) (n = 41) cohorts (n = 127; age 15.7 ± 2.2 years, 52% girls). Cardiopulmonary fitness was measured as peak oxygen consumption (VO2 peak/kg) during upright (RESISTANT) or supine (EMERALD) cycle ergometry and were stratified by cycle type. Goal achievement was defined as HbA1c < 7.5%, BP < 90th percentile, LDL-cholesterol < 100 mg/dL, HDL-cholesterol > 35 mg/dL, triglycerides < 150 mg/dL and BMI < 85th percentile. Participants were stratified into 3 groups: achieving 0-3 goals (n = 52), 4 goals (n = 48), and 5-6 goals (n = 27). Differences between groups were examined with generalized linear models. RESULTS: IS was lower in youth who met 0-3 goals (5.2 ± 3.4 mg/kg/min) vs those who met 4 goals (7.4 ± 4.1 mg/kg/min, P = .04) and those who met 5-6 goals (8.5 ± 4.3 mg/kg/min, P = .003), and remained significant after adjustments for sex and diabetes duration. Upright VO2 peak was lower in youth who met 0-3 goals (25.8 ± 4.6 mL/kg/min) vs those who met 4 goals (33.0 ± 7.8 mL/kg/min, P = .01) and those who met 5-6 goals (33.2 ± 4.4 mL/kg/min, P = .004). Similar and significant relationships were observed in EMERALD participants for supine VO2 peak. CONCLUSIONS: ADA/ISPAD goal achievement was associated with greater IS and cardiopulmonary fitness.

Using simple clinical measures to predict insulin resistance or hyperglycemia in girls with polycystic ovarian syndrome.

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

Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids.

Hyperandrogenic syndrome (HAS) is associated with insulin resistance (IR) and type 2 diabetes. Muscle IR in type 2 diabetes is linked with defects in mitochondrial oxidative capacity. In vivo muscle mitochondrial function has not been studied in HAS, especially in youth, who are early in the disease process. Our goal was to measure muscle mitochondrial oxidative function and peripheral IR in obese youth with HAS. Obese girls without HAS [n = 22, age 15(13,17) yr, BMI Z-score 2.05 ± 0.37] and with HAS [n = 35, age 15(14,16) yr, BMI Z-score 2.18 ± 0.30] were enrolled. Mitochondrial function was assessed with (31)phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU·m(-2)·min(-1) hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P < 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg·kg lean(-1)·min(-1), P < 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P < 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention.

Serum uromodulin inversely associates with aortic stiffness in youth with type 1 diabetes: A brief report from EMERALD study.

Youth with type 1 diabetes (T1D) carry greater cardiovascular disease (CVD) risk than their nondiabetic peers. Low serum uromodulin (SUMOD) associates with increased CVD mortality in adults. We found that T1D youth have low SUMOD. Lower SUMOD correlated with aortic stiffness, suggesting its potential as a CVD biomarker in T1D.

Nonalcoholic fatty liver disease in obese adolescent females is associated with multi-tissue insulin resistance and visceral adiposity markers.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and visceral adiposity in adults and boys, but girls with NAFLD are understudied. We sought to evaluate adipose, liver, and skeletal muscle insulin sensitivity in obese adolescent females with or without hepatic steatosis (HS) (intrahepatic triglyceride (IHTG) content >5.5%) along with cardiometabolic components typically associated with IR. STUDY DESIGN: 73 obese adolescent girls at high risk for NAFLD were enrolled. Participants underwent fasting labs, an MRI to measure IHTG and visceral fat, 31phosphorous MR spectroscopy for muscle mitochondrial function, 1H MR spectroscopy for intramyocellular lipid (IMCL), bicycle ergometry to assess VO2peak and a 4-phase hyperinsulinemic euglycemic clamp with isotope tracers to measure hepatic and peripheral IR. 29 participants had HS [age 15 yrs(13,16), BMI%ile 98.7(97.4,99.0), IHTG 10.4%(8.0,13.5)] and 44 did not [age 15 yrs(13,17), BMI%ile 98.5(96.2,99.0), IHTG 2.0%(1.1,3.0)]. RESULTS: During hyperinsulinemia, participants with HS vs. non-HS had failure to suppress free fatty acids (p = 0.008), endogenous glucose release (p = 0.002), and a lower glucose metabolic rate of disappearance (Rd) (p = 0.012). Girls with NALFD also had higher visceral fat (p < 0.001), systolic blood pressure (p = 0.026), triglycerides (p = 0.02), ALT (p < 0.01) and white blood cell count (p < 0.01), and lower adiponectin (p = 0.02). There was no difference between girls with and without HS in systemic glycerol turnover measured with glycerol release, or in IMCL, mitochondrial function or VO2peak. CONCLUSIONS: Obese adolescent girls with HS have evidence of multi-tissue IR, visceral adiposity, inflammation and multiple components of the metabolic syndrome, arguing for close cardiometabolic surveillance over time of girls with HS.

