Search

Background: Type 1 diabetes increases the risk of coronary artery disease (CAD). High-throughput metabolomics may be utilized to identify metabolites associated with disease, thus, providing insight into disease pathophysiology, and serving as predictive markers in clinical practice. Urine is less tightly regulated than blood, and therefore, may enable earlier discovery of disease-associated markers. We studied urine metabolomics in relation to incident CAD in individuals with type 1 diabetes., Methods: We prospectively studied CAD in 2501 adults with type 1 diabetes from the Finnish Diabetic Nephropathy Study. 209 participants experienced incident CAD within the 10-year follow-up. We analyzed the baseline urine samples with a high-throughput targeted urine metabolomics platform, which yielded 54 metabolites. With the data, we performed metabolome-wide survival analyses, correlation network analyses, and metabolomic state profiling for prediction of incident CAD., Results: Urinary 3-hydroxyisobutyrate was associated with decreased 10-year incident CAD, which according to the network analysis, likely reflects younger age and improved kidney function. Urinary xanthosine was associated with 10-year incident CAD. In the network analysis, xanthosine correlated with baseline urinary allantoin, which is a marker of oxidative stress. In addition, urinary trans-aconitate and 4-deoxythreonate were associated with decreased 5-year incident CAD. Metabolomic state profiling supported the usage of CAD-associated urinary metabolites to improve prediction accuracy, especially during shorter follow-up. Furthermore, urinary trans-aconitate and 4-deoxythreonate were associated with decreased 5-year incident CAD. The network analysis further suggested glomerular filtration rate to influence the urinary metabolome differently between individuals with and without future CAD., Conclusions: We have performed the first high-throughput urinary metabolomics analysis on CAD in individuals with type 1 diabetes and found xanthosine, 3-hydroxyisobutyrate, trans-aconitate, and 4-deoxythreonate to be associated with incident CAD. In addition, metabolomic state profiling improved prediction of incident CAD., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the Helsinki and Uusimaa Hospital District (491/E5/2006, 238/13/03/00/2015, HUS-3313-2018), and performed in accordance with the Declaration of Helsinki, with written informed consent obtained from the participants. Consent for publication: Not applicable. Competing interests: S.M. received a lecture honorarium from Encore Medical Education. P.-H.G. has received investigator-initiated research grants from Eli Lilly and Roche, is an advisory board member for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme, Mundipharma, Nestlé, Novartis, Novo Nordisk and Sanofi; and has received lecture fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Merck Sharp & Dohme, Medscape, Novartis, Novo Nordisk, PeerVoice and Sanofi., (© 2024. The Author(s).)

Background: Proteinuria is considered as a predictor for cardiovascular complications in diabetes mellitus (DM). However, no study has examined the association between changes in proteinuria and the risk of diabetic microvascular complications., Methods: Study participants were 71,825 DM patients who received urine dipstick test for proteinuria both in 2003-2004 and 2006-2007. They were categorized into four groups according to changes in proteinuria over 3 years (negative: negative → negative, resolved: proteinuria ≥ 1+ → negative, incident: negative → proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1+). Cox-proportional hazard model was used in assessing the adjusted hazard ratios (HR) and 95% confidence interval (CI) for incidence of retinopathy, and neuropathy (adjusted HR [95% CI])., Result: In all of DM patients, risk for comprehensive incidence of retinopathy and neuropathy increased in all types of proteinuria changes. In type 1 DM, HR for retinopathy and neuropathy generally increased in order of negative (reference), resolved (2.175 [1.150-4.114] and 1.335 [0.909-1.961]), incident (2.088 [1.185-3.680] and 1.753 [1.275-2.409]), and persistent proteinuria (1.314 [0.418-4.134] and 2.098 [1.274-3.455]). This pattern of relationship was similarly observed in type 2 DM for retinopathy and neuropathy: negative (reference), resolved (1.490 [1.082-2.051] and 1.164 [0.988-1.371]), incident (1.570 [1.161-2.123] and 1.291 [1.112-1.500]), and persistent proteinuria (2.309 [1.407-3.788] and 1.272 [0.945-1.712])., Conclusion: Risk for diabetic retinopathy and neuropathy generally increased in order of negative, resolved, incident, and persistent proteinuria. Once manifested proteinuria was associated with the increased risk of diabetic retinopathy and neuropathy even after remission of proteinuria., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Tubulointerstitial injury contributes to diabetic kidney disease (DKD) progression. We tested tubular biomarker associations with DKD development in type 1 diabetes (T1D)., Research Design and Methods: We performed a case-cohort study examining associations of tubular biomarkers, measured across seven time points spanning ∼30 years, with incident macroalbuminuria ("severely elevated albuminuria," urinary albumin excretion rate [AER] ≥300 mg/day) and sustained low estimated glomerular filtration rate (eGFR) (persistent eGFR <60 mL/min/1.73 m2) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Biomarkers included KIM-1 and sTNFR1 in serum/plasma, MCP-1 and EGF in urine, and a composite tubular secretion score reflecting secreted solute clearance. We assessed biomarkers using single values, as mean values from consecutive time points, and as change over consecutive time points, each as time-updated exposures., Results: At baseline, mean diabetes duration was 5.9 years, with mean HbA1c 8.9%, eGFR 125 mL/min/1.73 m2, and AER 16 mg/day. There were 4.8 and 3.5 cases per 1,000 person-years of macroalbuminuria and low eGFR, respectively. Assessed according to single biomarker values, KIM-1 was associated with risk of subsequent macroalbuminuria and low eGFR (hazard ratio [HR] per 20% higher biomarker 1.11 [95% CI 1.06, 1.16] and 1.12 [1.04, 1.21], respectively) and sTNFR1 was associated with subsequent macroalbuminuria (1.14 [1.03, 1.25]). Mean KIM-1 and EGF-to-MCP-1 ratio were associated with subsequent low eGFR. In slope analyses, increases in KIM-1 and sTNFR1 were associated with subsequent macroalbuminuria (per 20% biomarker increase, HR 1.81 [1.40, 2.34] and 1.95 [1.18, 3.21]) and low eGFR (2.26 [1.65, 3.09] and 2.94 [1.39, 6.23])., Conclusions: Serial KIM-1 and sTNFR1 are associated with incident macroalbuminuria and sustained low eGFR in T1D., (© 2024 by the American Diabetes Association.)

