Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study.

RATIONALE & OBJECTIVE: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Twenty adults with ADPKD (age, 31±6 years; 65% women; body mass index [BMI], 26.8 [22.7-30.4] kg/m2; estimated glomerular filtration rate [eGFR, 2021 CKD-EPI creatinine], 103±18mL/min/1.73m2; height-adjusted total kidney volume [HTKV], 731±370mL/m; Mayo classifications 1B [5%], 1C [42%], 1D [21%], and 1E [32%]) and 11 controls in normal weight category (NWC) (age, 25±3 years; 45% women; BMI, 22.5 [21.7-24.2] kg/m2; eGFR, 113±15mL/min/1.73m2; HTKV, 159±31mL/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo classifications). OUTCOME: HTKV and cyst burden by magnetic resonance imaging, kidney oxidative metabolism, and perfusion by 11C-acetate positron emission tomography/computed tomography, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: For categorical variables, χ2/Fisher's exact tests, and for continuous variables t tests/Mann-Whitney U tests. Pearson correlation was used to estimate the relationships between variables. RESULTS: Compared with NWC individuals, the participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs 0.424±0.171 [mg/kg lean/min]/(µIU/mL), P=0.04), lower median cortical perfusion (1.93 [IQR, 1.80-2.09] vs 0.68 [IQR, 0.47-1.04] mL/min/g, P<0.001) and lower median total kidney oxidative metabolism (0.17 [IQR, 0.16-0.19] vs. 0.14 [IQR, 0.12-0.15] min-1, P=0.001) in voxel-wise models excluding cysts. HTKV correlated inversely with cortical perfusion (r: -0.83, P < 0.001), total kidney oxidative metabolism (r: -0.61, P<0.001) and M/I (r: -0.41, P = 0.03). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSIONS: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements. FUNDING: Grants from government (National Institutes of Health, Centers for Disease Control and Prevention) and not-for-profit (JDRF) entities. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study numbers NCT04407481 and NCT04074668. PLAIN-LANGUAGE SUMMARY: In our study, we explored how a common genetic kidney condition, autosomal dominant polycystic kidney disease (ADPKD), relates to kidney metabolism. ADPKD leads to the growth of numerous cysts in the kidneys, which can impact their ability to work properly. We wanted to understand the kidneys' ability to process oxygen and blood flow in ADPKD. Our approach involved using advanced imaging techniques to observe kidney metabolism and blood flow in people with ADPKD compared with healthy individuals. We discovered that those with ADPKD had significant changes in kidney oxygen metabolism even when their kidney function was still normal. These findings are crucial as they provide deeper insights into ADPKD, potentially guiding future treatments to target these changes.

Puberty Is Associated with a Rising Hemoglobin A1c, Even in Youth with Normal Weight.

Our objective was to explore the longitudinal trajectory of hemoglobin A1c (HbA1c) in well-characterized youth (n = 84) with normal weight and obesity during puberty. HbA1c rose from early puberty to Tanner stage 5, even in healthy, normal weight youth, revealing important implications for defining normal glycemia and prediabetes in adolescents.

Two-Year Treatment With Metformin During Puberty Does Not Preserve ß-Cell Function in Youth With Obesity.

CONTEXT: Youth-onset type 2 diabetes is a disease of pubertal onset, associated with additional burden of pubertal insulin resistance on the ß-cell. OBJECTIVE: Evaluate the impact of metformin treatment during puberty, a critical window of cardiometabolic change, on insulin sensitivity (Si) and compensatory ß-cell response in youth with obesity. SETTING: Pediatric academic hospital clinical translational research center. PARTICIPANTS: Healthy youth in early puberty [Tanner stage (T) 2-3] with normoglycemia and obesity (n = 44). INTERVENTION: Double-blinded placebo-control trial of metformin during puberty (until T5). MAIN OUTCOME MEASURES: Insulin sensitivity (Si), insulin response [acute insulin response to glucose (AIRg)], and disposition index (DI), estimated from frequently sampled intravenous glucose tolerance testing; body fat (dual X-ray absorptiometry); and other laboratory parameters, collected at baseline, T4, and T5. Placebo-subtracted treatment effect was calculated using linear mixed models. RESULTS: At T5, metformin treatment, adjusting for sex, race, and baseline value, was associated with improved BMI z-score (-0.44 ±â€…0.16, P = 0.02), percentage body fat (%body fat; -3.4 ±â€…1.2%, P = 0.06), and waist circumference (-11.3 ±â€…3.2cm, P = 0.003). There were no significant treatment effects at T5 on Si or secretion: Si (0.85 ±â€…0.87 × 10-4/min-1/µIU/mL, P = 0.34), AIRg (-259 ±â€…386 µIU/mL, P = 0.51), or DI (508 ±â€…802 × 10-4/min-1, P = 0.53). High baseline DI predicted longitudinal decline in DI. CONCLUSIONS: Two years of metformin treatment in obese youth during puberty improved BMI and body fat, but not Si or ß-cell function. Of note, high DI in early puberty may be predictive of later decline in DI. Further studies are needed to develop strategies for preservation of ß-cell function in youth at risk for type 2 diabetes.

Feasibility and Acceptability of Accelerometer Measurement of Physical Activity in Pregnant Adolescents.

During pregnancy, physical activity relates to better maternal and child mental and physical health. Accelerometry is thought to be effective for assessing free-living physical activity, but the feasibility/acceptability of accelerometer use in pregnant adolescents has not been reported. In this short communication, we conducted secondary analysis of a small pilot study to describe the feasibility/acceptability of accelerometry in pregnant adolescents and the preliminary results of physical activity characteristics. Participants were recruited from a multidisciplinary adolescent perinatal clinic. Physical activity was assessed with wrist-worn accelerometers. Feasibility was described as median days of valid wear (≥10 h of wear/day) for the total sample and the number/percentage of participants with ≥4 days of valid wear. Sensitivity analyses of wear time were performed. Acceptability ratings were collected by structured interview. Thirty-six pregnant (14.6 ± 2.1 gestational weeks) adolescents (17.9 ± 1.0 years) participated. Median days of valid wear were 4 days. Seventeen participants (51.5%) had ≥4 days of valid wear. There were no differences in characteristics of adolescents with vs. without ≥4 days of valid wear. Twenty participants (60.6%) had ≥3 days of valid wear, 24 (72.7%) ≥2 valid days, and 27 (81.8%) ≥1 valid wear day. Acceptability ratings were neutral. Assessing physical activity with accelerometry in pregnant adolescents was neither feasible nor acceptable with the current conditions. Future research should investigate additional incentives and the potential utility of a lower wear-time criterion in pregnant adolescents.

The Impact of Obesity On Insulin Sensitivity and Secretion During Pubertal Progression: A Longitudinal Study.

CONTEXT: Physiologic changes in glucose metabolism are well-described to occur during puberty. However, there are important gaps in understanding the interaction between obesity and the normal physiologic changes during puberty, as well as how these changes could contribute to the increased risk of comorbidities, such as type 2 diabetes and dyslipidemia, in youth with obesity. OBJECTIVE: The objective of this study was to compare longitudinal changes in insulin sensitivity (Si) and secretion during pubertal progression in youth with obesity versus those with normal weight. DESIGN: Longitudinal observational study evaluating youth from early puberty (Tanner [T]2-T3) until puberty completion (T5). SETTING: Pediatric academic hospital Clinical Translational Research Center. PARTICIPANTS: Pubertal youth with normal weight (n = 47; 22 female, 25 male) and obesity (n = 37; 23 female, 14 male). MAIN OUTCOME MEASURES: Si, insulin response (acute insulin response to glucose, AIRg) and disposition index (DI) by intravenous glucose tolerance test at baseline (T2-T3), T4, and T5. RESULTS: Youth with obesity had significantly lower Si and higher AIRg at each time point (P < 0.001), but DI was similar between the groups. There were no group differences in trajectory of Si, AIRg or DI over time. Leptin, insulin-like growth factor-1, and obesity were most strongly associated with Si and AIRg at all time points. CONCLUSIONS: Obesity significantly impacts Si during puberty, even at the earliest stages. However, in general, obese youth have adequate ß-cell compensation for the significantly reduced Si of puberty. Future studies are needed to better predict the subset of youth who fail to maintain ß-cell compensation during puberty.

Protocol for a pilot randomized controlled feasibility study of brief interpersonal psychotherapy for addressing social-emotional needs and preventing excess gestational weight gain in adolescents.

BACKGROUND: Excess gestational weight gain (GWG) in pregnant adolescents is a major public health concern. Excess GWG increases risk of pregnancy complications as well as postpartum and offspring obesity and cardiometabolic disease. Prevention interventions for pregnant adults that target lifestyle modification (i.e., healthy eating/physical activity) show insufficient effectiveness. Pregnant adolescents have distinct social-emotional needs, which may contribute to excess GWG. From an interpersonal theoretical framework, conflict and low social support increase negative emotions, which in turn promote excess GWG through mechanisms such as overeating and physical inactivity. METHODS: The current manuscript describes the design of a pilot randomized controlled feasibility trial of adolescent interpersonal psychotherapy (IPT) to address social-emotional needs and prevent excess GWG. Up to 50 pregnant, healthy adolescents 13-19y, 12-18 weeks gestation are recruited from an interdisciplinary adolescent maternity hospital clinic and randomized to IPT + usual care or usual care alone. IPT involves 6 individual 60-minute sessions delivered by a trained behavioral health clinician during 12-30 weeks gestation. Sessions include relationship psychoeducation, emotion identification and expression, and teaching/role-playing communication skills. Between sessions, adolescents are instructed to complete a daily journal and to have conversations to work on relationship goals. Outcomes are assessed at baseline, mid-program, post-program, and 3-months postpartum. Primary outcomes are feasibility and acceptability based upon rate of recruitment, session attendance, program acceptability ratings, and follow-up retention. Secondary outcomes are perinatal social functioning, stress, depression, and eating behaviors assessed with validated surveys and interviews; perinatal physical activity and sleep measured via accelerometer; GWG from measured weights; and at 3-months postpartum only, maternal adiposity by dual energy x-ray absorptiometry, maternal insulin sensitivity derived from 2-hour oral glucose tolerance testing, and infant adiposity by air displacement plethysmography. DISCUSSION: This pilot trial will address a key gap in extant understanding of excess GWG prevention for a high-risk population of adolescents. If feasible and acceptable, brief psychotherapy to address social-emotional needs should be tested for its effectiveness to address excess GWG and postpartum maternal/infant health. If effective, such an approach has potential to interrupt an adverse, intergenerational cycle of social-emotional distress, obesity, and cardiometabolic disease among young mothers and their offspring. TRIAL REGISTRATION: ClinicalTrials.gov NCT03086161, retrospectively registered.

