Gregory Coe

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 (VO 2peak) 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 VO 2peak (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, VO 2peak was associated with CS, and the association remained significant after adjusting for age, sex, and IS (β±SE: −0.73±0.26, P=0.02). Among adolescents with T2D, CS was also associated with adiponectin, longitudinal strain with leptin, and VO 2peak with adiponectin and IS. Conclusions Adolescents with T2D had abnormal CS and reduced VO 2peak 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.

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.

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.

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.

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

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.

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.

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.

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.

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

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).