Objectives: To study the urinary neutrophil gelatinase-associated lipocalin (NGAL) and beta-2-microglobulin (β2M) levels as markers of tubular damage in children with type 1 diabetes (T1DM)., Methods: Forty T1DM children and 40 age-matched controls were enrolled. Subjects with coexisting kidney disorder, intake of oral glucose lowering drugs and syndromic diabetes mellitus were excluded. Fasting plasma glucose, glycated hemoglobin (HbA 1c ), kidney function, urinary albumin-creatinine ratio (UACR), NGAL and β2M were measured and compared in cases and controls., Results: The median (IQR) age of cases and controls was 10.6 (8, 14.2) and 10.7 (8.4, 13.7) years, respectively. Cases had disease duration of 4 (3, 6.8) years and HbA 1c 10.9 (9, 13.1) %. Microalbuminuria was seen in 14 (35 %). Median (IQR) levels of UACR were higher in cases than controls [19.38 (10.27, 35.26) and 6.49 (3.10, 11.65) µg/mg; p<0.001], similarly NGAL/creatinine [352.21 (191.49, 572.45) and 190.54 (125.91, 322.83) ng/mg; p=0.006], unlike β2M/creatinine [1.7 (0.43, 6.02) and 2.12 (1.05, 4.47) µg/mg; p=0.637]. Children with higher HbA 1c (≥10 %) had higher urinary ACR and tubular biomarkers than HbA 1c <10 % (p>0.05). Urinary ACR showed positive correlation with NGAL/creatinine (r=0.38, p=0.019) and β2M/creatinine (r=0.42, p=0.009)., Conclusions: Urinary biomarkers NGAL and β2M were elevated in the presence of normal urinary microalbumin levels suggestive of early tubular damage in T1DM., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Diabetic kidney disease (DKD) is one of the major microvascular complications of type 1 diabetes mellitus (T1DM). Some studies suggest that changes of renal tubular components emerge before the glomerular lesions thus introducing the concept of diabetic tubulopathy with urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a potential marker of DKD. This concept was not confirmed in all studies., Materials and Methods: In 198 T1DM patients with median age 15 years and diabetes duration over one year, an albumin/creatinine ratio (ACR) was determined and uNGAL measured in spot urine sample. Urine samples for ACR and uNGAL were also collected in the control group of 100 healthy children of similar age., Results: There was no significant difference in uNGAL concentration or uNGAL/creatinine between T1DM children and healthy subjects (6.9 (2.8-20.1) ng/mL vs 7.9 (2.9-21.0) ng/mL, P = 0.969 and 6.8 (2.2-18.4) ng/mg vs 6.5 (1.9-13.4) ng/mg, P = 0.448, respectively) or between T1DM subjects with albuminuria A2 and albuminuria A1 (P = 0.573 and 0.595, respectively). Among T1DM patients 168 (85%) had normal uNGAL concentrations, while in 30 (15%) patients uNGAL was above the defined cut-off value of 30.9 ng/mL. There was no difference in BMI, HbA1c and diabetes duration between patients with elevated uNGAL compared to those with normal uNGAL., Conclusions: We found no significant difference in uNGAL concentration or uNGAL/creatinine between T1DM children and healthy subjects or between albuminuria A2 and albuminuria A1 T1DM subjects. Therefore, uNGAL should not be recommended as a single marker for detecting diabetic kidney disease in children and adolescents., Competing Interests: Potential conflict of interest None declared., (Copyright Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Diabetic kidney disease (DKD) poses a significant health challenge for individuals with diabetes. At its initial stages, DKD often presents asymptomatically, and the standard for non-invasive diagnosis, the albumin-creatinine ratio (ACR), employs discrete categorizations (normal, microalbuminuria, macroalbuminuria) with limitations in sensitivity and specificity across diverse population cohorts. Single biomarker reliance further restricts the predictive value in clinical settings. Given the escalating prevalence of diabetes, our study uses proteomic technologies to identify novel urinary proteins as supplementary DKD biomarkers. A total of 158 T1D subjects provided urine samples, with 28 (15 DKD; 13 non-DKD) used in the discovery stage and 131 (45 DKD; 40 pDKD; 46 non-DKD) used in the confirmation. We identified eight proteins (A1BG, AMBP, AZGP1, BTD, RBP4, ORM2, GM2A, and PGCP), all of which demonstrated excellent area-under-the-curve (AUC) values (0.959 to 0.995) in distinguishing DKD from non-DKD. Furthermore, this multi-marker panel successfully segregated the most ambiguous group (microalbuminuria) into three distinct clusters, with 80% of subjects aligning either as DKD or non-DKD. The remaining 20% exhibited continued uncertainty. Overall, the use of these candidate urinary proteins allowed for the better classification of DKD and offered potential for significant improvements in the early identification of DKD in T1D populations., Competing Interests: Declaration of competing interest J-X.S. is CEO of Jinfiniti Precision medicine. However, the individual declares there are no competing interest or benefit received to them or the company in relation to this project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Interleukin-9 (IL-9) attenuates podocyte injury in experimental kidney disease, but its role in diabetic nephropathy is unknown. We sought to relate urinary IL-9 levels to the release of podocyte-derived extracellular vesicles (EVs) in youth with type 1 diabetes. We related urinary IL-9 levels to clinical variables and studied interactions between urinary IL-9, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) on urinary albumin/creatinine ratio (ACR) a functional measure of podocyte injury., Methods: We performed an analysis of urine samples and clinical data from a cohort of youth with type 1 diabetes (n = 53). Cytokines were measured using a Luminex platform (Eve Technologies), and nanoscale flow cytometry was employed to quantify urinary podocyte-derived EVs. All urinary measures were normalized to urinary creatinine., Results: Mean age was 14.7 ± 1.6 years, and the mean time from diagnosis was 6.7 ± 2.9 years. Mean HbA1c was 70.3 ± 13.9 mmol/mol, mean ACR was 1.3 ± 1.9 mg/mmol, and mean eGFR was 140.3 ± 32.6 ml/min/1.73 m 2 . IL-9 was inversely related to podocyte EVs (r = - 0.56, p = 0.003). IL-9 was also inversely related to blood glucose, HbA1C and eGFR (r = - 0.44, p = 0.002; r = - 0.41, p = 0.003; r = - 0.49, p < 0.001, respectively) and positively correlated with systolic BP (r = 0.30, p = 0.04). There was a significant interaction between IL-9, EVs and ACR (p = 0.0143), and the relationship between IL-9 and ACR depended on VEGF (p = 0.0083), TNFα (p = 0.0231) and IL-6 levels (p = 0.0178)., Conclusions: IL-9 is associated with podocyte injury in early type 1 diabetes, and there are complex interactions between urinary IL-9, inflammatory cytokines and ACR., (© 2022. The Author(s).)

Background: The clinical utility of Urinary C-Peptide to Creatinine Ratio (UCPCR) is well understood in people with different types of diabetes in Caucasian populations, but studies are lacking in African populations. We, therefore, aimed to examine Urinary C-Peptide to Creatinine Ratio levels among groups of people with different types of diabetes in a sub-Saharan African population., Methods: A total of 47 adults with diabetes; 10 with type 1 diabetes, 26 with type 2 diabetes, 11 with ketosis-prone diabetes, and 22 healthy control individuals, were recruited from Yaoundé Central Hospital in Cameroon. Fasting blood glucose and C-peptide were measured in venous blood and urine. Stimulated Urinary C-Peptide to Creatinine Ratio was determined in all subjects after ingestion of a standardized mixed meal. We compared the stimulated Urinary C-peptide to Creatinine Ration concentration in subjects with type 1 diabetes to the other groups., Results: The basal C-peptide and HOMA-β were lower in T1D than in the T2D group [median 57 (34, 69) vs. 398 (335, 502) pmol/l; p ≤ 0.001] and [median 3.0 (1.63, 5.25) vs. 30.6 (17.94, 45.03); p < 0.001] respectively. Also, basal C-peptide and HOMA-β were lower in T1D than in those with KPD [median 57 (34, 69) vs. 330 (265, 478) pmol/l; p = 0.003] and [median 3.0 (1.63, 5.25) vs. 47.1 (16.2, 63.1), p = 0.001] respectively. Basal C-peptide was not different between participants with T2D and KPD; 398 (335, 502) vs. 330 (265, 478) pmol/l, p = 0.19. Stimulated UCPCR was lower in T1D compared to T2D, KPD and control participants; [median 0.29 (0.14, 0.68) vs. 0.89 (0.40, 1.69) nmol/moll; p = 0.009], [median 0.29 (0.14, 0.68) vs. 1.33 (0.84, 1.59) nmol/mol; p = 0.006] and [median 0.29 (0.14, 0.68) vs. 1.21 (0.85, 1.21) nmol/mol; p = 0.005] respectively. However, stimulated UCPCR was similar between the T2D and KPD study participants; 0.89 (0.40, 1.69) vs. 1.33 (0.84, 1.59) nmol/mol, p = 0.36., Conclusions: Stimulated Urinary C-Peptide to Creatinine Ratio (UCPCR) is lower in participants with type 1 diabetes compared to those with other types of diabetes in this population. This means stimulated UCPCR could potentially differentiate type 1 diabetes from other diabetes types among people with diabetes in sub-Saharan Africa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Katte, Morfaw-Kibula, Agoons, Zemsi, Guewo-Fokeng and Sobngwi.)

Background: Tubular damage has a role in Diabetic Kidney Disease (DKD). We evaluated the early tubulointerstitial damage biomarkers in type-1 Diabetes Mellitus (T1DM) pediatric participants and studied the correlation with classical DKD parameters., Methods: Thirty-four T1DM and fifteen healthy participants were enrolled. Clinical and biochemical parameters [Glomerular filtration Rate (GFR), microalbuminuria (MAU), albumin/creatinine ratio (ACR), and glycated hemoglobin A1c (HbA1c)] were evaluated. Neutrophil gelatinase-associated lipocalin (NGAL), Hypoxia-inducible Factor-1α (HIF-1α), and Nuclear Factor of Activated T-cells-5 (NFAT5) levels were studied in the supernatant (S) and the exosome-like extracellular vesicles (E) fraction from urine samples., Results: In the T1DM, 12% had MAU >20 mg/L, 6% ACR >30 mg/g, and 88% had eGFR >140 ml/min/1.72 m 2 . NGAL in the S (NGAL-S) or E (NGAL-E) fraction was not detectable in the control. The NGAL-E was more frequent (p = 0.040) and higher (p = 0.002) than NGAL-S in T1DM. The T1DM participants with positive NGAL had higher age (p = 0.03), T1DM evolution (p = 0.03), and serum creatinine (p = 0.003) than negative NGAL. The NGAL-E correlated positively with tanner stage (p = 0.0036), the median levels of HbA1c before enrollment (p = 0.045) and was independent of ACR, MAU, and HbA1c at the enrollment. NFAT5 and HIF-1α levels were not detectable in T1DM or control., Conclusion: Urinary exosome-like extracellular vesicles could be a new source of early detection of tubular injury biomarkers of DKD in T1DM patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ugarte, Santapau, Gallardo, Garfias, Yizmeyián, Villanueva, Sepúlveda, Rocco, Pasten, Urquidi, Cavada, San Martin, Cano and Irarrázabal.)

