Plantar fascia thickness is longitudinally associated with retinopathy and renal dysfunction: A prospective study from adolescence to adulthood

Aim: The aim was to study the longitudinal relationship between plantar fascia thickness (PFT) as a measure of tissue glycation and microvascular (MV) complications in young persons with type 1 diabetes (T1DM). Methods: We conducted a prospective longitudinal cohort study of 152 (69 male) adolescents with T1DM who underwent repeated MV complications assessments and ultrasound measurements of PFT from baseline (1997-2002) until 2008. Retinopathy was assessed by 7-field stereoscopic fundal photography and nephropathy by albumin excretion rate (AER) from three timed overnight urine specimens. Longitudinal analysis was performed using generalized estimating equations (GEE). Results: Median (interquartile range) age at baseline was 15.1 (13.4-16.8) years, and median follow-up was 8.3 (7.0-9.5) years, with 4 (3-6) visits per patient. Glycemic control improved from baseline to final visit [glycated hemoglobin (HbA1c) 8.5% to 8.0%, respectively; p = .004]. Prevalence of retinopathy increased from 20% to 51% (p \u3c .001) and early elevation of AER (\u3e7.5 μg/min) increased from 26% to 29% (p = .2). A greater increase in PFT (mm/year) was associated with retinopathy at the final assessment (ΔPFT 1st vs. 2nd-4th quartiles, χ2 = 9.87, p = .02). In multivariate GEE, greater PFT was longitudinally associated with retinopathy [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.0-10.3] and early renal dysfunction (OR 3.2, CI 1.3-8.0) after adjusting for gender, blood pressure standard deviation scores, HbA1c, and total cholesterol. Conclusions: In young people with T1DM, PFT was longitudinally associated with retinopathy and early renal dysfunction, highlighting the importance of early glycemic control and supporting the role of metabolic memory in MV complications. Measurement of PFT by ultrasound offers a noninvasive estimate of glycemic burden and tissue glycation. © Diabetes Technology Society

Higher frequency of cardiovascular autonomic neuropathy in youth with type 2 compared to type 1 diabetes : Role of cardiometabolic risk factors

Objective Cardiovascular autonomic neuropathy (CAN) is an overlooked but common and serious diabetes complication. We examined CAN in youth with diabetes and associations with cardiovascular risk factors. Research Design and Methods This was a prospective cohort of youth aged <20 years with type 2 or type 1 diabetes (n = 66/1153, median age 15.4/16.5 years, duration 1.7/8.0 years), assessed between 2009 and 2020. CAN was defined as ≥2 abnormal heart rate variability measures across time, geometric, and frequency domains. Obesity was defined as BMI ≥ 95th percentile and severe obesity as ≥120% of 95th percentile. Multivariable generalized estimating equations (GEE) were used to examine putative risk factors for CAN, including diabetes type, obesity, and HbA1c. Results At most recent assessment, youth with type 2 versus type 1 diabetes had median: HbA1c 7.1% (54 mmol/mol) versus 8.7% (72 mmol/mol) and BMI SDS (2.0 vs. 0.7); frequency of CAN (47% vs. 27%), peripheral nerve abnormality (47% vs. 25%), hypertension (29% vs. 12%), albuminuria (21% vs. 3%), and severe obesity (35% vs. 2%). In multivariable GEE, CAN was associated with type 2 diabetes: Odds Ratio 2.53, 95% CI 1.46, 4.38, p = 0.001, higher BMI SDS: 1.49, 95% CI 1.29, 1.73, p < 0.0001, and obesity: 2.09, 95% CI 1.57, 2.78, p < 0.0001. Conclusions Youth with type 2 diabetes have a higher frequency of CAN, peripheral nerve abnormality, hypertension, albuminuria and severe obesity despite shorter diabetes duration and younger age. Our findings highlight the importance of targeting modifiable risk factors to prevent cardiovascular disease in youth with diabetes

The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes

Aims/hypothesis We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. Methods A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as ‘high-risk’ for future albuminuria and the lower two tertiles were deemed ‘low-risk’. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1–Q5) for associations with log10 ACR and ACR risk groups. Results Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2–Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1–Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. Conclusions/interpretation Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.This work was supported by the National Health and Medical Research Council of Australia (NHMRC 632521), JDRF (08-2007-902), Diabetes UK (DUK PO NO 2177 BDA:RD06/003341) and the British Heart Foundation

Insulin micro-secretion in Type 1 diabetes and related microRNA profiles

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood ( 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n= 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend< 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited

Cardiac autonomic dysfunction is associated with high-risk albumin-to-creatinine ratio in young adolescents with type 1 diabetes in AdDIT (adolescent type 1 diabetes cardio-renal interventional trial).

