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Introduction: To assess the Type 2 Diabetes Mellitus (T2DM) patients in association with Chronic Microvascular Complications at Glucose Peak Time and the association among chronic microvascular complications in T2DM patients and the glucose peak period in the typical steamed bread meal test., Methods: Overall 1095 T2DM patients were classified as three groups: (1) Group G1: glucose peak time ≤ 1 h (n = 84), Group G2: 1 h < glucose peak time ≤ 2 h (n = 648) and Group G3: glucose peak time > 2 h (n = 363). The clinical characteristics, insulin characteristics and glucose peak time and chronic microvascular complications markers of patients in each group was analyzed and compared. Statistical analyses were performed using SPSS 23.0, employing chi-square tests, Kruskal-Wallis tests, one-way ANOVA, and binary logistic regression analysis, with significance set at P < 0.05., Results: Age, length of disease, glycated hemoglobin (HbA1c), urine albumin-creatinine ratio (UACR), and the number of patients with diabetic retinopathy (DR) increased (all P < 0.05) in those with postponed glucose peak time, while insulinogenic indexes, the AUC for C-p (AUCC-p), fasting, and 120-min C-peptide (C-p) decreased (all P < 0.05). Only age was connected to patients with diabetic kidney disease (DKD) independently in binary logistic regression analysis, although delayed glucose peak time was related to the presence of patients with DR. (all P < 0.05)., Conclusion: Delayed glucose peak time contributed to DR. Attention should be paid to condition of chronic microvascular complications in T2DM patients with a postponed peak glucose timing., Competing Interests: Declaration of competing interest There is no potential conflict of interest about this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to investigate the short-and long-term effect on diabetic retinopathy (DR) in individuals with type 1 diabetes treated with continuous subcutaneous insulin injections (CSII) compared to those using multiple daily injections (MDI)., Methods: We conducted a register-based matched cohort study utilizing data from the Danish Registry of Diabetic Retinopathy as well as several other national Danish health registers. Our cohort consisted of all individuals with type 1 diabetes who attended the Danish screening program for DR from 2013 to 2022. We included individuals registered with CSII treatment, and compared them to individuals using MDI, matched by age, sex, and DR level. Cox regression analysis was performed to evaluate the outcomes., Results: The study included 674 individuals treated with CSII and 2006 matched MDI users. In our cohort 53.4 % were female and median age was 36 (IQR 27-47). Average follow-up risk-time was 4.8 years. There was no difference in the risk of DR worsening between the CSII group and MDI group (HR 1.05 [95%CI 0.91; 1.22], p = 0.49). However, an increased risk of focal photocoagulation was observed in the CSII group (HR 2.40 [95%CI 1.11; 5.19], p = 0.03)., Conclusions: Our findings indicate that CSII treatment does not confer a significant difference in the overall short- and long-term risk of DR worsening or ocular intervention compared to MDI treatment. These results provide insights into the DR outcomes of CSII treatment in individuals with type 1 diabetes., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Aims: There are limited studies on dipeptidyl-peptidase 4 inhibitor (DPP-4i), sodium glucose cotransporter 2 inhibitor (SGLT2-i), and glucagon-like peptide 1 (GLP-1) receptor agonist use and occurrence of diabetic macular edema (DME). The objective of this study was to determine the association between DPP-4i, SGLT2-i, and GLP-1 receptor agonist use and occurrence of DME., Methods: Proportional hazard models were used to evaluate the change in hazard of developing DME associated with DPP-4i, SGLT2-i, or GLP-1 receptor agonist use. Models accounted for age at DR diagnosis, DR severity (proliferative vs non-proliferative stage), time-weighted average of HbA1c level, sex, and self-reported race/ethnicity. A p-value ≤ 0.05 was considered statistically significant., Results: The hazard ratio of developing DME after diagnosis of DR was 1.2 (CI = 0.75 to 1.99; p = 0.43) for DPP-4i use, 0.93 (CI = 0.54 to 1.61; p = 0.81) for GLP-1 receptor agonist use, 0.82 (CI = 0.20 to 3.34; p = 0.78) for SGLT2-i use, 1.1 (CI = 0.75 to 1.59; p = 0.66) for any one medication use, 1.1 (CI = 0.62 to 2.09; p = 0.68) and for any two or more medications use., Conclusions: We did not find an association between DPP-4i, SGLT2-i, or GLP-1 receptor agonist use and increased hazard of development of DME among patients with DR., Competing Interests: Declaration of competing interest RMW reports receiving research support from Novo Nordisk outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To analyze the systemic and ocular outcomes in patients with young-onset type 2 diabetes (YO-DM2) based on grade of presenting diabetic retinopathy (DR)., Methods: Retrospective cohort study analysis of empaneled patients with type 2 diabetes <40 years old with retinopathy screening within the Los Angeles Department of Health Services between 01/01/2017-07/01/2021 were included. Patients were stratified based on presenting severity of DR determined on fundus photographs or clinical examination. Patient's systemic co-morbidities and ocular outcomes were then compared across each group. Procedural (e.g. intravitreal injections) and surgical interventions (e.g. pars plana vitrectomy) were documented as performed by the treating physician., Results: 2795 patients were screened from 12,456 patients diagnosed with diabetes younger than age 40 (22.4 %). Of these, 1496 patients were diagnosed with type 2 DM. 1084 (72.4 %) of patients presented without DR, 307 (20.5 %) presented with non-proliferative diabetic retinopathy (NPDR), and 105 (7.0 %) of patients presented with proliferative diabetic retinopathy (PDR). Increasing presenting diabetic retinopathy severity was associated with longer duration of diabetes, greater systemic comorbidities (e.g. diabetic foot disease, neuropathy, chronic kidney or end stage renal disease), worse baseline and final visual acuity, and required more procedural and surgical interventions., Conclusions: Worse presenting DR severity in patients young-onset type 2 diabetes was associated with greater comorbid systemic and ocular disease with worse visual acuity outcomes. <1 % of patients without diabetic retinopathy or with mild NPDR were likely to progress to PDR. Diabetic kidney disease was an independent risk factor for developing neovascular glaucoma and retinal detachments. Prompt evaluation and intervention in patients with YO-DM2 may help reduce the associated systemic and ocular morbidity., Competing Interests: Declaration of competing interest Pradeep Prasad has the following financial disclosures: Abbvie: C; Alimera Sciences, Inc.: C; DORC International, bv/Dutch Ophthalmic, USA: L; OD-OS GmbH: L; Regeneron Pharmaceuticals, Inc.: L. C=Consultant, L=Speaker/Lecturer. The other authors have no financial disclosures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To study the association between cystatin C and sight-threatening diabetic retinopathy (STDR) in Asian Indians with type 2 diabetes (T2DM)., Methods: In a cross-sectional study carried out at two tertiary centres in India in 2022, individuals with T2DM underwent clinical and ophthalmic assessments and estimation of serum cystatin C. Grading of DR was done by retina specialists. STDR was defined by the presence of severe non-proliferative DR (NPDR), proliferative DR (PDR) and/or diabetic macular edema. Receiver operating characteristic (ROC) curves were used to identify cystatin C cut-off value for detecting STDR., Results: Among 420 individuals with T2DM (mean age 56 ± 9 years; mean duration of diabetes 14.5 ± 7.9 years), 121 (24.1 %) had No-DR, 119 (28.3 %) had No-STDR and 200 (49.6 %) had STDR. Mean cystatin C level was significantly higher in individuals with STDR compared to those with no-STDR and No-DR (1.34 vs 1.06 vs 0.93 mg/L, p < 0.001). Cystatin C cut-off value ≥1.11 mg/L had a C statistic of 0.944 (95 % CI: 0.909-0.968, p < 0.001), 96.8 % sensitivity and 78.2 % specificity for detection of STDR., Conclusion: Elevated serum cystatin C was strongly associated with STDR and could possibly be used as a biomarker for screening for sight-threatening diabetic retinopathy., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Our study is aimed to investigate the relationship between high-density lipoprotein cholesterol to apolipoprotein A ratio (HDL-C/ApoA) and diabetic retinopathy (DR) in subjects with type 2 diabetes mellitus (T2DM)., Methods: We retrospect the consecutive medical files of 1058 subjects with T2DM and recorded their clinical information and laboratory findings. Subjects with T2DM were divided into DR group (n = 522) and non-DR group (n = 536). We compared the lipids values of the two groups. Meanwhile we also observed the prevalence of DR at different HDL-C/ApoA levels. Binary logistic regression was used to correct confounding factors. Smooth curve fitting model and subgroup analysis were used to determine the correlation, non-linear relationship and threshold effect between HDL/ApoA and DR., Results: HDL-C/ApoA value of DR group was significantly higher than non-DR group (0.88 ± 0.17 vs 0.84 ± 0.13, P < 0.05). The prevalence of DR significantly increased as HDL-C/ApoA level increased. There was association between HDL/ApoA levels and DR in the adjusted models (OR 1.55, 95%CI 0.60 to 4.02). After full adjustments for other relevant clinical covariates, patients with HDL/ApoA values in quartile 3 (Q3) had 1.50 times (95 % CI 1.00 to 2.17) and in Q4 had 2.39 times (95%CI 1.65 to 3.47) as high as the risk of DR compared with patients in Q1. HDL/ApoA showed a non-linear relationship with DR, with an inflection point value of 0.759. When HDL/ApoA>0.759, HDL/ApoA was significantly positively associated with DR (HR = 26.508, 95 % CI 7.623-92.174; P < 0.0001). Compared to patients with age < 60, HDL/ApoA was obviously associated with DR when age ≥ 60 (OR = 38.05, 95 % CI 8.06-179.69; P < 0.001)., Conclusions: HDL-C/ApoA was found to be associated with the incidence of DR in patients with T2DM. After adjusting potential related factors HDL-C/ApoA OR value was 1.55 (95%CI 0.60 to 4.02). A non-linear association between HDL/ApoA and DR was observed in T2DM. Subgroup analysis showed that age could alter the relationship between HDL/ApoA and DR., Competing Interests: Declaration of competing interest The authors declare that they have no conficts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims/hypothesis: We investigated associations among glucose time in range (TIR, 70-180 mg/dL), glycemic markers and prevalence of diabetic microangiopathy in people with diabetes undergoing hemodialysis (HD)., Methods: A total of 107 people with type 2 diabetes undergoing HD (HbA 1c 6.4 %; glycated albumin [GA] 20.6 %) using continuous glucose monitoring were analyzed in this observational and cross-sectional study., Results: HbA 1c and GA levels significantly negatively correlated with TIR, and positively correlated with time rate of hyperglycemia, but not with time rate of hypoglycemia. TIR of 70 % corresponded to HbA 1c of 6.5 % and GA of 21.2 %. The estimated HbA 1c level corresponding to TIR of 70 % in this study was lower than that previously reported in people with diabetes without HD. The prevalence of diabetic neuropathy was not significantly different between people with TIR ≥ 70 % and those with TIR < 70 % (P = 0.1925), but the prevalence of diabetic retinopathy in people with TIR ≥ 70 % was significantly lower than in those with TIR < 70 % (P = 0.0071)., Conclusion/interpretation: TIR correlated with HbA 1c and GA levels in people with type 2 diabetes on HD. Additionally, a higher TIR resulted in a lower rate of diabetic retinopathy., Research in Context: What is already known about this subject? What is the key question? What are the new findings? How might this impact on clinical practice in the foreseeable future?, Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Akinori HAYASHI reports speaker honoraria from Medtronic, Abbott, Terumo, Roche; research grants from Abbott and Roche outside of the submitted work. Naoya SHIMIZU. reports speaker honoraria from Medtronic. Takeshi MIYATSUKA reports speaker honoraria and a research grant from Abbott outside of the submitted work. The authors report no other potential conflicts of interest relevant to this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To develop a nomogram for the risk of diabetic retinopathy (DR) among type 2 diabetes mellitus (T2DM)., Methods: Questionnaires, physical examinations and biochemical tests were performed on 5900 T2DM patients in the Second Hospital of Shijiazhuang. The least absolute shrinkage and selection operator regression was used to optimize feature selection, and the importance of selected features was analyzed by random forest. Logistic regression was performed with selected features, and the nomogram was established based on the results. The Harrell's C-statistic, bootstrap-corrected C-statistic, area under curve (AUC), calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC) were used to validate the discrimination, calibration and clinical usefulness of the nomogram, and further assessment was running by external validation., Results: Predictors included duration of diabetes, diabetic neuropathy, diabetic kidney disease, diabetic foot, hyperlipidemia, hypoglycemic drugs, glycated albumin, Lactate dehydrogenase. The model displayed medium predictive power with a Harrell's C-statistic of 0.820, bootstrap-corrected C-statistic of 0.813 and AUC of 0.820 in the training set, and which was respectively 0.842, 0.835 and 0.842 in the validation set. The calibration curve displayed good agreement (P > 0.05). The DCA and CIC showed that the nomogram could be applied clinically if the risk threshold is between 2 % and 75 % and 2 %-88 % in validation set., Conclusions: This nomogram incorporating 8 features is useful to predict the risk of DR in T2DM patients., Competing Interests: Declaration of competing interest All authors declare they have no financial nor personal conflicts of interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: To understand the relationship of obesity and 27 circulating inflammatory biomarkers to the prevalence of non-proliferative diabetic retinopathy (NPDR) in youth with type 2 diabetes., Methods: Youth with type 2 diabetes who participated in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study were followed for 2-6.5 years. Digital fundus photographs were obtained in the last year of the study. Blood samples during the study were processed for inflammatory biomarkers, and these were correlated with obesity tertiles and presence of retinopathy., Results: Higher BMI was associated with an increase in circulating levels of metabolic biomarkers including high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor 1 (PAI-1), fibrinogen, LDL-cholesterol (LDL-C) and Apolipoprotein B (ApoB), tumor necrosis factor receptors 1 and 2 (TNFR-1 and -2), interleukin 6 (IL-6), E-selectin, and homocysteine, as well as a decrease in the metabolic risk markers HDL-cholesterol (HDLC), and insulin-like growth factor binding protein 1 (IGFBP-1). Although NPDR risk decreased with increasing obesity, it was not associated with any of the measured biomarkers., Conclusions: Circulating levels of measured biomarkers did not elucidate the "obesity paradox" of decreased NPDR in the most obese participants in the TODAY study., Trial Registration: clinicaltrials.govNCT00081328., Competing Interests: Declaration of competing interest Ruth S. Weinstock participates in multicenter clinical trials, through her institution, sponsored by Medtronic, Insulet, Eli Lilly, Boehringer Ingelheim, Kowa and Tolerion Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Assessing the hemodynamic changes of diabetic retinopathy (DR) using harmonic analysis of both non-invasively measured radial pulse and photoplethysmography (PPG) signals to propose a DR risk indicator., Methods: A total of 1879 patients with diabetes were followed on average of 3.5 years. The radial pulse and PPG signals were measured at the beginning of the trial. Kaplan-Meier curves of the DR risk indicator was analyzed. In addition, the correlation between the measurements of the radial pulse and PPG was evaluated., Results: In comparison of the patients' clinical