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 (31±6 years of age, 65% women, BMI: 26.8 [22.7, 30.4] kg/m2, eGFR (2021 CKD-EPI Creatinine): 103±18 ml/min/1.73m2, height-adjusted total kidney volume [HtTKV]: 731±370 ml/m, Mayo Classifications: 1B [5%], 1C [42%], 1D [21%], 1E [32%]) and 11 controls in normal weight category (NWC; 25±3 years of age, 45% women, BMI: 22.5 [21.7, 24.2] kg/m2, eGFR: 113±15 ml/min/1.73m2, HtTKV: 159±31 ml/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo Classifications). OUTCOMES: HtTKV and cyst burden by MRI, kidney oxidative metabolism and perfusion by 11C-acetate PET/CT, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: Chi-square/Fisher's exact tests used for categorical variables and t-tests/ Mann-Whitney U tests for continuous variables. Pearson correlation used to estimate the relationships between variables. RESULTS: Compared to NWC, 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 [p25, p75] cortical perfusion (1.93 [1.80, 2.09 vs. 0.68 [0.47, 1.04] mL/min/g, p<0.001) and lower median [p25, p75] total kidney oxidative metabolism (0.17 [0.16,0.19] vs. 0.14 [0.12, 0.15] min-1, p=0.001) in voxel-wise models excluding cysts. HtTKV 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. CONCLUSION: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements.

Bone Density in Transgender Youth on Gender-Affirming Hormone Therapy.

Some transgender youth are treated with gonadotropin-releasing hormone agonists (GnRHa) followed by testosterone or estradiol, which may impact bone mineral density (BMD). This cross-sectional study of transgender youth (n = 56, aged 10.4-19.8 years, 53% assigned female at birth [AFAB]) utilized total body dual-energy x-ray absorptiometry to evaluate BMD Z-scores, and associations between GnRHa duration, body mass index (BMI), and BMD. Participants on GnRHa alone (n = 19, 14 assigned male at birth [AMAB], 5 AFAB) at the time of the study visit were 13.8 [12.8, 15.3] (median [IQR]) years old, had been on GnRHa for 10 [5.5, 19.5] months, and began GnRHa at age 12 [10.4, 12.6] years. Total body BMD Z-score for individuals on GnRHa monotherapy was -0.10 [-0.8, 0.4] (AFAB, female norms) and -0.65 [-1.4, 0.22] (AMAB, male norms). AFAB participants (n = 21) on testosterone were age 16.7 [15.9, 17.8] years, had been on testosterone for 11 [7.3, 14.5] months, and started testosterone at age 16 [14.8, 16.8] years; total body BMD Z-score -0.2 [-0.5, 0] (male norms) and 0.4 [-0.2, 0.7] (female norms). AMAB participants (n = 16) were age 16.2 [15.1, 17.4] years, had been on estradiol for 11 [5.6, 13.7] months, and started estradiol at age 16 [14.4, 16.7] years; total body BMD Z-score -0.4 [-1.1, 0.3] (male norms) and -0.2 [-0.7, 0.6] (female norms). BMD Z-score was negatively correlated with GnRHa duration (male norms: r = -0.5, P = .005; female norms: r = -0.4, P = .029) and positively correlated with BMI (male norms: r = 0.4, P = .003; female norms: r = 0.4, P = .004). In this cross-sectional cohort, total body BMD Z-scores were slightly below average, but lowest in the AMAB group on GnRHa monotherapy.

Sleep duration and association with cardiometabolic health in adolescents and adults with type 1 diabetes: Results from the BCQR-T1D study.