Sex Differences in Effects of Obesity on Reproductive Hormones and Glucose Metabolism in Early Puberty.

CONTEXT: Obesity is known to impact reproductive function in adults, but little is known about its effects on reproductive hormones during puberty. OBJECTIVE: To assess sex differences in effects of obesity on reproductive hormones and their relation to insulin sensitivity and secretion. DESIGN: Cross-sectional study including anthropometrics, serum and urine reproductive hormone concentrations, and intravenous glucose tolerance testing (IVGTT) to assess acute insulin response to glucose (AIRg), and insulin sensitivity (Si). SETTING: Outpatient academic clinical research center. PATIENTS: Girls (52%) and boys (48%) who were normal weight (NW; n = 51, BMI-Z score = -0.11 ± 0.77, age = 11.5 ± 1.7 years) and obese (n = 53, BMI-Z score = 2.22 ± 0.33, age = 10.9 ± 1.5 years), Tanner stage 2 to 3. RESULTS: Boys with obesity had lower total testosterone (P < 0.0001) and higher concentrations of the urinary estradiol metabolite, E1c, (P = 0.046) than boys with NW. Girls with obesity had higher free androgen index (FAI; P = 0.03) than NW girls. Both boys and girls with obesity had lower sex hormone-binding globulin (SHBG; P < 0.0001) than NW. AIRg was inversely related to SHBG in boys (R = 0.6, P < 0.0001) and girls (R = 0.53, P = 0.0001). Si correlated with higher SHBG in boys (R2 = 0.67, P < 0.0001) and girls (R = 0.5, P = 0.0003), higher total testosterone for boys (R = 0.39, P = 0.01), and lower FAI for girls (R = -0.2, P = 0.04). CONCLUSION: Youth with obesity have lower SHBG than youth with NW, but obesity has differential effects on reproductive hormones in girls versus boys, which are apparent early in puberty. Ongoing longitudinal studies will evaluate the impact of obesity on reproductive hormones in girls and boys as puberty progresses.

Design of a randomized controlled trial to decrease depression and improve insulin sensitivity in adolescents: Mood and INsulin sensitivity to prevent Diabetes (MIND).

BACKGROUND: Depressive symptoms often manifest in adolescence and predict worsening insulin sensitivity, a key precursor in the path to ß-cell failure and type 2 diabetes (T2D). OBJECTIVE: To assess the efficacy of a six-week cognitive-behavioral group versus six-week health education group for improving insulin sensitivity and preserving ß-cell function in adolescent girls at-risk for T2D with depressive symptoms and evaluate mechanisms underlying the association between depression and insulin dynamics. DESIGN: Randomized controlled trial of N = 150 12-17-year-old girls with overweight/obesity (body mass index [BMI; kg/m2] ≥85th percentile), elevated depressive symptoms (Center for Epidemiologic Studies-Depression Scale [CES-D] total score > 20), and diabetes family history. METHODS: Girls at-risk for T2D with elevated depressive symptoms are recruited from the Denver-metropolitan area and randomized to participate in one of two six-week interventions. The cognitive-behavioral group is a depression prevention program involving psycho-education, restructuring negative thoughts, and behavioral activation. The health education group is a didactic control that provides knowledge about healthy living. Participants are assessed at baseline, immediate post-intervention, and one-year follow-up. Primary outcomes are insulin sensitivity and ß-cell function from oral glucose tolerance tests. Secondary outcomes are disinhibited eating, physical activity, sleep, and cortisol. SUMMARY: Results from this adequately powered randomized controlled trial will determine whether decreasing depressive symptoms with a behavioral health program preventatively alters insulin sensitivity and ß-cell function trajectories in adolescents at-risk for T2D. Results from the MIND Project will add to knowledge of the contribution of depressive symptoms to T2D risk.