Background: Cardiovascular disease (CVD) is the leading cause of mortality in type 1 diabetes (T1D) and relates strongly to insulin resistance (IR). Lean and obese T1D adolescents have marked IR. Metformin improves surrogate markers of IR in T1D, but its effect on directly-measured IR and vascular health in T1D youth is unclear. We hypothesized that 1) T1D adolescents have impaired vascular function, and 2) metformin improves this IR and vascular dysfunction. Methods: T1D adolescents and controls underwent MRI of the ascending (AA) and descending aorta (DA) to assess pulse wave velocity (PWV), relative area change (RAC), maximal (WSSMAX) and time-averaged wall shear stress (WSSTA). T1D participants also underwent assessment of carotid intima-media thickness (cIMT) by ultrasound, brachial distensibility (BrachD) by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate/insulin, [M/I]). T1D adolescents were randomized 1:1 to 3 months of 2000 mg metformin or placebo daily, after which baseline measures were repeated. Results: Forty-eight T1D adolescents ages 12–21 years (40% BMI ≥ 90th%ile; 56% female) and twenty-four nondiabetic controls of similar age, BMI and sex distribution were enrolled. T1D adolescents demonstrated impaired aortic health vs. controls, including elevated AA and DA PWV, reduced AA and DA RAC and elevated AA and DA WSSMAX and WSSTA. T1D adolescents in the metformin vs. placebo group had improved M/I (12.2±3.2 vs. −2.4±3.6 [mg/kg/min]/uIU/uL, p=0.005; 18.6±4.8 vs. −3.4±5.6 [mg/lean kg/min]/uIU/uL, p=0.005) and reduced weight (−0.5±0.5 vs. 1.6±0.5 kg, p=0.004), BMI (−0.2±0.15 vs. 0.4±0.15 kg/m2, p=0.005) and fat mass (−0.7±0.3 vs. 0.6±0.4 kg, p=0.01). M/I also improved in normal-weight participants (11.8±4.4 vs. −4.5±4.4 [mg/kg/min]/uIU/uL, p=0.02, 17.6±6.7 vs. −7.0±6.7 [mg/lean kg/min]/uIU/uL, p=0.02). The metformin group had reduced AA WSSMAX (−0.3±0.4 vs. 1.5±0.5 dyne/cm2, p=0.03), AA PWV, (−1.1±1.20 vs. 4.1±1.6 m/s, p=0.04) and far-wall diastolic cIMT (−0.04±0.01 vs. −0.00±0.01 mm, p=0.049) vs. placebo. Conclusions: T1D adolescents demonstrate IR and impaired vascular health vs. controls. Metformin improves IR, regardless of baseline BMI, and BMI, weight, fat mass, insulin dose, aortic and carotid health in T1D adolescents. Metformin may hold promise as a cardioprotective intervention in T1D.

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. Our goal 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 and 18 n7 fatty acids specific to de novo lipogenesis. Adipose, hepatic and peripheral insulin sensitivity (IS) were assessed with a 4-phase hyperinsulinemic-euglycemic clamp with isotope tracers. Results 49% PCOS had hepatic steatosis vs. 14% OB (p=0.02), and PCOS had higher n7 (43±4 nmol/g vs. 29±5; p=0.02). Peripheral IS was lower in PCOS (9.4(7.2,12.3) mg/lean kg/min vs. 14.5(13.1,18.05); 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 related to visceral fat and lipogenesis, but not to IS or androgens.

Insulin resistance (IR) increases cardiovascular morbidity and is associated with mitochondrial dysfunction. IR is now recognized to be present in type 1 diabetes; however, its relationship with mitochondrial function is unknown. We determined the relationship between IR and muscle mitochondrial function in type 1 diabetes using the hyperinsulinemic-euglycemic clamp and 31P-MRS before, during, and after near-maximal isometric calf exercise. Volunteers included 21 nonobese adolescents with type 1 diabetes and 17 nondiabetic control subjects with similar age, sex, BMI, Tanner stage, and activity levels. We found that youths with type 1 diabetes were more insulin resistant (median glucose infusion rate 10.1 vs. 18.9 mg/kglean/min; P < 0.0001) and had a longer time constant of the curve of ADP conversion to ATP (23.4 ± 5.3 vs. 18.8 ± 3.9 s, P < 0.001) and a lower rate of oxidative phosphorylation (median 0.09 vs. 0.21 mmol/L/s, P < 0.001). The ADP time constant (β = −0.36, P = 0.026) and oxidative phosphorylation (β = 0.02, P < 0.038) were related to IR but not HbA1c. Normal-weight youths with type 1 diabetes demonstrated slowed postexercise ATP resynthesis and were more insulin resistant than control subjects. The correlation between skeletal muscle mitochondrial dysfunction in type 1 diabetes and IR suggests a relationship between mitochondrial dysfunction and IR in type 1 diabetes.

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.

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.