Abstract: Microalbuminuria is associated with both with chronic kidney disease and various cardiovascular abnormalities. Given the common use of electrocardiograms (EKGs) in diagnosing cardiovascular dysfunction, this study is analyzing the relationship between EKG abnormalities and diabetic nephropathy in type 2 diabetes mellitus (DM) patients. The enrollments of this study were from the 10-year follow-up data (2003-2012) of the Diabetes Management through an Integrated Delivery System project. All study subjects underwent at least 1 EKG measurement. The urinary microalbuminuria was recorded annually. The logistic regression model was used to evaluate the association between EKG abnormalities and the occurrence of diabetic nephropathy in type 2 DM patients. The total of 1189 patients with type 2 DM are included in this study and a total of 552 patients had microalbuminuria during a 10-year follow-up. A significantly higher odds ratio of microalbuminuria occurrence (4.85) was found in the patients with premature supraventricular contraction or tachycardia compared to those without EKG abnormalities. The odds ratios of microalbuminuria occurrence were 1.00, 2.43, 2.64, and 2.98, respectively, for patients with insulin resistance in the Q (quartile) 1(as the reference), Q2, Q3, and Q4, respectively. Our findings can serve as a reference for the association between EKG abnormalities and the development of microalbuminuria in type 2 diabetes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aims/introduction: Thrombin exerts various pathophysiological functions by activating protease-activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria., Materials and Methods: Plasma HCII activity and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP), were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females)., Results: The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate-regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log-transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL-FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log-transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively)., Conclusions: The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early-stage DKD development, as represented by albuminuria., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Diabetes mellitus is a disease of dysregulated blood glucose homeostasis. The current pandemic of diabetes is a significant driver of patient morbidity and mortality, as well as a major challenge to healthcare systems worldwide. The global increase in the incidence of diabetes has prompted researchers to focus on the different pathogenic processes responsible for type 1 and type 2 diabetes. Similarly, increased morbidity due to diabetic complications has accelerated research to uncover pathological changes causing these secondary complications. Albuminuria, or protein in the urine, is a well-recognised biomarker and risk factor for renal and cardiovascular disease. Albuminuria is a mediator of pathological abnormalities in diabetes-associated conditions such as nephropathy and atherosclerosis. Clinical screening and diagnosis of diabetic nephropathy is chiefly based on the presence of albuminuria. Given the ease in measuring albuminuria, the potential of using albuminuria as a biomarker of cardiovascular diseases is gaining widespread interest. To assess the benefits of albuminuria as a biomarker, it is important to understand the association between albuminuria and cardiovascular disease. This review examines our current understanding of the pathophysiological mechanisms involved in both forms of diabetes, with specific focus on the link between albuminuria and specific vascular complications of diabetes.

Aims/introduction: The relationship between renal function and urinary glucose is poorly understood in diabetes patients who are not using sodium-glucose cotransporter 2 inhibitors. This study aimed to investigate the association of urinary glucose excretion with renal function prognosis in such patients., Materials and Methods: This retrospective cohort study included 1,172 patients with type 1 or 2 diabetes mellitus. Patients were recruited and data were collected between 1 January 2007 and 31 December 2011; follow-up data were collected until 30 June 2015. The primary outcome was set as a 30% decline in estimated glomerular filtration rate relative to baseline. The relationship between this outcome and urinary glucose was investigated using Cox proportional hazards model. For analysis, patients were categorized into two groups: urinary glucose <5 g/day or ≥5 g/day. Interaction terms were analyzed., Results: Multivariate analysis showed that the prognosis of renal function was significantly better in patients with high urinary glucose (≥5 g/day; adjusted hazard ratio 0.58, 95% confidence interval 0.35-0.96; P = 0.034). Significant interactions were observed between high urinary glucose and male sex (hazard ratio 0.33, 95% confidence interval 0.14-0.74; P = 0.007), and between high urinary glucose and longer duration of diabetes (≥10 years; hazard ratio 0.25, 95% confidence interval 0.11-0.58; P = 0.001)., Conclusions: The present study suggests that high urinary glucose is associated with prognosis in diabetes patients not taking sodium-glucose cotransporter 2 inhibitors. Measurement of 24-h urinary glucose excretion might have clinical utility for predicting renal prognosis., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: The purpose of the present study was to determine whether patients with DM1 have shown improvement, stabilization or deterioration of their urine albumin excretion levels during a close follow-up., Patients and Methods: A cohort of 84 patients, 18-76 years of age, a median duration of diabetes of 24 years (1-50 years) and a median follow-up duration of 12 years (1-37 years) were included in the study., Results: Among the 84 patients for whom we had UAE levels at the beginning and by the end of the study, mean glycosylated hemoglobin was statistically significantly decreased during the follow-up period, from 8.02±2.04-7.06±1.05% (p=0.036). Normoalbuminuria was present in 66 patients and remained so in 56 patients while 9 patients progressed to microalbuminuria and one patient to macroalbuminuria by the end of the study. Microalbuminuria was present in 15 patients: regression was observed in 8 patients, and progression in one patient. Regression of macroalbuminuria to microalbuminuria was noted in one patient and to normoalbuminuria was noted in one participant, too., Conclusions: Improvement of glycemic control with close monitoring of DM1 patients together with the appropriate use ACE or AT2 inhibitors and statins, seems to exert nephron-protective potential and to delay or even reverse the presence of micro/macroalbuminuria. This long term follow-up study has demonstrated a statistically significant increase in serum HDLcholesterol levels. The study also revealed that intensively treated diabetes patients may show reductions in serum ALP levels. Whether this finding is related to diabetic nephropathy, NAFLD, or diabetic hepatosclerosis remains to be assessed in future trials., Competing Interests: No conflict of interest has been declared by the authors., (Thieme. All rights reserved.)

Aims/hypothesis: The release of podocyte-derived microparticles into the urine may reflect early kidney injury in diabetes. We measured the urinary excretion of podocyte-derived microparticles in youth with type 1 and type 2 diabetes, and related the values to blood pressure, renal function and blood glucose levels., Methods: Cross-sectional, exploratory analysis of urine samples and clinical data from youth with type 1 (n = 53) and type 2 (n = 50) diabetes was carried out. Urinary podocyte-derived microparticle numbers, measured by flow cytometry, were assessed in relation to measures of blood glucose levels and renal function., Results: Podocyte-derived microparticle excretion (MPE) normalised to urinary creatinine (MP/UCr) was higher in type 1 vs type 2 diabetes (median [IQR] MP/UCr: 7.88 [8.97] vs 1.84 [8.62]; p < 0.0001), despite the type 2 diabetes group having higher blood pressure (systolic blood pressure, median [range]: 124 [110-154] vs 114 [94-143] mmHg) and higher proportions of microalbuminuria (44.0% vs 13.2%), but shorter time since diabetes diagnosis (median [range]: 1.2 [0.0-7.0] vs 6.4 [2.0-13.9] years), than the type 1 diabetes cohort. MPE in youth with type 1 diabetes was associated with blood glucose (p = 0.01) and eGFR (p = 0.03) but not HbA 1c , systolic or diastolic blood pressure or urine albumin/creatinine ratio. After adjustment for age at baseline, duration of diabetes, sex and BMI, the association with eGFR remained significant (p = 0.04). No associations were found between MPE and these clinical variables in youth with type 2 diabetes., Conclusions/interpretation: Significant associations between podocyte MPE, blood glucose levels and eGFR were observed in youth with type 1 diabetes but not in those with type 2 diabetes, notwithstanding increased renal pathology in the type 2 diabetes cohort. These findings suggest that podocyte injury differs in the two diabetes cohorts. Graphical abstract.

In this prospective controlled study, we examined 25 adults with adequately controlled (HbA1c level < 8.0%) type 1 diabetes mellitus (T1DM) and 49 conditionally healthy adults, intending to reveal the diversity of vitamin D metabolism in the setting of cholecalciferol intake at a therapeutic dose. All patients received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D 3 , 25(OH)D 2 , 1,25(OH) 2 D 3 , 3-epi-25(OH)D 3 and 24,25(OH) 2 D 3 ), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. The studied groups had no significant differences in baseline parameters except that the patients with diabetes showed higher baseline levels of free 25(OH)D ( p < 0.05). They also lacked a correlation between the measured and calculated free 25(OH)D in contrast to the patients from the control group (r = 0.41, p > 0.05 vs. r = 0.88, p < 0.05), possibly due to the glycosylation of binding proteins, which affects the affinity constant for 25(OH)D. The elevation of vitamin D levels after the administration of cholecalciferol was comparable in both groups, with slightly higher 25(OH)D 3 levels observed in the diabetes group throughout the study since Day 1 ( p < 0.05). Overall, our data indicate that in patients with adequately controlled T1DM 25(OH)D 3 levels and the therapeutic response to cholecalciferol is similar to that in healthy individuals.

Objective: To investigate the association between treatment-induced change in continuous glucose monitoring (CGM) time in range (TIR) and albuminuria in persons with type 1 diabetes (T1D) treated with sensor-augmented insulin pumps (SAP)., Research Design and Methods: Twenty-six out of 55 participants with albuminuria and multiple daily injection therapy (25% females; median 51 [interquartile range 46-63] years of age; glycated hemoglobin A 1c (HbA 1c ) 75 [68-88] mmol/mol [9.0% (8.4-10.4%)]; and urinary albumin-to-creatinine ratio (UACR) 89 [37-250] mg/g) were in a randomized controlled trial assigned to SAP therapy for 1 year. Anthropometrics, CGM data, and blood and urine samples were collected every 3 months., Results: Mean change (95% CI) in percentage of TIR (%TIR) was 13.2% (6.2; 20.2), in HbA 1c was -14.4 (-17.4; -10.5) mmol/mol (-1.3% [-1.6; -1.0]), and in UACR was -15% (-38; 17) (all P < 0.05). UACR decreased by 19% (10; 28) per 10% increase in %TIR ( P = 0.04), 18% (1; 30) per 10 mmol/mol decrease in HbA 1c ( P = 0.07), and 31% per 10-mmHg decrease in mean arterial pressure ( P < 0.001)., Conclusions: In this longitudinal study, treatment-induced increase in %TIR was significantly associated with decrease in albuminuria in T1D., (© 2020 by the American Diabetes Association.)