characteristics, years of diabetes, systolic blood pressure, HbA1C, ACR, urinary albumin and fourth harmonic (C4) were higher in the DR group, and eGFR and third harmonic (C3) were lower. Patients in the high-DR risk group had a 1.8-fold higher risk of developing retinopathy than those in the low-risk group (log-rank test, p < 0.001). The correlation coefficient between radial pulse and PPG measurements for C3 and C4 were 0.727 and 0.628, respectively., Conclusions: The harmonic analysis of radial pulse and PPG signals may be used to reflect the effect of DR in hemodynamics and the derived harmonic components may predict the risk of DR of patients with type 2 diabetes., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: The effect of Glucagon-like peptide 1 receptor agonists (GLP1 RA) on diabetic retinopathy (DR) remains controversial. Previous reviews combined data from randomized clinical trials (RCTs) with or without cardiovascular (CV) benefits and did not address confounders, therefore may have generated misleading results. The study aimed to examine the effect of GLP1RA on DR in type 2 diabetes (T2DM) in RCTs with or without CV benefits and distinguish the effect by major confounders., Methods: We conducted electronic searches of multiple databases and a manual search using references lists. We included 13 RCTs examining the effect of GLP1 RA on health outcomes/adverse events including DR or DR complications in T2DM. We performed a random-effects model meta-analysis., Results: GLP1RA was associated with an elevated risk of rapidly worsening DR in four major RCTs with CV benefits in T2DM (OR 1.23, 95 % CI 1.05-1.44). The association between GLP1 RA and DR was significant in subgroups of RCTs with length over 52 weeks (1.2, 1.00-1.43), using placebo as a comparator (1.22, 1.05-1.42). In subgroups with patients who had T2DM ≥10 years (1.19, 0.99-1.42) or with subjects enrolled from multiple countries (1.2, 0.99-1.46), the association appeared to be evident but did not reach statistical significance., Conclusions: GLP1 RA including liraglutide, semaglutide, and dulaglutide are associated with an increased risk of rapidly worsening DR in RCTs with CV benefits. Further data from clinical studies with longer follow-up purposefully designed for DR risk assessment, particularly including patients of established DR are warranted., (Copyright © 2022. Published by Elsevier Inc.)

Aims: Few studies investigated the association of genetic difference in metalloproteinase-2 (MMP-2) gene with diabetic retinopathy but with mixed outcome. To investigate the association between a set of MMP-2 genetic variants and the risk of diabetic retinopathy in an Arab Tunisian population with type 2 diabetes., Subjects and Methods: A retrospective case-control study comprising a total of 779 type 2 diabetes patients with or without diabetic retinopathy was conducted. Genotyping was prepared by TaqMan® SNP genotyping qRT-PCR. The variants used were rs243865 (C/T), rs243864 (T/G), rs243866 (G/T) and rs2285053 (C/T)., Results: The minor allele frequency (MAF) of the rs243864 MMP-2 variant was significantly higher among diabetic retinopathy patients. Setting homozygous wild type genotype carrier as reference, the rs243864T/G allele was associated with increased risk of diabetic retinopathy under the dominant, recessive, and additive models which persisted when key covariates were controlled for, while a reduced risk of diabetic retinopathy progression was seen after adjustment between non-proliferative and proliferative diabetic patients. Furthermore, the heterozygous genotype GT of the rs243866 variant is positively associated with the risk of proliferative diabetic retinopathy in the additive model. A limited linkage disequilibrium (LD) was revealed between the four-matrix metalloproteinase-2 variants. Four-loci haplotype analysis identified, GCTC, TTTC, and GCTT haplotypes to be positively associated with the risk of diabetic retinopathy., Conclusion: Our findings demonstrate that the MMP-2 variant rs243864 and 243866 are related to the susceptibility to diabetic retinopathy and the progression of the disease in an Arab Tunisian population with type 2 diabetes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Prevalence of cerebral small vessel disease (SVD) in elderly patients with diabetic retinopathy (DR) is higher than in those without DR. We determined the prevalence and severity of SVD in middle-aged patients with DR and compared it with those without DR (NODR) in a subset of the Indian population. We feel this information is critical with evolving trends of an increasing incidence of stroke at younger ages., Method: Institution-based analytical cross-sectional study with 88 middle-aged type 2 diabetes patients; 44 in each group with <10 years diabetes duration, <8% HbA1C value, and with no history of cardiovascular disease. The presence and severity of SVD were determined by magnetic resonance imaging (MRI)., Result: Prevalence of SVD was 59.1% among study participants; 70.5% in DR and 47.7% in NODR (p = .03). Significantly increased SVD score (p = .008), high SVD score (p = .030), and white matter hyperintensity (WMH) load (p = .017) were observed in DR compared to NODR. There was no difference in the load of lacune and microbleed. SVD score did not differ according to the severity of DR (p = .395). The location-wise study of MRI revealed a significantly higher SVD load at the centrum semiovale in DR than in NODR (p = .014). We observed a 2.6 times greater chance of SVD (Odds ratio: 2.6, 95% CI 1.1-6.3) and a 9.6 times greater chance of high SVD score (Odds ratio: 9.6, 95% CI 1.1-80.0) in DR compared to NODR., Conclusion: Significantly higher burden of SVD in DR was observed, particularly affecting the centrum semiovale suggesting an association of mid-life SVD with DR in this population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: To assess the prevalence of diabetic retinopathy (DR) and associated risk factors in Asian Indians with prediabetes., Methods: In a cross-sectional study conducted at two tertiary care diabetes centres in Chennai, India, clinical and biochemical assessment and nonmydriatic ultra-wide field fundus photography was performed in individuals with prediabetes (impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) based on oral glucose tolerance test (OGTT) and/or glycated hemoglobin (HbA1c) between 5.7% and 6.4% in 2019. The retinal photographs were graded by certified ophthalmologists. Systemic risk factors associated with DR in prediabetes were assessed., Results: The mean age of the 192 individuals with prediabetes was 48 ± 13 years (55.2% were males). DR was present in 12 (6.3%) individuals of which nine (4.7%) had mild non-proliferative DR (NPDR) and three (1.6%) had moderate NPDR. None had severe sight-threatening DR. The Poisson multiple regression analysis showed that after adjusting for other systemic covariates, HbA1c values ≥ 6% (6-6.4%) was associated with 2 times higher relative risk of DR (Risk ratio 1.95 (95% CI 1.07-3.545, p = 0.028) in comparison to HbA1c < 6%)., Conclusion: DR was present in about 6% of the Asian Indians with prediabetes. Higher HbA1c values among individuals with prediabetes was associated with twice the relative risk for DR. Robust control of HbA1c should be encouraged even before the diagnosis of diabetes is established., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Identifying and modulating risk factors is essential to prevent visual impairment due to diabetic retinopathy (DR). This study examines incident DR with metabolic and hormonal factors in newly-diagnosed, treatment naïve, individuals with Type2 Diabetes Mellitus (T2DM), over a 5 year period from diagnosis., Methods: 233 T2DM subjects underwent serial DR screening using digital photography and standardised Meal Tolerance Tests at diagnosis and after 1, 2 and 5 years. Subjects (179) with no DR throughout the 5-year study period were compared with those who developed DR (54)., Results: Of 233 subjects, 54(23.2%) developed DR by 5 years, background DR in 50(93%) and exudative maculopathy in 4(7%) individuals. Of these subjects, 12(22%) developed DR after 1 year, 15(28%) after 2 years and 27(50%) after 5 years. At baseline, those with DR at 5 years had higher HbA 1c (p = 0.017), higher fasting