OBJECTIVE: This study examined the association between cardiac autonomic dysfunction and high albumin-to-creatinine ratio (ACR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Adolescents recruited as part of a multicenter screening study (n = 445, 49% female, aged 10-17 years, mean duration 6.9 years; mean HbA1c 8.4%, 68 mmol/mol) underwent a 10-min continuous electrocardiogram recording for heart rate variability analysis. Time-domain heart rate variability measures included baseline heart rate, SD of the R-R interval (SDNN), and root mean squared difference of successive R-R intervals (RMSSD). Spectral analysis included sympathetic (low-frequency) and parasympathetic (high-frequency) components. Standardized ACR were calculated from six early morning urine collections using an established algorithm, reflecting age, sex, and duration, and stratified into ACR tertiles, where the upper tertile reflects higher nephropathy risk. RESULTS: The upper-tertile ACR group had a faster heart rate (76 vs. 73 bpm; P < 0.01) and less heart rate variability (SDNN 68 vs. 76 ms, P = 0.02; RMSSD 63 vs. 71 ms, P = 0.04). HbA1c was 8.5% (69 mmol/mmol) in the upper tertile vs. 8.3% (67 mmol/mol) in the lower tertiles (P = 0.07). In multivariable analysis, upper-tertile ACR was associated with faster heart rate (β = 2.5, 95% CI 0.2-4.8, P = 0.03) and lower RMSSD (β = -9.5, 95% CI -18.2 to -0.8, P = 0.03), independent of age and HbA1c. CONCLUSIONS: Adolescents at potentially higher risk for nephropathy show an adverse cardiac autonomic profile, indicating sympathetic overdrive, compared with the lower-risk group. Longitudinal follow-up of this cohort will further characterize the relationship between autonomic and renal dysfunction and the effect of interventions in this population.National Health and Medical Research Council, Australia (NHMRC) 632521, Australasian Paediatric Endocrine Group (APEG), Juvenile Diabetes Research Foundation, British Heart Foundation, Diabetes UK.This is the accepted manuscript. The final version is available at http://care.diabetesjournals.org/content/early/2015/01/01/dc14-1848

Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

<p>Abstract</p> <p>Background</p> <p>To determine association of nine single nucleotide polymorphisms (SNPs) in ADP ribosyltransferase-1 (ADPRT1), aldo-keto reductase family 1 member B1 (AKR1B1), receptor for advanced glycation end-products (RAGE), glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2), and plasminogen activator inhibitor-1 (PAI-1) genes with chronic renal insufficiency (CRI) among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS), and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set).</p> <p>Methods</p> <p>Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl) constituted the cases (n = 196), and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225). Allelic and genotypic constitution of 10 polymorphisms (SNPs) from five genes namely- <it>ADPRT1</it>, <it>AKR1B1, RAGE, GFPT2 </it>and <it>PAI-1 </it>with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes.</p> <p>Results</p> <p>Single nucleotide polymorphisms -429 T>C in <it>RAGE </it>and rs7725 C>T SNP in 3' UTR in <it>GFPT2 </it>gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in <it>GFPT2 </it>was a perfect target for predicted miRNA (hsa miR-378) suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor <it>TGF-β1 </it>(investigated using the same sample set and reported elsewhere) and <it>GFPT2 </it>genotype was observed.</p> <p>Conclusions</p> <p>Association of SNPs in <it>RAGE </it>and <it>GFPT2 </it>suggest that the genes involved in modulation of oxidative pathway could be major contributor to diabetic chronic renal insufficiency. In addition, GFPT2 mediated overproduction of TGF-β1 leading to endothelial expansion and thereby CRI seems likely, suggested by our observation of a significant interaction between GFPT2 with TGF-β1 genes. Further, identification of predicted miRNA targets spanning the associated SNP in <it>GFPT2 </it>implicates the rs7725 SNP in transcriptional regulation of the gene, and suggests <it>GFPT2 </it>could be a relevant target for pharmacological intervention. Larger replication studies are needed to confirm these observations.</p

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes.

BACKGROUND: Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting-enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. METHODS: We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima-media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine). RESULTS: The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima-media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. CONCLUSIONS: The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .)