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.

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.

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.

Inverse probability weighting is an effective method to address selection bias during the analysis of high dimensional data.

Omics studies frequently use samples collected during cohort studies. Conditioning on sample availability can cause selection bias if sample availability is nonrandom. Inverse probability weighting (IPW) is purported to reduce this bias. We evaluated IPW in an epigenome-wide analysis testing the association between DNA methylation (261,435 probes) and age in healthy adolescent subjects (n = 114). We simulated age and sex to be correlated with sample selection and then evaluated four conditions: complete population/no selection bias (all subjects), naïve selection bias (no adjustment), and IPW selection bias (selection bias with IPW adjustment). Assuming the complete population condition represented the "truth," we compared each condition to the complete population condition. Bias or difference in associations between age and methylation was reduced in the IPW condition versus the naïve condition. However, genomic inflation and type 1 error were higher in the IPW condition relative to the naïve condition. Postadjustment using bacon, type 1 error and inflation were similar across all conditions. Power was higher under the IPW condition compared with the naïve condition before and after inflation adjustment. IPW methods can reduce bias in genome-wide analyses. Genomic inflation is a potential concern that can be minimized using methods that adjust for inflation.

Bromocriptine quick-release as adjunct therapy in youth and adults with type 1 diabetes: A randomized, placebo-controlled crossover study.

AIM: To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes. MATERIALS AND METHODS: Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8 mg to 1.6 mg to 3.2 mg, minimum dose 1.6 mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry. RESULTS: Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areas under the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR. CONCLUSIONS: Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.

Follow-Up Mental Health Care in Youth and Young Adults With Type 1 Diabetes After Positive Depression Screen and/or Suicidal Ideation.

Individuals with type 1 diabetes have higher rates of depression and suicidal ideation than the general population, and symptoms of depression are often associated with higher A1C levels and complications. This study evaluated mental health follow-up rates in youth and young adults with type 1 diabetes who screened positive for depressive symptoms or suicidal ideation and identified differences between those who obtained follow-up mental health care and those who did not. Specifically, males were less likely to obtain follow-up, and those who had mental health follow-up had decreasing A1C over the following year. These findings suggest increased assistance and monitoring are needed to ensure follow-up mental health care is obtained.

Real-world performance of hybrid closed loop in youth, young adults, adults and older adults with type 1 diabetes: Identifying a clinical target for hybrid closed-loop use.

AIM: To describe real-world hybrid closed loop (HCL) use and glycaemic outcomes across the lifespan and identify a clinical threshold for HCL use associated with meeting the internationally recommended target of 70% sensor glucose time in range (TIR; 70-180 mg/dL). MATERIALS AND METHODS: Mixed models examined MiniMed 670G HCL use and glycaemic outcomes in 276 people with type 1 diabetes from four age groups: youth (aged <18 years), young adults (18-25 years), adults (26-49 years) and older adults (≥50 years) for 1 year. ROC analysis identified the minimum percentage HCL use associated with meeting the TIR goal of 70%. RESULTS: HCL use at month 1 was 70.7% ± 2.9% for youth, 71.0% ± 3.8% for young adults, 78.9% ± 2.1% for adults and 84.7% ± 3.8% in older adults. HCL use declined significantly at 12 months to 49.3% ± 3.2% in youth (P < .001) and 55.7% ± 4.3% in young adults (P = .002). HCL use was sustained at 12 months in adults (76.4% ± 2.2%, P = .36) and older adults (80.4% ± 3.9%, P = .36). HCL use of 70.6% was associated with 70% TIR (sensitivity 58.3%, specificity 85%, AUC 0.77). Older age, 80% or higher continuous glucose monitor use and four or more blood glucose checks per day were associated with attaining the HCL-use threshold. CONCLUSIONS: HCL use of 70% or higher may be a useful target for clinicians to use to assist people with diabetes in attaining glycaemic goals. Youth may struggle with HCL use more than adults and require clinical intervention to help sustain HCL use across time.

Proteomic Analysis Uncovers Multi-Protein Signatures Associated with Early Diabetic Kidney Disease in Youth with Type 2 Diabetes Mellitus.