The significant risks associated with pregnancies complicated by type 1 diabetes (T1D) were first recognized in the medical literature in the mid-twentieth century. Stringent glycemic control with hemoglobin A1c (HbA1c) values ideally less than 6% has been shown to improve maternal and fetal outcomes. The management options for pregnant women with T1D in the modern era include a variety of technologies to support self-care. Although self-monitoring of blood glucose (SMBG) and multiple daily injections (MDI) are often the recommended management options during pregnancy, many people with T1D utilize a variety of different technologies, including continuous glucose monitoring (CGM), continuous subcutaneous insulin infusion (CSII), and CSII including automated delivery or suspension algorithms. These systems have yielded invaluable diagnostic and therapeutic capabilities and have the potential to benefit this understudied higher-risk group. A recent prospective, multicenter study evaluating pregnant patients with T1D revealed that CGM significantly improves maternal glycemic parameters, is associated with fewer adverse neonatal outcomes, and minimizes burden. Outcome data for CSII, which is approved for use in pregnancy and has been utilized for several decades, remain mixed. Current evidence, although limited, for commercially available and emerging technologies for the management of T1D in pregnancy holds promise for improving patient and fetal outcomes., (© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: The early detection and treatment of diabetic nephropathy (DN) is of crucial importance as patients with diabetes mellitus represent the largest proportion of patients on dialysis, with the highest morbidity and mortality. Currently, the first clinical sign of incipient DN is microalbuminuria, but its precision is not optimal. Many studies now report that proteins and peptides are new biomarkers in urine that primarily depict the pathophysiology of DN and thus allow for improved diagnosis of DN., Objectives: The presentation of new concepts for the early detection and treatment of DN for better patient management., Material and Methods: A systematic literature search was carried out., Results: Many potential markers have been described in the search for new biomarkers to diagnose DN by urinary proteome analysis. However, many of these studies were not meaningful due to the small number of samples. This limitation led to inadequate validation of proteins that could not be confirmed as markers. However, the diagnostic benefit of CKD 273, a multimarker of 273 protein fragments, was sustainably demonstrated for the early diagnosis of DN. This multi-marker shows significant advantages in the precision of diagnosis and prognosis compared to albuminuria. Furthermore, many of its peptide markers map the molecular pathophysiology of DN., Conclusions: Clinical urinary proteome analysis shows great benefits and is already an appropriate tool for the early detection of incipient DN.

Background: Currently, microalbuminuria is the gold standard for detection and prediction of diabetic nephropathy (DN). However, microalbuminuria appears once significant kidney damage has actually occurred., Objectives: We investigated the diagnostic role of urinary Cyclophilin-A (uCypA), uCypA/creatinine ratio (uCypA/Cr) and serum Cystatin-C (sCysC) as biomarkers for early detection of DN in children with type 1 diabetes mellitus (T1DM) of short duration (2-5 years) before microalbuminuria emerges., Methods: uCypA, uCypA/Cr, and sCysC levels were assessed in three age- and sex-matched groups; microalbuminuric diabetic group (n = 31), normoalbuminuric diabetic group (n = 29), and control group (n = 30). Glomerular filtration rate was estimated (eGFR) based on both serum creatinine (eGFR-Cr) and sCysC (eGFR-CysC)., Results: Significantly higher sCysC and lower eGFR-CysC were detected in both diabetic groups compared to controls and in microalbuminuric compared to normoalbuminuric group. No detected significant difference in eGFR-Cr values across the studied groups. Both uCypA and uCypA/Cr were significantly elevated in microalbuminuric compared to both normoalbuminuric and control groups with no difference between normoalbuminuric and control groups. Prediction of microalbuminuria was conducted using sCysC with area under curve up to 0.980. Combined use of sCysC and uCypA had better diagnostic value than uCypA alone., Conclusion: sCysC is a promising early biomarker for DN in childhood T1DM before albuminuria detection. eGFR-CysC is superior to eGFR-Cr in evaluating renal status in childhood T1DM. uCypA and uCypA/Cr were useful tools in predicting microalbuminuria, although not regarded as diagnostic biomarkers for early-stage DN in T1DM children by the current study., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diabetes mellitus is the most prevalent endocrine disease in the world and is likely to be the major epidemic in human history. In current years, many modern anti-diabetic medicines have been produced and introduced into the markets, however, long-term treatment of diabetes using synthetic drugs is limited. Medicinal plants play a great role in the treatment of diabetes. Many medicinal plants and their related traditional treatments for diabetes are used throughout the world and represent promising alternatives for the management of diabetes treatment. Metabolomics researches on diabetes have contributed to many aspects of exploring biomarkers and understanding the progression of the disease at metabolic levels. In addition, in the last decade, a number of metabolomics studies have focused on investigating the action mechanism of various herbal medicines. This paper aims to highlight and review a series of metabolomics studies that carried out on the role of herbal medicines on obesity and diabetes, finding potential biomarkers and also characterizing the metabolic disturbances associated with diabetes development. The findings showed that the metabolism of glycolysis/gluconeogenesis (glucose, pyruvate, lactate), TCA cycle (succinate, citrate, β-hydroxybutyrate, 2-oxoglutarate), lipid metabolism (acetoacetate, acetate) and amino acid metabolic pathways (valine, leucine, and isoleucine, hippurate, creatine) were more significantly disturbed metabolic pathways and biomarkers in diabetic models and herbal medicines affect these metabolic pathways by different mechanisms., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Increased protein glycation, oxidation and nitration is linked to the development of diabetic nephropathy. We reported levels of serum protein glycation, oxidation and nitration and related hydrolysis products, glycation, oxidation and nitration free adducts in patients with type 1 diabetes (T1DM) during onset of microalbuminuria (MA) from the First Joslin Kidney Study, a prospective case-control study of patients with T1DM with and without early decline in GFR. Herein we report urinary excretion of the latter analytes and related fractional excretion values, exploring the link to MA and early decline in GFR. We recruited patients with T1DM and normoalbuminuria (NA) (n = 30) or new onset MA with and without early GFR decline (n = 22 and 33, respectively) for this study. We determined urinary protein glycation, oxidation and nitration free adducts by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC-MS/MS) and deduced fractional excretion using reported plasma levels and urinary and plasma creatinine estimates. We found urinary excretion of pentosidine was increased ca. twofold in patients with MA, compared to normoalbuminuria (0.0442 vs 0.0103 nmol/mg creatinine, P < 0.0001), and increased ca. threefold in patients with early decline in GFR, compared to patients with stable GFR (0.0561 vs 0.0176 nmol/mg creatinine, P < 0.01). Urinary excretion of all other analytes was unchanged between the study groups. Remarkably, fractional excretions of 6 lysine and arginine-derived glycation free adducts were higher in patients with early decline in GFR, compared to those with stable GFR. Impaired tubular reuptake of glycation free adducts by lysine and arginine transporter proteins in patients with early GFR decline is likely involved. We conclude that higher fractional excretions of glycation adducts are potential biomarkers for early GFR decline in T1DM and MA. Measurement of these analytes could provide the basis for identifying patients at risk of early decline in renal function to target and intensify renoprotective treatment.

Uncontrolled type-1 diabetes (T1DM) can lead to dyslipidaemia and albuminuria, which may promote cardiovascular injuries. However, some lipidemic factors could be useful in predicting cardiac dysfunction. Seventy-eight adolescents under insulin treatment due to a 6-year history of T1DM and were retrospectively examined. Glycemia, lipidemia, and albuminuria were measured in addition to development of cardiovascular abnormalities Both girls and boys showed higher HbA1c and fasting blood glucose and 27.1% females and 33.3% males exhibited microalbuminuria though their plasma levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL) and high-density lipoproteins (HDL lipoproteins were in the normal range. They exhibited a preserved systolic function, but 50% of females and 66.6% of males had developed diastolic failures. Interestingly, girls with diastolic dysfunction showed significantly lower concentrations of HDL and higher TC/HDL and TG/HDL ratios. In fact, low HDL levels (OR 0.93; 95% CI 0.88-0.99; p = 0.029) and high TC/HDL (OR 2.55; 95% CI 1.9-5.45; p = 0.016) and TG/HDL (OR 2.74; 95% CI 1.12-6.71; p = 0.028) ratios associated with the development of diastolic complications. The cut-off values for HDL, TC/HDL, and TG/HDL were 49 mg/dL, 3.0 and 1.85, respectively. HDL and TC/HDL and TG/HDL ratios may be useful for predicting diastolic dysfunction in girls with uncontrolled T1DM.