Youth With Type 1 Diabetes Have Adipose, Hepatic, and Peripheral Insulin Resistance.

Context: Adolescents with type 1 diabetes (T1D) have difficulty obtaining optimal glucose control, which may relate to insulin resistance (IR), especially during puberty. Moreover, IR increases the risk for cardiovascular disease, the leading cause of death in T1D. However, the tissue specificity of IR in adolescents with T1D has not been fully phenotyped. Objective: To assess adipose, hepatic, and peripheral insulin sensitivity in adolescents with and without T1D. Design and Setting: Thirty-five youth with T1D [median age, 16 (first and third quartiles, 14, 17) years; 53% female; median body mass index (BMI) percentile, 82nd (55th, 96th); late puberty; median hemoglobin A1c, 8.3% (7.3%, 9.4%)] and 22 nondiabetic youth of similar age, BMI, pubertal stage, and level of habitual physical activity were enrolled. Insulin action was measured with a four-phase hyperinsulinemic euglycemic clamp (basal and 10, 16, and 80 mU/m2/min) with glucose and glycerol isotope tracers. Results: Adolescents with T1D had a significantly higher rate of lipolysis (P < 0.0001) and endogenous glucose production (P < 0.001) and lower peripheral glucose uptake (glucose rate of disappearance, 6.9 ± 2.9 mg/kg/min for patients with T1D vs 11.3 ± 3.3 for controls; P < 0.0001) during hyperinsulinemia compared with controls. In youth with T1D, glucose rate of disappearance correlated with free fatty acid at the 80-mU/m2/min phase (P = 0.005), markers of inflammation (IL-6; P = 0.012), high-sensitivity C-reactive protein (P = 0.001), and leptin (P = 0.008)], but not hemoglobin A1c. Conclusions: Adolescents with T1D have adipose, hepatic and peripheral IR. This IR occurs regardless of obesity and metabolic syndrome features. Youth with T1D may benefit from interventions directed at improving IR in these tissues, and this area requires further research.

Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction.

AIMS: Insulin resistance (IR) correlates with mitochondrial dysfunction, free fatty acids (FFAs), and intramyocellular lipid (IMCL) in adults with type 2 diabetes (T2D). We hypothesized that muscle IR would relate to similar factors in T2D youth. METHODS: Participants included 17 youth with T2D, 23 normal weight controls (LCs), and 26 obese controls (OBs) of similar pubertal stage and activity level. RESULTS: T2D and OB groups were of similar BMI. T2D youth were significantly more IR and had higher calf IMCL and serum FFA concentrations during hyperinsulinemia. ADP time constant (ADPTC), a blood-flow dependent mitochondrial function measure, was slowed and oxidative phosphorylation rates lower in T2D. In multiple linear regression of the entire cohort, lack of FFA suppression and longer ADPTC, but not IMCL or HbA1c, were independently associated with IR. CONCLUSION: We found that elevated FFAs and mitochondrial dysfunction are early abnormalities in relatively well-controlled youth with T2D. Further, post-exercise oxidative metabolism appears affected by reduced blood flow, and is not solely an inherent mitochondrial defect. Thus, lowering FFAs and improving mitochondrial function and blood flow may be potential treatment targets in youth with T2D.