BACKGROUND: The onset of diabetic kidney disease (DKD) in youth with type 2 diabetes mellitus often occurs early, leading to complications in young adulthood. Risk biomarkers associated with the early onset of DKD are urgently needed in youth with type 2 diabetes. METHODS: We conducted an in-depth analysis of 6596 proteins (SomaScan 7K) in 374 baseline plasma samples from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study to identify multi-protein signatures associated with the onset of albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g), a rapid decline in estimated glomerular filtration rate (eGFR) [annual eGFR decline >3 mL/min/1.73m2 and/or ≥3.3% at two consecutive visits], and hyperfiltration (≥135 mL/min/1.73m2 at two consecutive visits). Elastic net Cox regression with 10-fold cross-validation was applied to the top 100 proteins (ranked by p-value) to identify multi-protein signatures of time to development of DKD outcomes. RESULTS: Participants in the TODAY study (14±2 years old, 63% female, 7±6 months diabetes duration) experienced high rates of early DKD: 43% developed albuminuria, 48% hyperfiltration, and 16% rapid eGFR decline. Increased levels of seven and three proteins were predictive of shorter time to develop albuminuria and rapid eGFR decline, respectively; 118 proteins predicted time to development of hyperfiltration. Elastic net Cox proportional hazards model identified multi-protein signatures of time to incident early DKD with concordance for models with clinical covariates and selected proteins between 0.81 and 0.96, while the concordance for models with clinical covariates only was between 0.56 and 0.63. CONCLUSIONS: Our research sheds new light on proteomic changes early in the course of youth-onset type 2 diabetes that associate with DKD. Proteomic analyses identified promising risk factors that predict DKD risk in youth with type 2 diabetes and could deepen our understanding of DKD mechanisms and potential interventions.

The impact of elexacaftor/tezacaftor/ivacaftor on body composition in a small cohort of youth with cystic fibrosis.

BACKGROUND: The effects of elexacaftor-tezacaftor-ivacaftor (ETI) on body composition in people with CF (pwCF) are unknown. METHODS: Dual-energy X-ray absorptiometry fat-free mass and fat mass adjusted for height (FMI) as well as oral glucose tolerance test derived measures of insulin secretion and sensitivity were compared before and after ETI initiation in eight pwCF. RESULTS: Patients median age: 22 years interquartile range (IQR: 16-28), 87.5% male, median time on ETI:11 months. Weight z-score increased from -0.52 to 0.18 (p = 0.014); FMI increased from 4.12 to 6.29 (p = 0.014). Insulin secretion (C pep iAUC/Gluc iAUC) increased from 8.71 to 14.21 (p = 0.021), insulin resistance (HOMA2 IR) increased from 0.73 to 1.25 (p = 0.014) and insulin sensitivity decreased (Matsuda) 8.88 to 5.58 (p = 0.036). CONCLUSIONS: ETI resulted in increased weight and fat mass. BMI and muscle mass did not change. Both insulin secretion and insulin resistance increased. Longer-term metabolic consequences of ETI need further investigation.

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.

Glycemia and ß-cell function before and after elexacaftor/tezacaftor/ivacaftor in youth and adults with cystic fibrosis.

Background: Diabetes is prevalent among people with CF (PwCF) and associated with worse clinical outcomes. CFTR modulators are highly effective in improving the disease course of CF. However, the effects of elexacaftor/tezacaftor/ivacaftor (ETI) on glucose metabolism in PwCF are unclear. Methods: Twenty youth and adults with CF underwent frequently sampled oral glucose tolerance tests (fsOGTT) before and after ETI initiation. Glucose, insulin, and C-peptide were collected at 0, 10, 30, 60, 90, and 120 min after 1.75 g/kg (max 75 g) of dextrose. HbA1c and continuous glucose monitoring (CGM) were collected in a subset. Estimates of insulin secretion (C-peptide index), insulin resistance (HOMA2 IR and IS(OGTT Cpep)), and ß-cell function (C-peptide oral disposition index, oDIcoeo), were compared before and after ETI. Results: Participants were a median (IQR) of 20.4 (14.1, 28.6) years old, 75 % male. Follow-up occurred 10.5 (10.0, 12.3) months after ETI initiation. BMI z-score increased from 0.3 (-0.3, 0.8) to 0.8 (0.4, 1.5), p = 0.013 between visits. No significant differences were observed in glucose tolerance, glucose area under the curve, nor fsOGTT glucose concentrations before and after ETI. Median (IQR) C-peptide index increased from 5.7 (4.1, 8.3) to 8.8 (5.5, 10.8) p = 0.013 and HOMA2 IR increased (p < 0.001), while oDIcoeo was unchanged (p = 0.67). HbA1c decreased from 5.5 % (5.5, 5.8) to 5.4 % (5.2, 5.6) (p = 0.003) while CGM variables did not change. Conclusions: BMI z-score and measures of both insulin resistance and insulin secretion increased within the first year of ETI initiation. ß-cell function adjusted for insulin sensitivity (oDIcoeo) did not change.