Introduction: glycaemic control is usually best achieved using the basal bolus regimen, however, this is not always available in resource-limited settings. Long-term complications like renal parenchymal disease are consequences of poor glycaemic control. Screening type 1 diabetes patients irrespective of their disease duration was used to buttress the need for ethical principles of justice to be incorporated in the care of type 1 diabetes children., Methods: urine albumin creatinine ratio (UAC) was calculated for 20 type 1 diabetes mellitus children in the endocrinology clinic after submitting early morning urine over a 4-month period. The calculated ratio was compared between duration of disease (< 5 years and > 5 years) and between insulin regimen types (mixtard and basal bolus). Repeat tests were done for children who had elevated UAC ratio levels after 2 months., Results: there were 5 males and 15 females and the mean UAC ratio of the cohort was 123mg/g with a range of 5.30 - 906 mg/g. Twelve children (8 diagnosed less than 5 years) had UAC ratio ≥ 30mg/g with a mean of 193.15. The repeat mean UAC ratio for these was 144.35 mg/g. Children who had diabetes for more than 5 years and were on mixtard had higher UAC ratio than those with diabetes < 5 years and on basal bolus., Conclusion: the prevalence of microalbuminuria is high in our cohort of type 1 diabetes children and these were children on mixtard and had diabetes greater than 5 years., Competing Interests: The authors declare no competing interests., (Copyright: Iroro Enameguolo Yarhere et al.)

Background: The aim of the study is to identify the effect of salt intake and diabetes itself on blood pressure (BP) profile and microalbuminuria in children with type one diabetes mellitus (T1DM). Our hypothesis is that higher amount of salt consumption and/or hyperglycemia may impair blood pressure pattern in children with T1DM., Methods: This cross-sectional study included 84 children and adolescents with T1DM (62% females, age 13.9 ± 3.2 years, disease duration 7.3 ± 3.1 years, 43% poorly controlled diabetes) and 54 aged- and sex-matched healthy children with an adequately collected 24-h urine samples. Urine sodium, creatinine, and microalbumin were measured and salt intake was assessed on the basis of sodium excretion in 24-h urine. Blood pressure profile of the children with T1DM was evaluated with 24-h ambulatory blood pressure monitoring., Results: Compared to the children with well-controlled diabetes, children with poorly controlled diabetes had significantly higher standard deviation scores (SDS) of nighttime systolic BP (0.22 ± 1.28 vs - 0.87 ± 0.76, p = 0.003) and lower dipping in diastole (13.4 ± 5.9 vs 18.4 ± 8.1, p = 0.046). Among T1DM group, children with the highest quartile of salt intake had higher nighttime systolic and diastolic BP-SDS (0.53 ± 1.25 vs - 0.55 ± 0.73, p = 0.002 and 0.89 ± 1.19 vs 0.25 ± 0.63, p = 0.038, respectively) and lower dipping in systole compared to their counterparts (7.7 ± 5.0 vs 11.5 ± 6.1, p = 0.040). High averaged HbA1c was independently associated with higher both daytime and nighttime systolic BP-SDS (p = 0.010, p < 0.001) and nighttime diastolic BP-SDS (p = 0.001), and lower diastolic dipping (p = 0.001). High salt intake was independently associated with higher nighttime systolic BP-SDS (p = 0.002) and lower systolic dipping (p = 0.019). A 24-h MAP-SDS was the only independent risk factor for microalbuminuria (p = 0.035)., Conclusion: Beside poor diabetic control, high salt consumption appears to be an important modifiable risk factor for impaired BP pattern, which contributes to the development of diabetic kidney disease in children with T1DM.

Type 2 diabetes mellitus (T2DM) is frequently misdiagnosed in children and treated as type 1 DM (T1DM) with insulin. Urinary C-peptide to creatinine ratio (UCPCR) can be used to measure ß cell function and endogenous insulin. We aimed to assess the value of UCPCR to differentiate T2DM from T1DM in pediatric patients. We assessed UCPCR from urine sample taken 2 h after lunch in 50 children with T1DM and 30 children with T2DM (duration of the disease ≥ 2 years and without renal impairment). Fasting and postprandial C-peptide levels were also evaluated in all included children. Receiver operating characteristic (ROC) curve was performed to assess the optimal UCPCR cutoff level to differentiate T2DM from T1DM in children. UCPCR was significantly lower in children with T1DM compared with those with T2DM (P < 0.001). There was a significant positive correlation between UCPCR and fasting C-peptide, postprandial C-peptide, and age of onset. There was a significant negative correlation between the UCPCR and both HbA1c and duration of DM in T1DM. Fasting C-peptide had a sensitivity of 63%, a specificity of 84% at a cutoff point ≥ 1.3 ng/ml to differentiate T2DM from T1DM. Postprandial C-peptide had a sensitivity of 87%, a specificity of 86% at a cutoff point ≥ 3.2 ng/ml to differentiate T2DM from T1DM. Finally, UCPCR had a sensitivity of 97%, a specificity of 88% at a cutoff point ≥ 0.28 nmol/nmol to differentiate T2DM from T1DM in pediatric patients.Conclusion: UCPCR is an easy noninvasive reliable marker to differentiate T2DM from T1DM in pediatric patients.What is Known:• Type 2 DM (T2DM) is frequently misdiagnosed in children and treated as type 1 DM (T1DM) with insulin.• Urinary C-peptide to creatinine ratio (UCPCR) can be used to measure ß cell function and endogenous insulin.What is New:• We revealed that UCPCR had a sensitivity of 97%, a specificity of 88% at a cutoff point ≥ 0.28 nmol/nmol to differentiate T2DM from T1DM.• UCPCR is an easy noninvasive dependable marker to diagnose T2DM from T1DM in pediatric patients.

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia., Competing Interests: The authors have declared that no competing interests exist.

Aims/hypothesis: We examined whether candidate biomarkers in serum or urine can improve the prediction of renal disease progression in type 1 diabetes beyond prior eGFR, comparing their performance with urinary albumin/creatinine ratio (ACR)., Methods: From the population-representative Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) we sampled 50% and 25% of those with starting eGFR below and above 75 ml min -1 [1.73 m] -2 , respectively (N = 1629), and with median 5.1 years of follow-up. Multiplexed ELISAs and single molecule array technology were used to measure nine serum biomarkers and 13 urine biomarkers based on our and others' prior work using large discovery and candidate studies. Associations with final eGFR and with progression to <30 ml min -1 [1.73] m -2 , both adjusted for baseline eGFR, were tested using linear and logistic regression models. Parsimonious biomarker panels were identified using a penalised Bayesian approach, and their performance was evaluated through tenfold cross-validation and compared with using urinary ACR and other clinical record data., Results: Seven serum and seven urine biomarkers were strongly associated with either final eGFR or progression to <30 ml min -1 [1.73 m] -2 , adjusting for baseline eGFR and other covariates (all at p<2.3 × 10 -3 ). Of these, associations of four serum biomarkers were independent of ACR for both outcomes. The strongest associations with both final eGFR and progression to <30 ml min -1 [1.73 m] -2 were for serum TNF receptor 1, kidney injury molecule 1, CD27 antigen, α-1-microglobulin and syndecan-1. These serum associations were also significant in normoalbuminuric participants for both outcomes. On top of baseline covariates, the r 2 for prediction of final eGFR increased from 0.702 to 0.743 for serum biomarkers, and from 0.702 to 0.721 for ACR alone. The area under the receiver operating characteristic curve for progression to <30 ml min -1 [1.73 m] -2 increased from 0.876 to 0.953 for serum biomarkers, and to 0.911 for ACR alone. Other urinary biomarkers did not outperform ACR., Conclusions/interpretation: A parsimonious panel of serum biomarkers easily measurable along with serum creatinine may outperform ACR for predicting renal disease progression in type 1 diabetes, potentially obviating the need for urine testing.

Aims/introduction: To clarify the prevalence of albuminuria and renal dysfunction, and related factors in Japanese patients with diabetes, we analyzed the baseline data of the Japan Diabetes Complication and its Prevention prospective study., Materials and Methods: We used the data of 355 patients with type 1 diabetes and 5,194 patients with type 2 diabetes to evaluate the prevalence of albuminuria and renal dysfunction, and related factors. A binomial logistic regression analysis was used to investigate independent contributing factors for estimated glomerular filtration rate <60 mL/min/1.73 m 2 or albuminuria., Results: The prevalence of microalbuminuria and macroalbuminuria was 15.2% (54/355) and 3.1% (11/355) in type 1 diabetes patients, and 25.0% (1,298/5,194) and 5.1% (265/5,194) in type 2 diabetes patients, respectively. The proportion of renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ) was 9.9% (35/355) in type 1 diabetes patients, and 15.3% (797/5,194) in type 2 diabetes patients. The proportion of patients with renal dysfunction with normoalbuminuria was 7.3% (26/355) for type 1 diabetes patients, and 9.0% (467/5,194) for type 2 diabetes patients. The factors related to albuminuria in type 2 diabetes patients were glycated hemoglobin, hypertension, age, duration of diabetes, body mass index and estimated glomerular filtration rate. In contrast, factors to related renal dysfunction were age, duration of diabetes, dyslipidemia, hypertension, body mass index, male sex and albuminuria., Conclusions: We showed the recent prevalence of albuminuria and renal dysfunction, and related factors in Japanese type 1 and type 2 diabetes patients using the baseline data of the Japan Diabetes Complication and its Prevention prospective study. The current results suggest that renal disease in patients with type 2 diabetes is heterogeneous, and different mechanisms might be involved in albuminuria and deterioration of renal function., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis are captured by the urinary peptidome. To elucidate the early kidney response to chronic hyperglycemia, we conducted a peptidomic investigation into urines from otherwise healthy youths with type 1 diabetes and their non-diabetic peers using unbiased and targeted mass spectrometry-based techniques. This cross-sectional study included two separate cohorts for the discovery ( n = 30) and internal validation ( n = 30) of differential peptide excretion. Peptide bioactivity was predicted using PeptideRanker and subsequently verified in vitro Proteasix and the Nephroseq database were used to identify putative proteases responsible for peptide generation and examine their expression in diabetic nephropathy. A total of 6550 urinary peptides were identified in the discovery analysis. We further examined the subset of 162 peptides, which were quantified across all thirty samples. Of the 15 differentially excreted peptides ( p < 0.05), seven derived from a C-terminal region ( 589 SGSVIDQSRVLNLGPITRK 607 ) of uromodulin, a kidney-specific protein. Increased excretion of five uromodulin peptides was replicated in the validation cohort using parallel reaction monitoring ( p < 0.05). One of the validated peptides (SGSVIDQSRVLNLGPI) activated NFκB and AP-1 signaling, stimulated cytokine release, and enhanced neutrophil migration in vitro. In silico analyses highlighted several potential proteases such as hepsin, meprin A, and cathepsin B to be responsible for generating these peptides. In summary, we identified a urinary signature of uromodulin peptides associated with early type 1 diabetes before clinical manifestations of kidney disease and discovered novel bioactivity of uromodulin peptides in vitro Our present findings lay the groundwork for future studies to validate peptide excretion in larger and broader populations, to investigate the role of bioactive uromodulin peptides in high glucose conditions, and to examine proteases that cleave uromodulin., (© 2020 Van et al.)

Multiple genetic strategies are available to help improve understanding of diabetic nephropathy. This methods chapter provides an overview of phenotype considerations specific to diabetic nephropathy and biobank essentials, and provides detailed methodology for a common benchtop wet-lab approach (Ion Torrent semiconductor sequencing) including in silico genetic variant identification from next-generation sequencing data to identify genetic risk factors for diabetic nephropathy.

Background: Recent studies have suggested that hyperglycaemia influences the bile acid profile and concentrations of secondary bile acids in the gut., Introduction: This study aimed to measure changes in the bile acid profile in the gut, tissues, and faeces in type 1 Diabetes (T1D) and Type 2 Diabetes (T2D)., Methods: T1D and T2D were established in a mouse model. Twenty-one seven-weeks old balb/c mice were randomly divided into three equal groups, healthy, T1D and T2D. Blood, tissue, urine and faeces samples were collected for bile acid measurements., Results: Compared with healthy mice, T1D and T2D mice showed lower levels of the primary bile acid, chenodeoxycholic acid, in the plasma, intestine, and brain, and higher levels of the secondary bile acid, lithocholic acid, in the plasma and pancreas. Levels of the bile acid ursodeoxycholic acid were undetected in healthy mice but were found to be elevated in T1D and T2D mice., Conclusion: Bile acid profiles in other organs were variably influenced by T1D and T2D development, which suggests similarity in effects of T1D and T2D on the bile acid profile, but these effects were not always consistent among all organs, possibly since feedback mechanisms controlling enterohepatic recirculation and bile acid profiles and biotransformation are different in T1D and T2D., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict., Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques., Results: At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was -5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68-0.79; p < 0.001)., Conclusion: Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors., (© 2020 S. Karger AG, Basel.)

Introduction: Few studies assessing the relationship between oxidative stress and glycemic variability in children with type 1 diabetes mellitus (T1DM) are available, and most of them reported no significant results., Objective: To assess the relationship between glucose control, glycemic variability, and oxidative stress as measured by urinary excretion of 8-iso-prostanglandin F2-alpha (8-iso-PGF2α) in children with T1DM., Materials and Methods: A cross-sectional study including 25 children with T1DM. Participants were evaluated during five days in two different situations: 1st phase during a summer camp, and 2nd phase in their everyday life at home. The following data were collected in each study phase:. - Six capillary blood glucose measurements per day. Mean blood glucose (MBG) levels and glucose variability parameters, including standard deviation, coefficient of variation, and mean amplitude of glycemic excursions (MAGE), were calculated. - Capillary HbA1c level. - 24-h urine sample to measure 8-iso-PGF2α., Results: There were no statistically significant differences in urinary 8-iso-PGF2α levels (142±37 vs. 172±61pg/mg creatinine) and glucose control and glycemic variability parameters between both phases. In the 2nd phase, statistically significant correlations were found between urinary 8-iso-PGF2α and HbA1c levels (r=0.53), MBG (r=0.72), standard deviation (r=0.49), and MAGE (r=0.42). No significant correlations between glucose control, glycemic variability and urinary 8-iso-PGF2α excretion were found in the 1st phase., Conclusions: A significant correlation was found between glycemic variability and HbA1c level and urinary 8-iso-PGF2α excretion in a group of children with T1DM during their daily lives. Additional studies are needed to confirm this finding and to explore its long-term impact on health., (Copyright © 2019 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Chronic renal inflammation and fibrosis are common sequelae in diabetes mellitus (DM) and are major causes of premature mortality. Although upregulation of NPPC expression occurs in response to renal inflammation in experimental animals, nothing is known of the molecular forms of C-type natriuretic peptide (CNP) products in urine of people with DM or links with renal function., Methods: ProCNP products in urine were characterized with HPLC and a range of antisera directed to specific epitopes of amino-terminal proCNP (NTproCNP). The 5-kDa intact peptide was quantified in spot urine samples from healthy adults and 202 participants with DM selected to provide a broad range of renal function., Results: The predominant products of proCNP in urine were consistent with the 2-kDa fragment (proCNP 3-20) and a smaller peak of intact (5-kDa) fragment (proCNP 1-50, NTproCNP). No peaks consistent with bioactive forms (proCNP 82-103, 50-103) were identified. The urine NTproCNP to creatinine ratio (NCR) was more reproducible than the albumin to creatinine ratio (ACR) and strongly associated with the presence of chronic kidney disease. In models predicting independence, among 10 variables associated with renal function in DM, including plasma NTproCNP, only 3 (sex, ACR, and plasma creatinine) contributed to NCR., Conclusions: Characterization of the products of proCNP in urine confirmed the presence of NTproCNP. In spot random urine from study participants with DM, NCR is inversely associated with estimated glomerular filtration rate. In contrast to ACR, NCR reflects nonvascular factors that likely include renal inflammation and fibrosis., (© 2019 American Association for Clinical Chemistry.)

We examined if urinary angiotensinogen (uAOG), a marker of intrarenal renin-angiotensin system activity, antedates stage 3 chronic kidney disease (CKD) using samples from participants in the Diabetes Control and Complications Trial (DCCT) and later in the Epidemiology of Diabetes Intervention and Complications (EDIC) trial. In a nested case-control design, cases were matched at the outcome visit (eGFR less than 60, 21-59 mL/min per 1.73 m 2 ) on age, gender, and diabetes duration, with controls: eGFR (95, 75-119, mL/min per 1.73 m 2 .) Additionally, in an exploratory analysis progressive renal decline (PRD), defined as eGFR loss >3.5 mL/min per 1.73m 2 /year, was evaluated using only data from EDIC because no progressions were observed during DCCT. At the EDIC visit, which antedated the GFR outcome visit by 2 years (range 1-7years) the median uAOG/creatinine was markedly higher in cases than in controls (13.9 vs. 3.8 ng/mg P = 0.003) whereas at the DCCT visit, which antedated the GFR outcome by 17 to 20 years it was not (2.75 vs. 3.16 ng/mg, respectively). The Odds Ratio for uAOG and CKD stage 3 development was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 1.82 (1.00-3.29) but no longer significant when Albumin Excretion Ratio (AER) was included 1.21 (0.65-2.24).In the PRD analysis, uAOG/creatinine was sixfold higher in participants who experienced PRD than in those who did not (26 vs. 4.0 ng/mg, P = 0.003). The Odds Ratio for uAOG and PRD was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 2.48 (1.46-4.22) but no longer significant when AER was included 1.32 (0.76-2.30). In people with type1 diabetes, a robust increase in uAOG antedates the development of stage 3 CKD but is not superior to AER in predicting this renal outcome. Increased uAOG moreover is associated with PRD, an index of progression to End Stage Kidney Disease (ESKD)., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Early diabetic kidney disease (DKD) occurs in adolescents with type 1 diabetes (T1D). Lower serum uromodulin (SUMOD) predicts DKD progression in adults with T1D. In this study, we demonstrate that lower SUMOD is associated with urinary albumin excretion in adolescents with T1D, suggesting a potential relationship between SUMOD and early kidney dysfunction in T1D youth., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Homeostasis imbalance of selenium (Se) in diabetes has received great attention. This study investigated serum and urinary Se levels in patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), type 1 diabetes (T1D), and type 2 diabetes (T2D) in Northeast Chinese populations. From January 2010 to October 2011, patients with IFG (n = 12), IGT (n = 15), T1D (n = 25), T2D (n = 137), and healthy controls (n = 50) were enrolled in the First Hospital of Jilin University. Se was detected using inductively coupled plasma spectrometer. The serum Se level was dramatically lower in patients with T1D and was significantly higher in IFG subjects, and the urinary Se concentration was markedly lower in IGT and T2D groups. The serum Se levels were positively correlated with serum zinc (Zn) in both IFG and IGT groups, while urinary Se were positively associated with urinary Zn and copper (Cu) in IGT group. The serum Se levels were positively correlated with serum Cu in both T1D and T2D groups, and urinary levels of Se were positively associated with serum zinc and urinary Cu, Zn, calcium (Ca), and magnesium (Mg) and negatively correlated with serum Ca and Mg in T2D group, while the urinary levels of Se were positively correlated with urinary Zn and Mg both in peripheral neuropathy (DPN) and retinopathy (DR) groups. One month of simvastatin therapy reduced serum Se levels. These results suggest the potential role of Se in diabetes should receive attention.