Leptin is associated with cardiopulmonary fitness independent of body-mass index and insulin sensitivity in adolescents with type 1 diabetes: a brief report from the EMERALD study.

Cardiopulmonary fitness is decreased in type 1 diabetes for reasons that are incompletely understood. In this study, leptin was associated with exercise capacity independent of insulin sensitivity (IS) and body mass index (BMI), suggesting that leptin may relate to cardiopulmonary fitness by mechanisms beyond IS and/or obesity.

Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome.

OBJECTIVE: Obese girls with polycystic ovarian syndrome (PCOS) have decreased insulin sensitivity (IS), muscle mitochondrial dysfunction and increased liver fat, which may contribute to their increased risk for type 2 diabetes. Less is known regarding normal-weight girls with PCOS. METHODS: Normal-weight girls with PCOS [n =18, age 15.9 ± 1.8 years, body mass index (BMI) percentile 68 ± 18] and normal-weight controls (NWC; n = 20; age 15.0 ± 2.1 years, BMI percentile 60 ± 21) were studied. Tissue-specific IS was assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers and a 2-hour oral glucose tolerance test (OGTT). Hepatic fat was determined using magnetic resonance imaging. Postexercise muscle mitochondrial function was assessed with 31P MR spectroscopy. RESULTS: Both groups had similar demographics, anthropomorphics, physical attributes, habitual physical activity levels and fasting laboratory values, except for increased total testosterone and DHEAS in PCOS. Clamp-assessed peripheral IS was lower in PCOS (10.4 ± 2.4 mg/kg/min vs 12.7 ± 2.1; P = 0.024). The 120-minute OGTT insulin and glucose concentrations were higher in PCOS (114 IU/mL ± 26 vs 41 ± 25, P = <0.001 and 119 ± 22 mg/dL vs 85 ± 23, P = 0.01, respectively). Muscle mitochondrial ADP and phosphocreatine time constants were slower in PCOS. Despite a higher percentage liver fat in PCOS, hepatic IS was similar between groups, as was adipose IS. CONCLUSIONS: Normal-weight girls with PCOS have decreased peripheral IS and muscle mitochondrial dysfunction, abnormal glucose disposal, relative postprandial hyperinsulinemia, and increased hepatic fat compared to NWC. Despite a normal BMI, multiple aspects of metabolism appear altered in normal-weight girls with PCOS.

Hepatic Steatosis is Common in Adolescents with Obesity and PCOS and Relates to De Novo Lipogenesis but not Insulin Resistance.

OBJECTIVE: Increased liver fat and type 2 diabetes are prevalent in women with polycystic ovarian syndrome (PCOS) and cause excess mortality, yet little is known about their development during adolescence. The objective of this study was to measure hepatic steatosis and related metabolic contributors in girls with obesity, with and without PCOS. METHODS: Nondiabetic adolescents with obesity, 41 with PCOS (PCOS; age 15.0 [13.0-16.0] years, BMI 35.2 ± 0.61 kg/m2 ) and 30 without PCOS (OB; age 14.5 [13.0-17.0], BMI 33.2 ± 1.8), were studied. Visceral and liver fat were assessed with MRI. Serum measures included androgens and 16:1 and 18:1 N7 fatty acids specific to de novo lipogenesis. Adipose, hepatic, and peripheral insulin sensitivity (IS) were assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers. RESULTS: Forty-nine percent of the PCOS group had hepatic steatosis versus fourteen percent of the OB group (P = 0.02), and the PCOS group had higher N7 (43 ± 4 vs. 29 ± 5 nmol/g; P = 0.02). Peripheral IS was lower in PCOS (9.4 [7.2-12.3] vs. 14.5 [13.1-18.05 mg/lean kg/min]; P < 0.001) as was hepatic (P = 0.006) and adipose IS (P = 0.005). Percent liver fat correlated with N7 (R = 0.46, P = 0.02) and visceral fat (R = 0.42, P < 0.001), not androgens or peripheral IS. CONCLUSIONS: Nearly 50% of nondiabetic girls with PCOS and obesity have hepatic steatosis, which relates to visceral fat and lipogenesis, but not to IS or androgens.