plasma glucose (PG) (p = 0.031) and postprandial PG (p = 0.009). They were associated with reduced basal β-cell secretory function (M 0 ) (p = 0.025), lower (p = 0.000) postprandial β-cell responsiveness (M 1 ) and β-cell function (HOMA-B) (p = 0.044)., Conclusions: There is an independent association between glycaemic control and β-cell dysfunction at the time of diagnosis of T2DM, with incident DR over a follow-up period of 5 years., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: There is a paucity of studies regarding the association between long-term glycemic variability with the risk of diabetic retinopathy (DR) in patients with type 2 diabetes. Therefore, the purpose of this study is to explore the association of glycated albumin (GA) variability and HbA1c variability with the risk of DR in patients with type 2 diabetes., Methods: This prospective cohort study included 315 inpatients with type 2 diabetes (191 males and 124 females) with at least 3 measurements of GA and HbA1c within 2years prior to the baseline investigation. Different GA and HbA1c variability markers were calculated, including CV, variability independent of the mean (VIM), and the average real variability (ARV). Cox proportional hazard regression models were used to explore the association between visit-to-visit variability of GA and HbA1c and the risk of DR., Results: After an average follow-up of 3.42years, 81 patients developed incident DR. Multivariable-adjusted (diabetes duration, smoking status, systolic blood pressure, albumin to creatinine ratio, triglycerides, using fibrates, and mean HbA1c) hazard ratios of DR associated with each unit increase in GA-CV, GA-VIM, and GA-ARV were 1.05 (95% CI 1.02-1.09), 1.69 (95% CI 1.24-2.32), and 1.13 (95%CI 1.04-1.23), respectively. However, there was no significant association between visit-to-visit HbA1c variability and the risk of DR., Conclusions: The present study indicated that visit-to-visit variability of GA can predict the risk of incident DR in patients with type 2 diabetes, and the prediction ability is independent of the average HbA1c levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To determine whether biomarkers for diabetic kidney disease (DKD) can be used to determine the prevalence, progression and/or incidence of diabetic retinopathy (DR) complicating type 2 diabetes., Methods: Proteomic biomarkers were measured in baseline fasting plasma from 958 Fremantle Diabetes Study Phase II participants whose baseline and, in those returning for follow-up (n = 764), Year 4 fundus photographs were graded for DR presence/severity. The performance of PromarkerD (three biomarkers and readily available clinical variables which identify prevalent DKD and predict incident DKD and estimated glomerular filtration rate decline ≥30% over four years) for detecting DR prevalence, progression and incidence was assessed using the area under the receiver operating curve (AUC). Logistic regression determined whether individual proteins were associated with DR outcomes after adjusting for the most parsimonious model., Results: Plasma apolipoprotein A-IV (APOA4) was independently associated with moderate non-proliferative DR at baseline (OR (95% CI): 1.64 (1.01, 2.67), P = 0.047). Model discrimination was poor for all PromarkerD predicted probabilities against all DR outcomes (AUC ≤0.681)., Conclusions: PromarkerD and its constituent biomarkers were not consistently associated with DR prevalence or temporal change. APOA4 was associated with prevalent DR, but not DR incidence or progression. Distinct pathophysiological mechanisms may underlie DKD and DR., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The heterogeneity in myocardial repolarization increases the risk of ventricular arrhythmias and sudden death in patients with diabetes mellitus (DM). The Tp-e interval and Tp-e/QTc ratio are found to be useful in the prediction of ventricular arrhythmias. In this study, we aimed to investigate the Tp-e interval and Tp-e/QTc ratio in diabetic patients with and without microvascular complications., Materials and Methods: This cross-sectional observational study included patients with type 2 DM who presented to the endocrinology outpatient clinic. Diabetic microvascular complications were evaluated. The Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were also calculated., Results: A total of 240 patients with type 2 DM (148 patients had microvascular complications) were included in the study. Diabetic neuropathy rate was 30.4%, diabetic nephropathy rate was 38.4%, and diabetic retinopathy rate was 21.7%. Upon comparing patients according to Tp-e/QTc ratio, the median Tp-e/QTc interval of the group of patients with complications was 0.21 (0.19-0.23) and the median Tp-e/QTc ratio of the group of patients without complications was 0.19 (0.18-0.20) (p < 0.001). When patients were grouped according to the presence and severity of retinopathy, the Tp-e/QTc ratio was more prolonged in the proliferative retinopathy group [0.27 (0.23-0.30)] than the non-proliferative retinopathy group [0.20 (0.19-0.22), p < 0.001]. When patients were grouped according to the presence and severity of nephropathy, the Tp-e/QTc ratio was more prolonged in the macroalbuminuria and microalbuminuria group than the normoalbuminuric group [0.25 (0.21-0.30), 0.23 (0.19-0.24), and 0.19 (0.20-0.22), respectively, p = 0.002]., Conclusions: Our study is the first to demonstrate the association of the Tp-e interval and Tp-e/QTc ratio with the presence and severity of microvascular complications in patients with type 2 DM., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Does Diabetic Retinopathy (DR) relate to a previous dramatic reduction of HbA1c in Type 2 Diabetes (T2D)?, Methods: In patients hospitalized for T2D, we collected HbA1c values from previous years, and we defined "Rapid declinors" by a more than -3% reduction between two consecutive HbA1c, and "sustained moderate declinors" by HbA1c declining less than -3%. We analyzed the relation between DR and previous HbA1c courses, adjusted for other risk factors., Results: Our 680 patients had a mean HbA1c at 8.7 ± 1.7% at admission and 8.7 ± 1.8 to 9.0 ± 2.2% during previous years (1500 HbA1C values collected), and 24% had a DR. A previous rapid decline of HbA1c occurred in 13.5% of subjects and related to DR (OR = 1.86, 95%CI:1.02-3.40), especially proliferative (OR = 2.64, 95%CI:1.02-6.80), after adjustment for age, gender, body mass index, arterial hypertension and diabetic kidney disease, blood lipids and statin treatment, duration of diabetes and mean previous HbA1c. A previous moderate reduction of HbA1c as occurred in 28.3% other subjects was not related to DR., Conclusions: In subjects hospitalized for T2D, a previous rapid decline of HbA1c was related to proliferative DR, whereas a sustained moderate decline appeared to be safe., Competing Interests: Declaration of competing interest No competing financial interests exist. No conflict of interest and no disclosure exist., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To examine the relationship between serum myostatin levels and diabetic retinopathy in individuals with type 2 diabetes mellitus (DM)., Methods: This cross-sectional study evaluated 246 individuals with type 2 DM. Analysis of covariance was performed after adjusting for confounders. A logistic regression model was used to evaluate the relationship between serum myostatin levels and diabetic retinopathy., Results: Serum myostatin levels were significantly higher in individuals with diabetic retinopathy than in those without. After adjusting for other covariates, the mean serum myostatin levels were significantly different according to the severity of retinopathy (without diabetic retinopathy, 2234 pg/mL; non-proliferative diabetic retinopathy, 2698 pg/mL; and proliferative diabetic retinopathy, 3076 pg/mL; p for trend = 0.004). The multivariate analysis showed that serum myostatin levels were significantly associated with diabetic retinopathy (odds ratio for every 1 standard deviation-increase in logarithmic value, 1.77; 95% confidence interval: 1.21-2.59; p = 0.003)., Conclusion: Serum myostatin levels were positively associated with diabetic retinopathy in individuals with type 2 DM., (Copyright © 2020 Elsevier Inc. All rights reserved.)

As the diabetes epidemic in the United States continues to worsen, so too does the prevalence of diabetic retinopathy (DR). DR is divided broadly into nonproliferative and proliferative stages, with or without vision-threatening macular edema. Progression to proliferative DR is associated with vision loss that is often irreparable, and a rapid decline in health-related quality of life. Vascular endothelial growth factor (VEGF)-A is upregulated in the diabetic eye, and has been identified as a key driver of DR pathogenesis. With this perspective, we review the published phase III clinical trial data of anti-VEGF therapies approved for the treatment of DR in the United States. Using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale, in which an improvement of ≥2 steps is considered clinically significant, approximately one-third of patients with DR and macular edema experience this level of improvement after 1 year of treatment with either ranibizumab or aflibercept. The rates of clinically significant DR improvement with ranibizumab could be twice that in the subgroup of patients with moderately severe or severe nonproliferative DR and macular edema. These clinical trial data indicate that intraocular inhibition of VEGF is a rational approach for the management of DR., (Copyright © 2019. Published by Elsevier Inc.)

Aim: To study the factors protecting against diabetic retinopathy (DR) in patients with over a decade-long history of type 2 diabetes mellitus., Methods: A total of 490 patients with type 2 diabetes mellitus lasting for ≥10 years were divided into DR and no diabetic retinopathy (no DR) groups. Their basic information was collected, including age, sex, and duration of diabetes mellitus, as well as pertinent laboratory data. Potential correlations between these factors and DR were evaluated using multivariate analysis., Results: Overall, 208 patients met the diagnostic criteria for DR. Multivariate logistic regression was used to evaluate factors with P < 0.10 after univariate analysis. Age, total bilirubin, and total cholesterol were found to be protective factors against DR. Presence of diabetic kidney disease and diabetic peripheral neuropathy, duration of diabetes mellitus, apolipoprotein B, blood urea nitrogen, and prothrombin time were found to be risk factors for DR., Conclusions: We conclude that total cholesterol is a protective factor against DR. Specifically, it was confirmed that high levels of total cholesterol reduce the risk of DR. These findings may provide a basis for new diet and lifestyle guidelines for patients with diabetes mellitus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: The aim was to determine if persistent c-peptide in long duration childhood onset (<17 years) type 1 diabetes (T1D) related to microvascular complications., Methods: Pittsburgh Epidemiology of Diabetes Complications (EDC) participants (n = 185) had serum c-peptide levels measured by Mercodia ultra-sensitive ELISA at the 25-year follow-up exam. Microvascular complications between those with and without detectable c-peptide were compared., Results: Eighteen (9.7%) participants had detectable median c-peptide levels of 3.8 (2.6, 12.2) pmol/L and did not differ from those without detectable levels. No differences in microalbuminuria, confirmed distal symmetric polyneuropathy, renal failure, or between those with one or more complications were found between the two groups. Proliferative retinopathy (PR) was marginally lower in those with detectable c-peptide (33.3% vs 55.1%, p = 0.08). However, those with c-peptide were somewhat less likely to have fasted for a full 8-h (66.7% vs. 84.9%, p = 0.09). Excluding those not fully fasted, PR no longer approached significance but macroalbuminuria became marginally lower in those with detectable levels (23.4% vs 0%, p = 0.07)., Conclusions: Low levels of c-peptide in T1D patients of long duration were detected but were not strongly related to microvascular complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: To evaluate the associations between HbA1c variability and long-term glycemic control with microvascular complications in type 1 diabetes (T1D) patients and multiethnic background., Methods: T1D adults with ≥10 years of follow-up and ≥ 2 HbA1c measurements were included. Glycemic variability was evaluated by the standard deviation (HbA1c-SD), and coefficient of variation (HbA1c-CV), and glycemic control by mean HbA1c over 10 years. Diabetic retinopathy (DR), increased urinary albumin excretion rate (UAER) and reduced glomerular filtration rate (eGFR) were diagnosed. Cardiac autonomic neuropathy (CAN) was diagnosed by cardiac reflex tests. Associations between glycemic parameters with complications were assessed by multivariate logistic regressions., Results: 220 patients were included. Simultaneously adjusted for each other, mean HbA1c was independently associated with DR (OR: 2.82; 95%CI: 1.45-5.50), increased UAER (OR: 1.97; 95%CI: 1.14-3.09) and CAN (OR: 4.42; 95%CI: 1.45-13.51); whereas HbA1c-CV was independently associated with DR (OR: 8.93; 95%CI: 1.86-42.87) and reduced eGFR (OR: 7.02; 95%CI: 1.47-35.55)., Conclusions: Long-term glycemic control was associated with DR, increased UAER and CAN, while glycemic variability was additionally associated with DR and impaired renal function; suggesting that both good and stable glycemic status might be important to prevent microvascular complications in T1D patients and multiethnic background., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To compare microvascular and macrovascular complication rates among Ghanaians with type 2 diabetes (T2D) living in Ghana and in three European cities (Amsterdam, London and Berlin)., Methods: Data from the multicenter Research on Obesity and Diabetes among African Migrants (RODAM) study were analyzed. 650 Ghanaian participants with T2D (206 non-migrant and 444 migrants) were included. Logistic regression analyses were used to determine the association between migrant status and microvascular (nephropathy and retinopathy) and macrovascular (coronary artery disease (CAD), peripheral artery disease (PAD) and stroke) complications with adjustment for age, gender, socioeconomic status, alcohol, smoking, physical activity, hypertension, BMI, total-cholesterol, and HbA1c., Results: Microvascular and macrovascular complications rates were higher in non-migrant Ghanaians than in migrant Ghanaians (nephropathy 32.0% vs. 19.8%; PAD 11.2% vs. 3.4%; CAD 18.4% vs. 8.3%; and stroke 14.5% vs. 5.6%), except for self-reported retinopathy (11.0% vs. 21.6%). Except nephropathy and stroke, the differences persisted after adjustment for the above-mentioned covariates: PAD (OR 7.48; 95% CI, 2.16-25.90); CAD (2.32; 1.09-4.93); and retinopathy (0.23; 0.07-0.75)., Conclusions: Except retinopathy, the rates of microvascular and macrovascular complications were higher in non-migrant than in migrant Ghanaians with T2D. Conventional cardiovascular risk factors did not explain the differences except for nephropathy and stroke., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To analyze the duration and extent