Background Diabetic nephropathy (DN) is a significant cause of morbidity and mortality in young adults with type 1 diabetes (T1D). Microalbuminuria (MA) is generally considered as the earliest manifestation of DN. However, it has been shown that MA may be temporary and not reflect permanent renal failure. For this reason, sensitive markers are needed for the detection of kidney damage in the early period. Urinary tubular injury markers increase in the early period of diabetes. These tubular markers are rather indicators of acute renal damage. The objective of this study was to measure the urinary netrin-1 level, a marker of tubular injury in children with normoalbuminuric (NA) T1D, and to determine its relationship with short-term fluctuations in blood glucose using fructosamine levels. Methods Netrin-1 levels in spot urine samples from 82 children with T1D (median age 13.6 years) without MA or hypertension and from 59 healthy controls (median age 11.3 years) with a similar distribution of age and body mass index (BMI) were compared. The relationship of the netrin-1 levels with diabetes parameters such as fructosamine, hemoglobin A1c (HbA1c) or duration of diabetes was investigated. Results Urinary netrin-1 level was found to be higher in patients with T1D than in healthy controls (590 [interquartile range (IQR) = 811] pg/mg-creatinine [pg/mg-cr] and 396 [IQR = 742] pg/mg-cr, respectively) (p = 0.03). Urinary netrin-1 was found to correlate with HbA1c (p = 0.007, r = 0.320) and fructosamine (p = 0.04, r = 0.310) but not with average HbA1c in the last year (p = 0.14, r = -0.19), duration of diabetes (p = 0.83, r = 0.02) or other diabetes indices. Conclusions These results support the idea that tubular damage occurs early in the course of diabetes. However, the fact that netrin-1 is related to fructosamine and HbA1c but not to the duration of diabetes or average HbA1c in the last year may suggest that the tubular damage markers are affected by short-term fluctuations in blood glucose.

Introduction: Urinary C-peptide creatinine ratio (UCPCR) is used as a marker of endogenous insulin secretion. This study aims to assess the effectiveness of UCPCR for distinguishing between type 1 diabetes (T1DM) and non-T1DM (monogenic diabetes and T2DM) and predicting therapeutic choices in type 2 diabetes (T2DM) patients., Methods: Twenty-three patients with genetically confirmed monogenic diabetes (median age 35.0 years (interquartile range 30.0-47.0), 13 (56.5%) men), 56 patients with T1DM (median age 46.0 years (interquartile range 26.5-59.5), 28 (50.0%) men), 136 patients with T2DM (median age 53.0 years (interquartile range 42.0-60.0), 87 (64.0%) men), and 59 healthy subjects (median age 36.0 years (30.0-42.0), 26 (44.1%) men) were included. UCPCR was collected in the morning. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cut-off values to differentiate T1DM from non-T1DM. This UCPCR cut-off was used to divide T2DM patients into two groups, and the two groups were compared., Results: The UCPCR was lower in patients with T1DM compared with T2DM, monogenic diabetes, and healthy subjects, while the UCPCR was similar in T2DM and monogenic diabetes. A UCPCR cut-off of ≥0.21 nmol/mmol distinguished between monogenic diabetes and T1DM (area under the curve [AUC], 0.949) with 87% sensitivity and 93% specificity. UCPCR ≥ 0.20 nmol/mmol had 82% sensitivity and 93% specificity for distinguishing between T2DM and T1DM, with an AUC of 0.932. UCPCR was not reliable for distinguishing between monogenic diabetes and T2DM (AUC, 0.605). Twenty-five of 136 (18.4%) T2DM patients had UCPCR ≤ 0.20 nmol/mmol. Compared with T2DM patients with a UCPCR > 0.20 nmol/mmol, T2DM patients with UCPCR ≤ 0.20 nmol/mmol had a lower serum C-peptide (fasting C-peptide, 0.39 nmol/L vs. 0.66 nmol/L, P < 0.001; postprandial C-peptide, 0.93 nmol/L vs. 1.55 nmol/L, P < 0.001), lower BMI (22.8 kg/m 2 vs. 25.2 kg/m 2 , P = 0.006), and higher percentage of insulin or secretagogue therapy (92.0% vs. 59.5%, P = 0.002)., Conclusions: UCPCR is a practical and noninvasive marker that can distinguish between TIDM and T2DM or monogenic diabetes. UCPCR ≤ 0.20 nmol/mmol reflects severe impaired beta cell function and the need for insulin or secretagogue therapy in T2DM patients., Competing Interests: Wang Yanai, Gao Ying, Cai Xiaoling, Chen Ling, Zhou Lingli, Ma Yumin, Gong Siqian, Han Xueyao, and Ji Linong declare that they have no conflict of interest.

Background: Serum carotenoids are commonly used as biomarkers of fruit and vegetable (F/V) intake in the general population. Although hyperglycemia induces oxidative stress, it is unknown whether this pathway is associated with lower serum carotenoid concentrations in individuals with type 1 diabetes. Consequently, the utility of serum carotenoids as markers of F/V intake in individuals with type 1 diabetes is unclear., Objective: The study objectives were: 1) to investigate the relationship of glycemic control, oxidative stress, dietary carotenoid and F/V intake with serum carotenoid concentrations in youth with type 1 diabetes and 2) to determine whether glycemic control or oxidative stress moderates the association of carotenoid and F/V intake with serum carotenoids., Design: The study was a secondary analysis of baseline data from youth with type 1 diabetes. Blood samples were drawn from youth with type 1 diabetes to assess carotenoids and markers of glycemic control (glycated hemoglobin and 1,5-anhydroglucitol); urine samples were used to assess oxidative stress (8-iso-prostaglandin F 2α ); and 3-day diet records completed by families were used to determine F/V and carotenoid intake., Participants/setting: The study participants were youth with type 1 diabetes (n=136; age range: 8 to 16.9 years; diabetes duration ≥1 year; glycated hemoglobin: 5.8% to 11.9%) enrolled in a nutrition intervention trial from 2010 to 2013 at a tertiary diabetes center in Boston, MA., Main Outcome Measures: Serum carotenoids (total carotenoids and α-carotene, β-carotene, lycopene, β-cryptoxanthin, and lutein+zeaxanthin)., Statistical Analysis: Regression analyses were used to estimate the association of glycemic control, oxidative stress, F/V and carotenoid intake with serum carotenoids, as well as the role of glycemic control and oxidative stress in moderating diet-serum carotenoid associations., Results: Greater F/V intake (β=0.35, P<0.001) and carotenoid intake (β=0.28, P<0.01) were associated with higher total serum carotenoids, and no moderation by glycemic control or oxidative stress was observed. Greater hyperglycemia, as indicated by lower 1,5-anhydroglucitol (β=0.27, P<0.01), was related to lower serum carotenoids; however, glycated hemoglobin was not associated with serum carotenoids. 8-Iso-prostaglandin F2α was not associated with glycemic control or serum carotenoids., Conclusions: Findings support the validity of serum carotenoids as markers of F/V and carotenoid intake in youth with type 1 diabetes., (Published by Elsevier Inc.)

Na + /H + exchanger isoform 3 (NHE3) contributes to Na + /bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knockdown [Pax8-Cre; NHE3-knockout (KO) mice] were generated. NHE3-KO mice had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate, and glucose (phosphoenolpyruvate carboxykinase) in proximal tubules and H + and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in nondiabetic and diabetic NHE3-KO versus wild-type mice but was associated with renal upregulation of proinflammatory markers. Higher renal phosphoenolpyruvate carboxykinase expression in NHE3-KO mice was associated with lower Na + -glucose cotransporter (SGLT)2 and higher SGLT1 expression, indicating a downward tubular shift in Na + and glucose reabsorption. NHE3-KO was associated with lesser kidney weight and glomerular filtration rate (GFR) independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing kidney weight and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type mice; stronger SGLT1 engagement could have affected kidney weight and GFR responses. Chronic kidney disease in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids and the tricarboxylic acid cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in nondiabetic NHE3-KO mice, possibly reflecting branched-chain amino acids use for ammoniagenesis and tricarboxylic acid cycle upregulation to support formation of ammonia, bicarbonate, and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.