Youth with type 1 diabetes have worse strain and less pronounced sex differences in early echocardiographic markers of diabetic cardiomyopathy compared to their normoglycemic peers: A RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) Study.

OBJECTIVE: Diabetic cardiomyopathy is a major cause of morbidity, but limited data are available on early cardiac abnormalities in type 1 diabetes (T1D). We investigated differences in myocardial strain in adolescents with and without T1D. We hypothesized that adolescents with T1D would have worse strain than their normoglycemic peers, which boys would have worse strain than girls, and that strain would correlate with glycemic control and adipokines. METHODS: We performed fasting laboratory measures and echocardiograms with speckle tracking to evaluate traditional echocardiographic measures in addition to longitudinal (LS) and circumferential (CS) strain, and in adolescents (15±2years) with (19 boys; 22 girls) and without (16 boys; 32 girls) type 1 diabetes. RESULTS: Compared to controls, adolescents with type 1 diabetes had significantly lower CS (-20.9 vs. -22.7%, p=0.02), but not LS (p=0.83). Boys with T1D had significantly lower LS than girls with T1D (-17.5 vs. -19.7%, p=0.047), adjusted for Tanner stage. The significant sex differences observed in indexed left ventricular mass, left end-diastolic volume, diastolic septal and posterior wall thickness in our controls were lacking in adolescents with T1D. CONCLUSIONS: Our observations suggest that youth with T1D have worse myocardial strain than normoglycemic peers. In addition, the relatively favorable cardiac profile observed in girls vs. boys in the control group, was attenuated in T1D. These early cardiovascular changes in youth with T1D are concerning and warrant longitudinal and mechanistic studies.

Cardiopulmonary Dysfunction and Adiponectin in Adolescents With Type 2 Diabetes.

BACKGROUND: Myocardial mechanics are altered in adults with obesity and type 2 diabetes (T2D); insulin resistance and adipokines have been implicated as important risk factors for cardiovascular disease, but these relationships are poorly described in adolescents. We hypothesized that obese adolescents and adolescents with T2D would have abnormal cardiac function compared to lean adolescents. In addition, we hypothesized that insulin sensitivity (IS), adiposity, and adipokines would be associated with altered cardiac strain and cardiopulmonary fitness in adolescents with T2D. METHODS AND RESULTS: Adolescents (15±2 years) with T2D (n=37), obesity without diabetes (n=41), and lean controls (n=31) of similar age and pubertal stage underwent echocardiography with speckle tracking, assessment of IS by hyperinsulinemic-euglycemic clamp, body composition by dual-energy x-ray absorptiometry, peak oxygen consumption (VO2peak) by cycle ergometry, adiponectin, and leptin. Compared to lean and to obese controls, adolescents with T2D had significantly lower cardiac circumferential strain (CS) (-18.9±4.6 [T2D] versus -21.5±3.5 [obese] versus -22.0±4.2% [lean], P=0.04) and VO2peak (37.6±7.5 [T2D] versus 43.4±8.2 [obese] versus 47.6±8.6 mL/lean kg/min [lean], P<0.0001). In T2D youth, VO2peak was associated with CS, and the association remained significant after adjusting for age, sex, and IS (ß±SE: -0.73±0.26, P=0.02). Among adolescents with T2D, CS was also associated with adiponectin, longitudinal strain with leptin, and VO2peak with adiponectin and IS. CONCLUSIONS: Adolescents with T2D had abnormal CS and reduced VO2peak compared to obese and lean controls, which may represent the earliest evidence of cardiac functional impairment in T2D. Low adiponectin, rather than conventional risk factors and IS, correlated with CS, while both adiponectin and IS related to cardiopulmonary fitness.