of the legacy effect on diabetic complications in real-world patients with type 2 diabetes., Methods: This was a retrospective cohort study. We included the following three cohorts of patients: diabetic retinopathy (DR) (n = 1107), diabetic kidney disease (DKD) (n = 1486), and cardiovascular disease (CVD) (n = 1485). Patients were enrolled from 1995 to 1999 and followed up to 2017. Endpoints were DR incidence, ≥40% decrease in estimated glomerular filtration rate, and CVD incidence. The relationships between HbA1c as a time-dependent variable and the risk of reaching each endpoint were analyzed using multivariate Cox regression models., Results: A total of 313 patients developed DR, 316 developed DKD, and 177 developed CVD. Hazard ratios as a function of time-dependent HbA1c (moving mean) accumulated over time. This accumulation was largest for DR, followed by DKD and CVD. The hazard ratios for each endpoint reached a plateau during the preceding 14-19 years., Conclusions: The effect of past glycemic control may continue during 14-19 years, with a greater effect during ≤10 years. Therefore, the end of the legacy effect could be 15-20 years. This effect may be the greatest for DR, followed by DKD, and the smallest for CVD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To determine whether: 1) retinal vessel diameters in pregnant and non-pregnant women with type 1 diabetes (T1D) alter the relationship of pregnancy to severity of diabetic retinopathy (DR); and 2) retinal vessel diameters in early pregnancy alter the relationship of severity of DR in the mother to severe adverse outcome in the infant., Methods: Two cohorts of women with T1D, one composed of pregnant women and the other of non-pregnant women of child-bearing age, were recruited in Wisconsin. Baseline examinations (including retinal photography and collection of diabetes-related characteristics) were conducted, with follow-up approximately one year later. Retinal images were graded according to the modified Airlie House classification protocol, and retinal vessel diameters were measured from digitized images. The latter were included in analyses as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE)., Results: In multivariate models: 1) Pregnancy was significantly associated with both incidence (OR = 4.43, CI = 1.42-13.79) and progression (OR = 2.62, CI = 1.52-4.51) of DR. Neither CRAE nor CRVE were significant, but their addition modestly altered the associations of pregnancy to worsening DR; 2) Baseline retinopathy (OR = 1.28, CI = 1.05-1.57) was associated with severe adverse outcome in the infant. This association was unchanged by adjustment for retinal vessel diameters., Conclusions: Pregnancy is associated with worsening DR in women with T1D. DR severity in early pregnancy is associated with severe adverse outcome in the infant. The retinal vessel diameters CRAE and CRVE were not associated with these outcomes but were modest confounders of the association of pregnancy to worsening DR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: In this cross-sectional study, we explored the utility of corneal confocal microscopy (CCM) measures for detecting diabetic polyneuropathy (DPN) and their association with clinical variables, in a cohort with type 2 diabetes., Methods: CCM, nerve conduction studies, and assessment of symptoms and clinical deficits of DPN were undertaken in 144 participants with type 2 diabetes and 25 controls. DPN was defined according to the Toronto criteria for confirmed DPN., Results: Corneal nerve fiber density (CNFD) was lower both in participants with confirmed DPN (n = 27) and in participants without confirmed DPN (n = 117) compared with controls (P = 0.04 and P = 0.01, respectively). No differences were observed for CNFD (P = 0.98) between participants with and without DPN. There were no differences in CNFL and CNBD between groups (P = 0.06 and P = 0.29, respectively). CNFD was associated with age, height, total- and LDL cholesterol., Conclusions: CCM could not distinguish patients with and without neuropathy, but CNFD was lower in patients with type 2 diabetes compared to controls. Age may influence the level of CCM measures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Serum uric acid (SUA) and bilirubin at high levels had both pro-oxidant and anti-oxidant properties. The present study aimed to examine additive interactions between SUA and total bilirubin (TBIL) for the risk of micro-vascular disease (MVD) in type 2 diabetes mellitus (T2DM)., Methods: A cross-sectional survey of 6713 inpatients with T2DM was conducted in 81 tertiary care hospitals in China. MVD was defined as having either prior diabetic retinopathy (DR) or diabetic nephropathy (DN). Binary logistic regression was used to estimate odds ratios of SUA and TBIL for MVD. Additive interaction was measured by three indices, i.e., relative excess risk due to interaction, attributable proportion due to interaction and synergy index., Results: Among 6713 inpatients, 408 (6.08%) suffered from MVD. SUA ≥ 283 μmol/l (i.e., its media) was defined as high SUA, and TBIL <11.5 μmol/l (n = 2290 or 34.11%) was defined as low TBIL. Overall, 621 patients were exposed to co-presence of high SUA and low TBIL. The co-presence of both factors greatly increased the effect sizes from 1.03(95%CI: 0.72-1.46) (high SUA alone) or 0.70(95%CI: 0.48-1.05) (low TBIL alone) to 1.90 (95%CI: 1.26-2.87) for MVD in multivariable analysis. The additive interaction of both factors was significant for MVD in both univariable analysis and multivariable analysis., Conclusions: Co-presence of both high SUA and low TBIL indentified a group of patients at a markedly increased risk of MVD in high-risk Chinese patients with T2DM., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: To determine the relationship between early markers of diabetes control and diabetic retinopathy (DR) in type 1 diabetes., Methods: A historic cohort study was conducted on 712 patients from the CARéDIAB database. HbA 1c and usual metabolic parameters were measured one year after diagnosis of diabetes. First occurrences of severe hypoglycemia and ketoacidosis during follow-up were selected as time-dependent markers of diabetes control. Data were analyzed in a Cox model using SPSS software to predict DR with significance level at p-value <0.05., Results: In multivariate regression, any diabetic retinopathy was predicted by HbA 1c (HR = 1.38; CI = 1.25-1.52; p < 0.0001), severe hypoglycemia (HR = 3; CI = 1.99-4.52; p < 0.0001), ketoacidosis (HR = 1.96; CI = 1.17-3.22; p = 0.009), and age at diagnosis (HR = 1.016; CI = 1.002-1.031; p = 0.02). Proliferative DR was predicted by HbA 1c (HR = 1.67; CI = 1.51-1.79; p < 0.0001), severe hypoglycemia (HR = 3.67; CI = 2.74-5.25; p < 0.0001), and ketoacidosis (HR = 2.37; CI = 1.56-3.18; p < 0.0001)., Conclusion: This study shows that the failure to achieve diabetes control after the first year of diagnosis as well as early episodes of acute diabetes complications may contribute to the occurrence of diabetic retinopathy in type 1 diabetes patients., (Copyright © 2018. Published by Elsevier Inc.)