Real-World Use of a New Hybrid Closed Loop Improves Glycemic Control in Youth with Type 1 Diabetes.

Objective: To describe real-world outcomes for youth using the Tandem t:slim X2 insulin pump with Control-IQ technology ("Control-IQ") for 6 months at a large pediatric clinic. Methods: Youth with type 1 diabetes, who started Control-IQ for routine care, were prospectively followed. Data on system use and glycemic control were collected before Control-IQ start, and at 1, 3, and 6 months after start. Mixed models assessed change across time; interactions with baseline hemoglobin A1c (HbA1c) and age were tested. Results: In 191 youth (median age 14, 47% female, and median HbA1c 7.6%), percent time with glucose levels 70-180 mg/dL (time-in-range [TIR]) improved from 57% at baseline to 66% at 6 months (P < 0.001). The proportion of participants reaching TIR target (>70%) doubled from 23.5% at baseline to 47.8% at 3 months, sustaining at 46.7% at 6 months (P < 0.001). Glucose management indicator (approximation of HbA1c) improved from 7.5% at baseline to 7.1% at 3 months and 7.2% at 6 months (P < 0.001). Those with higher baseline HbA1c experienced the most substantial improvements in glycemic control. Percent time using the Control-IQ feature was 86.4% at 6 months, and <4% of cohort discontinued use. Conclusion: The Control-IQ system clinically and significantly improved glycemic control in a large sample of youth. System use was high at 6 months, with only a small proportion discontinuing use, indicating potential for sustaining results long term.

Epigenome-Wide Association Study of Infant Feeding and DNA Methylation in Infancy and Childhood in a Population at Increased Risk for Type 1 Diabetes.

We assessed associations between infant diet (e.g., breastfeeding and introduction to solid foods) and DNA methylation in infancy and childhood. We measured DNA methylation in peripheral blood collected in infancy (9-15 months of age) in 243 children; and in a subset of 50 children, we also measured methylation in childhood (6-9 years of age) to examine persistence, and at birth (in cord blood) to examine temporality. We performed multivariable linear regression of infant diet on the outcome of methylation using epigenome-wide and candidate site approaches. We identified six novel CpG sites associated with breastfeeding duration using an EWAS approach. One differentially methylated site presented directionally consistent associations with breastfeeding (cg00574958, CPT1A) in infancy and childhood but not at birth. Two differentially methylated sites in infancy (cg19693031, TXNIP; cg23307264, KHSRP) were associated with breastfeeding and were not present at birth; however, these associations did not persist into childhood. Associations between infant diet and methylation in infancy at three sites (cg22369607, AP001525.1; cg2409200, TBCD; cg27173510, PGBD5) were also present at birth, suggesting the influence of exposures other than infant diet. Infant diet exposures are associated with persistent methylation differences in CPT1A, which may be one mechanism behind infant diet's long-term health effects.

Acute Hyperinsulinemia Alters Bone Turnover in Women and Men With Type 1 Diabetes.