AIM: Type 1 diabetes (T1D) increases the risk of morbidity and mortality from cardiovascular disease, and insufficient sleep is prevalent. Emerging evidence suggests a link between sleep and cardiometabolic health, but this has not been examined across the lifespan in individuals with T1D. We aimed to examine associations between sleep and cardiometabolic health in adolescents and adults with T1D in a secondary analysis of data from a 4-week double-blind, random-order, placebo-controlled crossover trial of bromocriptine quick release (BCQR) therapy with a 4-week washout in between conditions. MATERIALS AND METHODS: Forty-two adults (19-60 years) and 42 adolescents (12-18 years) with T1D >9 months completed 1 week of home monitoring with wrist-worn actigraphy to estimate sleep duration and continuous glucose monitoring, anthropometrics, arterial stiffness, magnetic resonance imaging (adolescents only), and fasting laboratory testing at each treatment phase. RESULTS: Sixty-two per cent of adolescents and 74% of adults obtained <7 h of sleep per night at baseline. After adjustment for age, sex and diabetes duration, baseline sleep <7 h per night was associated with a higher body mass index, a higher waist circumference, a higher systolic blood pressure, worse arterial stiffness and a lower estimated insulin sensitivity (all p < .05). When examined by age group, associations between sleep duration and cardiometabolic health outcomes remained significant, predominantly for adolescents. In adolescents only, wake time was significantly later (p = .027) and time in bed was significantly longer with BCQR versus placebo (p = .049). CONCLUSIONS: Objectively measured sleep <7 h per night was prevalent in adolescents and adults with T1D and associated with poorer cardiometabolic health markers. Small changes in sleep were seen following BCQR treatment in adolescents only. Sleep may be an important and novel target for improving cardiometabolic health in individuals with T1D.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Glycoprotein Acetyls Associate With Intraglomerular Hemodynamic Dysfunction, Albuminuria, Central Adiposity, and Insulin Resistance in Youth With Type 1 Diabetes.

OBJECTIVES: Glycoprotein acetyls (GlycA's) are biomarkers of systemic inflammation and cardiovascular disease, yet little is known about their role in type 1 diabetes (T1D). In this study we examined the associations among GlycA's, central adiposity, insulin resistance, and early kidney injury in youth with T1D. METHODS: Glomerular filtration rate and renal plasma flow by iohexol and p-aminohippurate clearance, urine albumin-to-creatinine ratio (UACR), central adiposity by dual-energy x-ray absorptiometry, and estimated insulin sensitivity were assessed in 50 youth with T1D (16±3.0 years of age, 50% female, glycated hemoglobin 8.7±1.3%, T1D duration 5.7±2.6 years). Concentrations of GlycA were quantified by targeted nuclear magnetic resonance spectroscopy. Correlation and multivariable linear regression analyses were performed. RESULTS: GlycA's were higher in girls vs boys (1.05±0.26 vs 0.84±0.15 mmol/L, p=0.001) and in participants living with overweight/obesity vs normal weight (1.12±0.23 vs 0.87±0.20 mmol/L, p=0.0004). GlycA's correlated positively with estimated intraglomerular pressure (r=0.52, p=0.001), UACR (r=0.53, p<0.0001), and trunk mass (r=0.45, p=0.001), and inversely with estimated insulin sensitivity (r=-0.36, p=0.01). All relationships remained significant after adjustment for age, sex, and glycated hemoglobin. CONCLUSIONS: As biomarker of inflammation, GlycA's were higher in girls and those with overweight or obese body habitus in T1D. GlycA's associated with parameters of early kidney dysfunction, central adiposity, and insulin resistance.

Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

OBJECTIVE: ß-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS: Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS: Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS: Youth with type 2 diabetes demonstrated severe ß-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

Understanding diabetes heterogeneity: key steps towards precision medicine in diabetes.

Diabetes is a highly heterogeneous condition; yet, it is diagnosed by measuring a single blood-borne metabolite, glucose, irrespective of aetiology. Although pragmatically helpful, disease classification can become complex and limit advances in research and medical care. Here, we describe diabetes heterogeneity, highlighting recent approaches that could facilitate management by integrating three disease models across all forms of diabetes, namely, the palette model, the threshold model and the gradient model. Once diabetes has developed, further worsening of established diabetes and the subsequent emergence of diabetes complications are kept in check by multiple processes designed to prevent or circumvent metabolic dysfunction. The impact of any given disease risk factor will vary from person-to-person depending on their background, diabetes-related propensity, and environmental exposures. Defining the consequent heterogeneity within diabetes through precision medicine, both in terms of diabetes risk and risk of complications, could improve health outcomes today and shine a light on avenues for novel therapy in the future.

Respecting tribal voices in the development of a gestational diabetes risk reduction preconception counseling program for American Indian/Alaska Native adolescent females: a qualitative study.

