Amy Baumgartner

Delayed Skeletal Muscle Mitochondrial ADP Recovery in Youth With Type 1 Diabetes Relates to Muscle Insulin Resistance

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.

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.

Renal Function Is Associated With Peak Exercise Capacity in Adolescents With Type 1 Diabetes

OBJECTIVE Diabetic nephropathy and cardiovascular disease are strongly related in adults with type 1 diabetes, yet little is known about this relationship in adolescents prior to the onset of detectable clinical disease. We hypothesized that cardiopulmonary fitness would be directly associated with albumin-to-creatinine ratio (ACR) and inversely related to estimated glomerular filtration rate (eGFR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Sixty-nine adolescents with type 1 diabetes and 13 nondiabetic control subjects of similar pubertal stage and BMI had insulin sensitivity (glucose infusion rate [GIR]), measured by hyperinsulinemic-euglycemic clamp, and lean body mass, measured by DEXA. Cardiopulmonary fitness was measured by cycle ergometry to obtain peak volume of oxygen (VO2peak), and renal function was measured by eGFR using the Bouvet equation (measuring creatinine and cystatin C levels) and ACR. RESULTS Adolescents (15.5 ± 2.2 years of age) with type 1 diabetes (6.3 ± 3.8 years diabetes duration) had reduced VO2peak (31.5 ± 6.3 vs. 36.2 ± 7.9 mL/kg ⋅ min, P = 0.046) and VO2peak/lean kg (43.7 ± 7.0 vs. 51.0 ± 8.6 mL/lean kg ⋅ min, P = 0.007) compared with nondiabetic control subjects. eGFR was inversely associated with VO2peak and VO2peak/lean kg after adjusting for sex, Tanner stage, GIR, HbA1c level, systolic blood pressure, and LDL cholesterol level (β ± SE, VO2peak: −0.19 ± 0.07, P = 0.02; VO2peak/lean kg: −0.19 ± 0.09, P = 0.048). Moreover, participants in the highest tertile for eGFR had significantly lower sex- and Tanner-adjusted VO2peak and VO2peak/lean kg compared with participants in the lowest tertile. CONCLUSIONS Adolescents with type 1 diabetes had reduced exercise capacity, which was strongly associated with renal health, independent of insulin sensitivity. Future studies should examine the underlying interrelated pathophysiology in order to identify probable targets for treatment to reduce cardiovascular and renal complications.

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.

Alternate glycemic markers reflect glycemic variability in continuous glucose monitoring in youth with prediabetes and type 2 diabetes

To determine whether the alternate glycemic markers, fructosamine (FA), glycated albumin (GA), and 1,5‐anhydroglucitol (1,5AG), predict glycemic variability captured by continuous glucose monitoring (CGM) in obese youth with prediabetes and type 2 diabetes (T2D).

The role of glycemia in insulin resistance in youth with type 1 and type 2 diabetes

Hyperglycemia has traditionally been considered a major contributor to insulin resistance (IR) in type 1 diabetes (T1D), yet studies examining the relationship between HbA1c and IR are conflicting. Glucose measures captured by continuous glucose monitoring (CGM) (eg, peak glucose, standard deviation, hypoglycemia) in youth have not been explored as predictors of insulin sensitivity (IS).

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.