Type 1 diabetes (T1D) increases fracture risk across the lifespan. The low bone turnover associated with T1D is thought to be related to glycemic control, but it is unclear whether peripheral hyperinsulinemia due to dependence on exogenous insulin has an independent effect on suppressing bone turnover. The purpose of this study was to test the bone turnover marker (BTM) response to acute hyperinsulinemia. Fifty-eight adults aged 18 to 65 years with T1D over 2 years were enrolled at seven T1D Exchange Clinic Network sites. Participants had T1D diagnosis between age 6 months to 45 years. Participants were stratified based on their residual endogenous insulin secretion measured as peak C-peptide response to a mixed meal tolerance test. BTMs (CTX, P1NP, sclerostin [SCL], osteonectin [ON], alkaline phosphatase [ALP], osteocalcin [OCN], osteoprotegerin [OPG], osteopontin [OPN], and IGF-1) were assessed before and at the end of a 2-hour hyperinsulinemic-euglycemic clamp (HEC). Baseline ON (r = -0.30, p = .022) and OCN (r = -0.41, p = .002) were negatively correlated with age at T1D diagnosis, but baseline BTMs were not associated with HbA1c. During the HEC, P1NP decreased significantly (-14.5 ± 44.3%; p = .020) from baseline. OCN, ON, and IGF-1 all significantly increased (16.0 ± 13.1%, 29.7 ± 31.7%, 34.1 ± 71.2%, respectively; all p < .001) during the clamp. The increase in SCL was not significant (7.3 ± 32.9%, p = .098), but the decrease in CTX (-12.4 ± 48.9, p = .058) neared significance. ALP and OPG were not changed from baseline (p = .23 and p = .77, respectively). Baseline ON and SCL were higher in men, but OPG was higher in women (all p ≤ .029). SCL was the only BTM that changed differently in women than men. There were no differences in baseline BTMs or change in BTMs between C-peptide groups. Exogenous hyperinsulinemia acutely alters bone turnover, suggesting a need to determine whether strategies to promote healthy remodeling may protect bone quality in T1D. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Continuous glucose monitoring abnormalities in cystic fibrosis youth correlate with pulmonary function decline.

BACKGROUND: To characterize glucose patterns with continuous glucose monitoring (CGM) in cystic fibrosis (CF) and assess relationships between CGM and clinical outcomes. METHODS: 110 CF youth and healthy controls (HC), 10-18 years, wore CGM up to 7 days. Correlations between CGM and lung function and BMI z-score change over the prior year were determined. RESULTS: Multiple CGM measures were higher in CF Normal Glycemic (CFNG) youth versus HC (peak glucose, excursions >140 mg/dl/day, %time > 140 mg/dl, standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)). Hypoglycemia was no different among groups. In CF, decline in FEV1% and FVC% correlated with maximum CGM glucose, excursions >200 mg/dl/day, SD, and MAGE. CONCLUSIONS: CFNG youth have higher glucoses and glucose variability than HC on CGM. Higher and more variable glucoses correlate with lung function decline. Whether earlier treatment of CGM abnormalities improves lung function in CF requires further study.

Hemoglobin A1c Accurately Predicts Continuous Glucose Monitoring-Derived Average Glucose in Youth and Young Adults With Cystic Fibrosis.

OBJECTIVE: In cystic fibrosis (CF), hemoglobin A1c (HbA1c) is thought to underestimate glycemia. However, few studies have directly assessed the relationship between HbA1c and average glucose in CF. We determined the relationships among glycemic markers-HbA1c, fructosamine (FA), glycated albumin (%GA), and 1,5-anhydroglucitol (1,5-AG)-and continuous glucose monitoring (CGM) in CF, hypothesizing that alternate markers would better predict average sensor glucose (ASG) than HbA1c. RESEARCH DESIGN AND METHODS: CF participants and a group of healthy control subjects (HCs), ages 6-25 years, wore CGM for up to 7 days. Pearson correlations assessed the relationships between CGM variables and HbA1c, FA, %GA, and 1,5-AG. The regression line between HbA1c and ASG was compared in CF versus HC. Linear regressions determined whether alternate markers predicted ASG after adjustment for HbA1c. RESULTS: CF (n = 93) and HC (n = 29) groups wore CGM for 5.2 ± 1 days. CF participants were 14 ± 3 years of age and 47% were male, with a BMI z score -0.1 ± 0.8 and no different from HCs in age, sex, or BMI. Mean HbA1c in CF was 5.7 ± 0.8% (39 ± 9 mmol/mol) vs. HC 5.1 ± 0.2% (32 ± 2 mmol/mol) (P < 0.0001). All glycemic markers correlated with ASG (P ≤ 0.01): HbA1c (r = 0.86), FA (r = 0.69), %GA (r = 0.83), and 1,5-AG (r = -0.26). The regression line between ASG and HbA1c did not differ in CF versus HC (P = 0.44). After adjustment for HbA1c, %GA continued to predict ASG (P = 0.0009) in CF. CONCLUSIONS: HbA1c does not underestimate ASG in CF as previously assumed. No alternate glycemic marker correlated more strongly with ASG than HbA1c. %GA shows strong correlation with ASG and added to the prediction of ASG beyond HbA1c. However, we are not advocating use of HbA1c for diabetes screening in CF based on these results. Further study will determine whether glycemic measures other than ASG differ among different types of diabetes for a given HbA1c.