BACKGROUND: American Indians and Alaska Natives (AI/AN) are disproportionately affected by adolescent obesity, adolescent pregnancy and gestational diabetes mellitus (GDM). GDM is associated with increased risk for perinatal death, obesity, and subsequent type 2 diabetes (T2D) for the offspring. Moreover, mothers with GDM are also at increased risk for T2D post-partum. Yet few lifestyle interventions exist to reduce GDM risk prior to pregnancy. We describe the process of adapting an existing validated preconception counseling intervention for AI/AN adolescent girls at-risk for GDM and their mothers. Perspectives and recommendations were gathered from a diverse array of stakeholders to assure the new program called Stopping GDM was culturally responsive and developed with tribal voices and perspectives represented. METHODS: We conducted focus groups and individual interviews with multiple AI/AN stakeholders (n = 55). Focus groups and interviews were digitally recorded, transcribed verbatim, and analyzed using a thematic content approach to construct cross-cutting themes across the focus groups and interviews. RESULTS: Four key themes emerged reflecting issues important to planning a reproductive health intervention: 1) Limited awareness, knowledge, and health education resources about GDM; 2) The importance of acknowledging traditional AI/AN values and the diversity of traditions and culture among AI/AN tribes; 3) The need to cultivate healthy decision-making skills and empower girls to make safe and healthy choices; and 4) Lack of communication about reproductive health between AI/AN mothers and daughters and between AI/AN women and health care professionals. CONCLUSION: Findings have been used to inform the cultural tailoring and adaptation of an existing preconception counseling program, originally designed for non-AI/AN adolescent girls with diabetes, for AI/AN adolescents at-risk for GDM in future pregnancies.

Obesity dominates early effects on cardiac structure and arterial stiffness in people with type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2D) and obesity are global epidemics leading to excess cardiovascular disease (CVD). This study investigates standard and novel cardiac MRI parameters to detect subclinical cardiac and central vascular dysfunction in inactive people with and without T2D. METHODS: Physically inactive age and BMI-similar premenopausal women and men with ( n  = 22) and without [ n  = 34, controls with overweight/obesity (CWO)] uncomplicated T2D were compared to an age-similar and sex-similar reference control cohort ( n  = 20). Left ventricular (LV) structure, function, and aortic stiffness were assessed by MRI. Global arterial pulse wave velocity (PWV) was assessed using carotid-to-femoral applanation tonometry. Regional PWV was measured via 2D phase-contrast MRI and 4D flow MRI. RESULTS: Global arterial PWV did not differ between CWO and T2D. 2D PC-MRI PWV in the ascending aorta was higher in people with T2D compared with CWOs ( P  < 0.01). 4D flow PWV in the thoracic aorta was higher in CWO ( P  < 0.01), and T2D ( P  < 0.001) compared with RC. End-diastolic volume, end-systolic volume, stroke volume, and cardiac output were lower in CWO and T2D groups compared with reference control. CONCLUSION: Subclinical changes in arterial stiffening and cardiac remodeling in inactive CWO and T2D compared with reference control support obesity and/or physical inactivity as determinants of incipient CVD complications in uncomplicated T2D. Future studies should determine the mechanistic causes of the CVD complications in greater detail in order to create therapeutic targets. CLINICAL TRIAL REGISTRATION: Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex (NCT03419195).

Comparing American Indian/Alaska Native Adolescent Daughters' and Their Mothers' Awareness, Knowledge, Attitudes, and Behaviors Regarding Risk for Gestational Diabetes: Implications for Mother-Daughter Communication on Reproductive Health.