Background: Hypertension is one of the strongest risk factors for stroke in the general population, while systolic blood pressure has been shown to independently increase the risk of stroke in type 1 diabetes. The aim of this study was to elucidate the association between different blood pressure variables and risk of stroke in type 1 diabetes, and to explore potential nonlinearity of this relationship., Methods: We included 4105 individuals with type 1 diabetes without stroke at baseline, participating in the nationwide Finnish Diabetic Nephropathy Study. Mean age at baseline was 37.4 ± 11.9 years, median duration of diabetes 20.9 (interquartile range 11.5-30.4) years, and 52% were men. Office systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Based on these pulse pressure (PP) and mean arterial pressure (MAP) were calculated. Strokes were classified based on medical and autopsy records, as well as neuroimaging. Cox proportional hazard models were performed to study how the different blood pressure variables affected the risk of stroke and its subtypes., Results: During median follow-up time of 11.9 (9.21-13.9) years, 202 (5%) individuals suffered an incident stroke; 145 (72%) were ischemic and 57 (28%) hemorrhagic. SBP, DBP, PP, and MAP all independently increased the risk of any stroke. SBP, PP, and MAP increased the risk of ischemic stroke, while SBP, DBP, and MAP increased the risk of hemorrhagic stroke. SBP was strongly associated with stroke with a hazard ratio of 1.20 (1.11-1.29)/10 mmHg. When variables were modeled using restricted cubic splines, the risk of stroke increased linearly for SBP, MAP, and PP, and non-linearly for DBP., Conclusions: The different blood pressure variables are all independently associated with increased risk of stroke in individuals with type 1 diabetes. The risk of stroke, ischemic stroke, and hemorrhagic stroke increases linearly at blood pressure levels less than the current recommended treatment guidelines.

The link between cardiac autonomic neuropathy and risk of cardiovascular disease is highlighted as an area in which research is needed. This study was undertaken to evaluate the association between measures of cardiac autonomic function and cardiac vascular function in type 1 diabetes using new and sensitive methods. This was a cross-sectional study in patients with type 1 diabetes, stratified by normoalbuminuria ( n = 30) and macroalbuminuria ( n = 30), and in healthy control subjects ( n = 30). Cardiac autonomic function was evaluated using heart rate variability (HRV) indices, cardiovascular autonomic reflex tests (CARTs), and cardiac 123 I-metaiodobenzylguanidine (MIBG) imaging. Cardiac vascular function was assessed as myocardial flow reserve (MFR) measured by cardiac 82 Rb-positron emission tomography/computed tomography. The measures of cardiac autonomic function (except low frequency-to-high frequency ratio and the Valsalva test ratio) were positively correlated to MFR in unadjusted analysis. All the HRV indices lost significance after adjustment for age and heart rate. After further adjustment for relevant cardiovascular risk factors, the late heart-to-mediastinum ratio directly measuring the function of adrenergic receptors and sympathetic integrity (from the MIBG scintigraphy) and the 30-to-15 ratio (a CART), remained positively associated with MFR ( P ≤ 0.04). Cardiac autonomic dysfunction, including loss of cardiac sympathetic integrity in type 1 diabetes, is associated with and may contribute to impaired myocardial blood flow regulation., (© 2019 by the American Diabetes Association.)

Background: Exosomes are potential markers for several diseases and health problems. Type 1 diabetes (T1D) has increasingly been reported in children and the world T1D has become the main type of diabetes in children. This study aimed to understand the function of urinary exosomal miRNAs in T1D in children., Methods: We collected urinary samples from 30 healthy controls and 30 T1D in children. All exosomes were isolated with a combined centrifugation and were characterized by electron microscopy and western blot. The small RNA sequence was used to detect the urinary exosomal miRNAs, and miRNA markers were validated by real-time quantitative PCR. Two exosome diagnostic miRNAs were confirmed by receiver operating characteristic analyses., Results: In this study, we found higher urinary exosomal miR-424 and miR-218 expression in T1D in children than in healthy controls. Urinary exosomal miR-424 and miR-218 showed better accuracy for T1D diagnose in children., Conclusions: Our results suggest that urinary exosomal miR-424 and miR-218 are biomarkers for T1D detection in children; miR-424 and miR-218 may be predictive of T1D prognosis in children.

Objective: Histopathological changes in the kidney in type 1 diabetes mellitus (T1DM) begin before detection of microalbuminuria. Therefore, there is interest in finding a better biomarker for the early detection of diabetic kidney injury. The aim of this present study was to determine whether urinary indicators of fibrosis are detectable early in the development of T1DM in children and if they may predict progressive renal injury., Methods: Urinary matrix metalloproteinase 2 and 9 (MMP2 and MMP9), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) and transforming growth factor-β1 (TGF-β1) were assessed in 33 patients with T1DM with normal renal functions and in 24 healthy controls. Microalbuminuria was not present in the patient group with the exception of three patients. The results were adjusted to urine creatinine (Cr) and the differences between patients and controls were evaluated. These measurements were repeated after one year and the results were compared with the first year results., Results: Urine MMP2/Cr, MMP9/Cr, TIMP1/Cr, TIMP2/Cr, TGF-β1/Cr were not different between the patient and control groups (p>0.05). There were also no significant differences between the first and second year results for these biomarkers (p>0.05). None of these parameters were correlated with hemoglobin A1c, body mass index and duration of T1DM. Interestingly, all parameters were negatively correlated to age of onset of T1DM (p<0.05)., Conclusion: Our findings suggest that urinary biomarkers of fibrosis do not show an increase in diabetic children without microalbuminuria. The results also indicate that the risk of early fibrosis may increase as age of onset of T1DM decreases.

The effect of chromium (Cr) and iron (Fe) on prevalence of diabetes has received great attention. This study investigated serum and urinary Cr and Fe levels among patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), type 1 diabetes (T1D), and type 2 diabetes (T2D) in the Northeast Chinese population. From January 2010 to October 2011, patients with IFG ( n =12), IGT ( n =15), T1D ( n =25), T2D ( n =137) and healthy controls ( n =50) were enrolled in the First Hospital of Jilin University. Trace elements were detected using an inductively coupled plasma spectrometer. Serum Cr levels decreased in T2D without complications, diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), and diabetic nephropathy (DN) ( P <0.05). The urinary Cr level in T1D was the highest of all, which significantly exceeded those of the T2D groups with and without complications. No significant differences of serum Fe levels were found among all groups. The urinary Fe level of T1D was significantly increased ( P <0.05). The correlation between serum Cr and serum Fe in T2D was obviously positive ( P <0.05). One month of simvastatin therapy exerted no effects on serum or urinary Cr and Fe levels. These results suggest the potential role of Cr and Fe in diabetes should receive attention.

Despite research progresses, the chance to accurately predict the risk for diabetic nephropathy (DN) is still poor. So far, the first evidence of DN is micro-albuminuria, which is detected only 10-20 years after the onset of diabetes. Our goal is to develop new predictive tools of nephropathy starting from urine, which can be easily obtained using noninvasive procedures and it is directly related to kidney. Since it is reasonable to suppose that, in predisposed patients, the mechanisms leading to nephropathy start acting since the diabetes onset, urine from children with recent diagnosis of type 1 diabetes was subjected to proteomic analysis in comparison to age-matched controls. Targeted confirmation was performed on children with a longer history of diabetes using Western Blotting and applying a urinary lipidomic approach. To definitively understand whether the observed alterations could be related to diabetic nephropathy, urine from diabetic adults with or without albuminuria was also examined. For the first time, lipid metabolisms of prostaglandin and ceramide, which are significantly and specifically modified in association with DN, are shown to be already altered in children with a recent diabetes diagnosis. Future studies on larger cohorts are needed to improve the validity and generalizability of these findings. Data are available via ProteomeXchange with identifier PXD011183 Submission details: Project Name: Urinary proteomics by 2DE and LC-MS/MS. Project accession: PXD011183 Project DOI: https://doi.org/10.6019/PXD011183 SIGNIFICANCE: Nephropathy is a very common diabetic complication. Once established, its progression can only be slowed down but full control or remission is achieved in very few cases, thus posing a large burden on worldwide health. The first evidence of diabetic nephropathy (DN) is micro-albuminuria, but only 30% of patients with micro-albuminuria progress to proteinuria, while in some patients it spontaneously reverts to normo-albuminuria. Thus, there is clear need for biomarkers that can accurately predict the risk to develop DN. Herein, by applying proteomic and lipidomic approaches on urine samples, we show that alteration of prostaglandin and ceramide metabolisms specifically occurs in association with DN. Interestingly, we demonstrate that the modification of these metabolic pathways is an early event in diabetic patients, suggesting the identified changed proteins as possible predictive biomarkers of diabetes-induced renal function decline., (Copyright © 2018 Elsevier B.V. All rights reserved.)

C-peptide level is recognized as an important indicator of diabetes diagnosis. A sensitive and specific double-antibody sandwich enzyme-linked immunosorbent assay for the detection of C-peptide based on double antibody sandwich method was studied in this paper. The rabbit and hen were innunized with PLL-C-peptide and BSA-C-peptide respectively to obtain specific Yolk antibody (IgY) and polyclonal antibody used to construct the sandwich ELISA for the measurement of C-peptide. The limit of detection was 0.51 μg/mL and the half maximal inhibitory concentration (IC50) was 3.26 μg/mL. The method developed in the study showed no evident cross-reactivity with other similar analogs. The detection standard curve of C-peptide exhibited a good linearity (R 2  = 0.9896, n = 15). 17 types of the urine of diabetes patients on c-peptide levels compared with the hospital type of diabetes information, with a conclusion of a high consistent rate. Therefore, the methods could be selectively used for rapid screening of C-peptide in human urine, and the type of diabetes has some referential significance., (Copyright © 2018. Published by Elsevier B.V.)