PURPOSE: The purpose of the study was to describe, compare, and examine associations at baseline of reproductive health awareness, knowledge, health beliefs, communication and behaviors related to gestational diabetes (GDM) and GDM risk reduction in a vulnerable population of both American Indian/Alaska Native (AIAN) adolescent girls and their mothers. METHODS: Descriptive/comparative/correlational analyses examined multitribal baseline data on 149 mother-daughter (M-D) dyads (N = 298; daughter age = 12-24 years) enrolled in a longitudinal study to adapt and evaluate a culturally relevant diabetes preconception counseling (PC) program (Stopping-GDM). The associations between GDM risk reduction awareness, knowledge, health beliefs, and behaviors (eg, daughters' eating, physical activity, reproductive-health [RH] choices/planning, M-D communication, daughters' discussions on PC) were examined. Data collected online from 5 national sites. RESULTS: Many M-D lacked awareness/knowledge of GDM and risk reduction. Both M-D were unaware of the girl's risk for GDM. Mothers' knowledge and beliefs on GDM prevention/RH were significantly higher than daughters. Younger daughters had greater self-efficacy healthy living. Overall sample reported low to moderate scores for both M-D communication and daughters' GDM and RH risk-reduction behaviors. CONCLUSIONS: Knowledge, communication, and behaviors to prevent GDM were low in AIAN M-D, especially daughters. More than daughters, mothers perceive greater risk of GDM for daughters. Early culturally responsive dyadic PC programs could help decrease risk of developing GDM. Implications for M-D communication is compelling.

Hypoglycemia in children and young adults with cystic fibrosis during oral glucose tolerance testing vs. continuous glucose monitoring.

BACKGROUND: Hypoglycemia is common in people with cystic fibrosis (pwCF) during oral glucose tolerance tests (OGTTs) and in the free-living setting, yet its pathophysiology remains unclear. OBJECTIVE: To evaluate hypoglycemia in children and young adults with CF by OGTT and continuous glucose monitoring (CGM). METHODS: A 3-h OGTT was performed in children and young adults with CF and healthy controls (HC). Individuals were classified as experiencing hypoglycemia on OGTT (glucose <70 mg/dL) or not. Insulin, C-peptide, glucose, glucagon, and incretins were measured. CGM was performed for 7 days in the free-living setting. Measures of insulin sensitivity, beta cell function accounting for insulin sensitivity, and insulin clearance were calculated. RESULTS: A total of 57 participants (40 CF and 17 HC) underwent assessment. Rates of hypoglycemia by OGTT were similar in pwCF (53%, 21/40) compared to HC (35%, 6/17), p = 0.23. PwCF compared to HC had higher A1c; on OGTT higher and later glucose peaks, later insulin peaks; and on CGM more glucose variability. CF Hypo+ versus CF Hypo- had higher lung function, higher insulin sensitivity, higher beta cell function accounting for insulin sensitivity, and decreased CGM variability. When comparing CF Hypo+ to HC Hypo+, although rates of hypoglycemia are similar, pwCF had blunted glucagon responses to hypoglycemia. OGTT hypoglycemia was not associated with CGM hypoglycemia in any group. CONCLUSION: Youth with CF have increased insulin sensitivity and impaired glucagon response to hypoglycemia on OGTT. Hypoglycemia on OGTT did not associate with free-living hypoglycemia.

Cognitive-behavioral therapy and exercise training in adolescent females with elevated depression symptoms and at-risk for type 2 diabetes: Protocol for a randomized controlled trial.

BACKGROUND: Adolescent-onset type 2 diabetes (T2D) is a major public health concern of growing proportions. Prevention, therefore, is critical. Unfortunately, standard-of-care treatment for T2D prevention (e.g., exercise training) show insufficient effectiveness and do not address key modifiable barriers (e.g., depression symptoms) to exercise engagement. Depression symptoms are associated with both poorer physical fitness and greater insulin resistance, the key risk factor in adolescent-onset T2D. Thus, a targeted prevention approach that addresses depression symptoms in combination with exercise training may offer a novel approach to mitigating T2D risk. METHODS: This manuscript describes the design and study protocol for a multi-site, four-arm randomized controlled trial comparing the efficacy of group cognitive-behavioral therapy, group exercise training, and their combinations for the targeted prevention of worsening insulin resistance in N = 300 adolescent females at-risk for T2D with BMI ≥85th percentile and elevated depression symptoms. All four intervention arms will run in parallel and meet weekly for 1 h per week for 6-week to 6-week segments (12 weeks total). Outcomes are assessed at baseline, 6-week mid-treatment, 12-week follow-up, and 1-year follow-up. RESULTS: The primary outcome is insulin resistance. Key secondary outcomes include insulin sensitivity, cardiorespiratory fitness, physical activity, depression symptoms, and body measurements. CONCLUSION: Study findings will guide the ideal sequencing of two brief T2D prevention interventions for ameliorating the course of insulin resistance and lessening T2D risk in vulnerable adolescents. These interventions will likely be cost-effective and scalable for dissemination, having the potential for significant public health impact on communities at risk for T2D.

Triglyceride content of lipoprotein subclasses and kidney hemodynamic function and injury in adolescents with type 1 diabetes.

AIMS: Elevated triglycerides (TG) are associated with development and progression of kidney disease, and TG distributions across lipoprotein subclasses predict kidney dysfunction in adults with type 1 diabetes (T1D). Little is known regarding these relationships in youth. METHODS: In this single center study conducted from October 2018-2019, lipid constituents from lipoprotein subclasses were quantified by targeted nuclear magnetic resonance spectroscopy. Glomerular filtration rate (GFR), renal plasma flow (RPF), afferent arteriolar resistance (RA), efferent arteriolar resistance (RE), intraglomerular pressure (PGLO), urine albumin-to-creatinine ratio (UACR), and chitinase-3-like protein 1 (YKL-40), a marker of kidney tubule injury, were assessed. Cross-sectional relationships were assessed by correlation and multivariable linear regression (adjusted for age, sex, HbA1c) models. RESULTS: Fifty youth with T1D (age 16 ± 3 years, 50 % female, HbA1c 8.7 ± 1.3 %, T1D duration 5.7 ± 2.6 years) were included. Very-low-density lipoprotein (VLDL)-TG concentrations correlated and associated with intraglomerular hemodynamic function markers including GFR, PGLO, UACR, as did small low-density lipoprotein (LDL)-TG and small high-density lipoprotein (HDL)-TG. YKL-40 correlated with all lipoprotein subclasses. CONCLUSION: TG within lipoprotein subclasses, particularly VLDL, associated with PGLO, GFR, albuminuria, and YKL-40. Lipid perturbations may serve as novel targets to mitigate early kidney disease.

Youth-onset type 2 diabetes mellitus: an urgent challenge.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Bromocriptine Improves Central Aortic Stiffness in Adolescents With Type 1 Diabetes: Arterial Health Results From the BCQR-T1D Study.

BACKGROUND: The presence of vascular dysfunction is a well-recognized feature in youth with type 1 diabetes (T1D), accentuating their lifetime risk of cardiovascular events. Therapeutic strategies to mitigate vascular dysfunction are a high clinical priority. In the bromocriptine quick release T1D study (BCQR-T1D), we tested the hypothesis that BCQR would improve vascular health in youth with T1D. METHODS: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating the cardiovascular and metabolic impact of BCQR in T1D. Adolescents in the BCQR-T1D study were randomized 1:1 to phase-1: 4 weeks of BCQR or placebo after which blood pressure and central aortic stiffness measurements by pulse wave velocity, relative area change, and distensibility from phase-contrast magnetic resonance imaging were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. RESULTS: Thirty-four adolescents (mean age 15.9±2.6 years, hemoglobin A1c 8.6±1.1%, body mass index percentile 71.4±26.1, median T1D duration 5.8 years) with T1D were enrolled and had magnetic resonance imaging data available. Compared with placebo, BCQR therapy decreased systolic (∆=-5 mmHg [95% CI, -3 to -7]; P<0.001) and diastolic blood pressure (∆=-2 mmHg [95% CI, -4 to 0]; P=0.039). BCQR reduced ascending aortic pulse wave velocity (∆=-0.4 m/s; P=0.018) and increased relative area change (∆=-2.6%, P=0.083) and distensibility (∆=0.08%/mmHg; P=0.017). In the thoraco-abdominal aorta, BCQR decreased pulse wave velocity (∆=-0.2 m/s; P=0.007) and increased distensibility (∆=0.05 %/mmHg; P=0.013). CONCLUSIONS: BCQR improved blood pressure and central and peripheral aortic stiffness and pressure hemodynamics in adolescents with T1D over 4 weeks versus placebo. BCQR may improve aortic stiffness in youth with T1D, supporting future longer-term studies.

Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes.

BACKGROUND: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. METHODS: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. RESULTS: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR. CONCLUSIONS: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.

Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes.

Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10-6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher ß-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04,0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the ß-cell pPS with reduced ß-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.