Aim: To characterize the risk uveitis, scleritis or episcleritis in relation to diabetes, glycaemic control, and co-existence of retinopathy., Methods: Using the Royal College of General Practitioners Research and Surveillance Centre database, we established the prevalence of acute uveitis and scleritis or episcleritis over a six-year period among populations without(n = 889,856) and with diabetes(n = 48,584). We evaluated the impact of glycaemic control on disease risk. Regression modeling was used to identify associations, adjusting for clinical and demographic confounders., Results: Incidence of acute uveitis was higher among patients with diabetes; Type 1 OR:2.01 (95% CI 1.18-3.41; p = 0.009), and Type 2 OR:1.23 (1.05-1.44; p = 0.01). Glycaemic control was established as an important effect modifier for uveitis risk, whereby those with poorer control suffered higher disease burden. Results confirmed a dose-response relationship such that very poor glycaemic control OR:4.72 (2.58-8.65; p < 0.001), poor control OR:1.57 (1.05-2.33; p = 0.03) and moderate control OR:1.20 (0.86-1.68; p = 0.29) were predictive of uveitis. Similar results were observed when evaluating retinopathy staging: proliferative retinopathy OR:2.42 (1.25-4.69; p = 0.01). These results were not maintained for scleritis or episcleritis., Conclusion: Acute uveitis is more common in patients with diabetes; at highest risk are those with type 1 disease with poor glycaemic control. Glycaemic improvements may prevent recurrence., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: To describe to what extent microvascular complications exhibit clustering in persons with Type 1 diabetes, and to assess whether the presence of one complication modified the strength of the association between the other two., Methods: We conducted a cross-sectional analysis of the electronic medical records of 2276 persons with Type 1 diabetes treated in a specialized care hospital in Denmark in 2013. We used log-linear analysis to describe associations between diabetic kidney disease, neuropathy and retinopathy and logistic regression models to quantify the magnitude of associations adjusting for potential confounders., Results: The median duration of diabetes was 24 years and median HbA1c was 63 mmol/mol (7.9%). We found strong indication of clustering and found no evidence that presence of one complication modified the association between the other two. In models adjusted for diabetes duration and HbA 1c , persons with neuropathy had an OR of 2.15 (95% CI: 1.73-2.66) for concurrent diabetic kidney disease. Those with retinopathy had an OR of 2.49 (1.92-3.24) for diabetic kidney disease and of 2.66 (1.94-3.64) for neuropathy., Conclusions: Microvascular complications in persons with Type 1 diabetes exhibit strong clustering. However, the association between any pair of complications is not modified by the presence of the third., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: To investigate the role of ophthalmic imaging markers - namely retinal thickness measures and corneal nerve morphology - in predicting four-year development and worsening of diabetic retinopathy (DR) in type 1 diabetes (T1DM)., Methods: 126 eyes of 126 participants with T1DM were examined at baseline and after four years. Diabetic retinopathy (DR) was graded using the Early Treatment Diabetic Retinopathy Study scale. HbA 1c , nephropathy, neuropathy, cardiovascular factors, and retinal thickness using optical coherence tomography (OCT) and corneal nerve fiber length (CNFL) using corneal confocal microscopy at baseline were assessed by univariate and step-wise multiple logistic regression, and their diagnostic capabilities for single and combined measures., Results: Four-year development of DR was 19% (13 of 68 without DR at baseline). Worsening of DR was seen in 43% (25 of 58 with DR at baseline). When adjusted for potential confounders, a lower CNFL (AUC=0.637, p=0.040, 64% sensitivity and 64% specificity at 14.9mm/mm 2 cut-off), higher triglycerides (AUC=0.669, p=0.012, 64% sensitivity, 62% specificity at 0.85mmol/L) and an elevated vibration threshold (AUC=0.708, p=0.002, 96% sensitivity, 40% specificity at 3.55Hz) were significant predictors for four-year worsening of DR., Conclusions: Reduced CNFL, elevated vibration perception threshold and higher triglycerides can predict future worsening of DR., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: This study presents nine patients with mitochondrial tRNA Leu (UUR) m.3243A>G mutation and compares the clinical characteristics and diabetes complications with type 1 diabetes (T1DM) or early onset type 2 diabetes (T2DM)., Methods: The study covers 9 patients with MIDD, 33 patients with T1DM and 86 patients (age of onset ≤35years) with early onset T2DM, matched for sex, age at onset of diabetes, duration of diabetes. All patients with MIDD were confirmed as carrying the m.3243A>G mitochondrial DNA mutation. Serum HbA1c, beta-cell function, retinal and renal complications of diabetes, bone metabolic markers, lumbar spine and femoral neck BMD bone mineral density were compared to characterize the clinical features of all patients., Results: Nine patients were from five unrelated families, and the mean (SD) onset age of those patients was 31.2±7.2year. Two patients required insulin at presentation, and six patients progressed to insulin requirement after a mean of 7.2years. β-Cell function in the MIDD group was intermediate between T1DM and early-onset T2DM. In MIDD, four patients were diagnosed as diabetic retinopathy (4/9) and five patients (5/9) had macroalbuminuria. The number of patients with diabetic retinopathy and macroalbuminuria in the MIDD group was comparable to T1DM or early-onset T2DM. The rate of osteoporosis (BMD T-score<-2.5 SD) in the patient with MIDD was higher than the T1DM or early-onset T2DM group., Conclusion: Our study indicates that of the nine subjects with MIDD, three patients (1-II-1, 1-II-3, 1-II-4) who came from the same family had a history of acute pancreatitis. Compared with T1DM or early-onset T2DM matched for sex, age, duration of diabetes, MIDD patients had the highest rate of osteoporosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To explore whether type 2 diabetes (T2D) is a risk factor for dementia conversion in patients with mild cognitive impairment (MCI)., Methods: A longitudinal nested case-control study in which 101 T2D patients and 101 non-diabetic patients with MCI matched by age and gender were included., Results: The dementia conversion rate was 57.4% in T2D patients vs. 42.6% in non-diabetic subjects (p=0.02). T2D and APOE ε4 allele were independent risk factors for developing dementia., Conclusion: T2D is an independent risk factor for dementia conversion in MCI patients. This finding has significant clinical implications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To describe a decade long telemedicine screening for diabetic retinopathy (DR) in the metropolitan area of Padova (North-East Italy) and to report about prevalence/incidence of DR and maculopathy, rate of progression to STDR and optimal screening interval in patients with no DR at first examination., Methods: Observational, longitudinal, cohort study; 9347 patients with Type 1 and Type 2 diabetes mellitus (DM) underwent 17,344 fundus exams (three-45° color photos per eye) in two diabetes clinics and were graded in the Reading Centre, by certified personnel. The incidence of STDR, progression of maculopathy and risk factors were evaluated by log Rank test (Kaplan-Meier method). A receiver operating curve was used to determine the optimal screening interval in patients who at the first examination had no DR., Results: The overall prevalence of DR was 27.6%:12.5% mild non proliferative (NPDR), 11.3% moderate NPDR, 2.9% severe NPDR and 0.9% proliferative (PDR). The overall prevalence of maculopathy was 5.7%: 2.8% mild, 2.2% moderate, and 0.7% severe maculopathy. The 10-year incidence of STDR was: 0.6% in no DR, 5.5% in mild NPDR and 21.1% in moderate NPDR at first examination. The 10-year incidence of maculopathy was: 2.1% mild, 1.7% moderate and 0.2% severe. The incidence of STDR in patients with type 1 and type 2 DM and duration>10years was 8.21% and 8.15%;in type 1 DM with duration <10years was 5.5% and in type 2 DM and duration <10years was 1.91%.In patients with no DR at first screening, the best (sensitivity-specificity) follow-up interval is 2.5years., Conclusions: Screening every 2.5-year in patients without DR at the first examination seems to be adequate. Duration of disease is a relevant risk factor for progression to STDR, however patients with type 1 DM and duration <10years have greater incidence of STDR than patients with type 2 DM and similar disease duration. Epidemiologic data from this decade-long screening program in the North East of Italy may serve for implementing a national screening program., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To determine the incidence of hospitalisations and risk factors for vascular complications experienced during early adulthood in patients with childhood onset type 1 diabetes., Methods: A population-based childhood onset type 1 diabetes cohort was identified from a statewide register (1992-2012). Data linkage was used to identify a matched comparison cohort. Hospital admissions data were extracted to follow up both cohorts into early adulthood (1975-2012)., Results: The type 1 diabetes cohort (n=1316) had a mean age of diagnosis of 9.5years, 49.5% were women and mean age at the end of follow-up was 26.3years (range 18-38). Within the type 1 diabetes cohort 32 (2.4%) were hospitalised with a vascular complication during early adulthood. Poor glycaemic control during paediatric management was associated with a significant increase in risk for ophthalmic complication with 19.4% (n=12/62) of those with a mean HbA1c >12% (108mmol/mol) diagnosed compared to 0.72% (n=5/696) of those with mean HbA1c <9% (75mmol/mol), adjusted hazard ratio 8.4 (95% CI 2.0, 34.7)., Conclusion: Severe vascular complications requiring hospital admission continue to be observed during early adulthood. Both women and those with poor glycaemic control are at increased risk of requiring a hospital admission for these complications during early adulthood., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: Young onset type 2 diabetes patients (T2DM-Y) have been shown to possess an increased risk of developing microvascular complications particularly diabetic retinopathy. However, the molecular mechanisms are not clearly understood. In this study, we investigated the serum levels of monocyte chemotactic protein 1 (MCP-1) and cathepsin-D in patients with T2DM-Y without and with diabetic retinopathy., Methods: In this case-control study, participants comprised individuals with normal glucose tolerance (NGT=40), patients with type 2 diabetes mellitus (T2DM=35), non-proliferative diabetic retinopathy (NPDR=35) and proliferative diabetic retinopathy (PDR=35). Clinical characterization of the study subjects was done by standard procedures and MCP-1 and cathepsin-D were measured by ELISA., Results: Compared to control individuals, patients with T2DM-Y, NPDR and PDR exhibited significantly (p<0.001) higher levels of MCP-1. Cathepsin-D levels were also significantly (p<0.001) higher in patients with T2DM-Y without and with diabetic retinopathy. Correlation analysis revealed a positive association (p<0.001) between MCP-1 and cathepsin-D levels. There was also a significant negative correlation of MCP1/cathepsin-D with C-peptide levels. The association of increased levels of MCP-1/cathepsin-D in patients with DR persisted even after adjusting for all the confounding factors., Conclusion: As both MCP-1 and cathepsin-D are molecular signatures of cellular senescence, we suggest that these biomarkers might be useful to predict the development of retinopathy in T2DM-Y patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To test whether the rate of diabetic retinopathy development in a population calculated from the prevalence of retinopathy and duration of diabetes can be used to assess their prior glycemic control., Research Design and Methods: 9281 patients with type 2 diabetes (T2DM) were grouped by duration of diabetes and plotted against the % of retinopathy in each band. The slope was used to calculate retinopathy development/year (RD/y). We correlated the RD/y with updated HbA1c within groups of different ethnicity, age of diabetes onset, year of the eye examination, socio-economic status and fluency in English., Results: Differences in ethnicity, age of diabetes onset and year of the eye examination affect RD/y to a degree predictable from their respective updated HbA1c. No such relationship with updated HbA1c was evident when a factor has no apparent effect on RD/y., Conclusions: This relationship between prevalence of retinopathy and duration of diabetes can be used to assess future retinopathy burden. Perhaps more intriguing, the camera can be reversed to allow an estimate of prior glycemic control of a population from its retinopathy prevalence. Health care organizations can use this method to project future needs and to assess adequacy of prior glycemic control., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Retinopathy is increasingly recognized in prediabetic populations, and may herald increased risk of metabolic worsening. The Early Diabetes Intervention Program (EDIP) evaluated worsening of glycemia in screen-detected Type 2 diabetes, following participants for up to 5years. Here we have evaluated whether the presence of retinopathy at the time of detection of diabetes was associated with accelerated progression of glycemia., Methods: We prospectively studied 194 participants from EDIP with available baseline retinal photographs. Retinopathy was determined at baseline using 7-field fundus photography and defined as an Early Treatment of Diabetic Retinopathy Study Scale grading score of ≥20., Results: At baseline, 12% of participants had classical retinal lesions indicating retinopathy. In univariate Cox proportional hazard analysis, the presence of retinopathy at baseline was associated with a doubled risk of progression of fasting plasma glucose (HR 2.02; 95% CI 1.05-3.89). The retinopathy effect was robust to individual adjustment for age and glucose, the most potent determinants of progression in EDIP., Conclusion: Retinopathy was associated with increased risk of progression of fasting plasma glucose among adults with screen-detected, early diabetes. Early detection of retinopathy may help individualize more aggressive therapy to prevent progressive metabolic worsening in early diabetes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Advanced glycation end-products (AGEs) are involved in diabetic retinopathy (DR). Their accumulation in tissues can be analyzed by measuring the skin autofluorescence (sAF). We hypothesized that renal insufficiency, another cause of high sAF, may disturb the relation between sAF and DR., Research Design and Methods: We measured sAF with an AGE-Reader in 444 patients with type 2 diabetes (T2D), and we analyzed their retinal status. The associations of sAF with DR, and interaction with renal insufficiency were estimated by multivariate logistic regression analysis., Results: Mean age was 62years (standard deviation (SD) 10years), diabetes duration 13 (9) years and mean HbA1C 8.9% (1.8). The prevalence of DR was 21.4% and increased with age, diabetes duration, arterial hypertension, renal parameters (serum creatinine and albumin excretion rates), and sAF. The prevalence of macular edema (ME) was 8.6% and increased with the duration of diabetes, but not with sAF (p=0.11). There was a significant interaction between renal insufficiency and sAF for the relation with DR or ME (p=0.02). For the 83% patients without renal insufficiency (estimated GFR>60mL/min/1.73m2), sAF was related to DR or ME after multivariate adjustment: OR 1.87 (1.09-3.19). The 17% patients with renal insufficiency had the highest rates of DR or ME (38.6%) and the highest sAF, unrelated to each other., Conclusions: In T2D patients with renal insufficiency, the high sAF does not relate to retinopathy, which should be systematically searched due to its high frequency. For other patients, a high sAF argues for DR screening., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: This study investigated the associations between the common hepatocyte nuclear factor-1A (HNF1A) variants and the risk of diabetic retinopathy (DR) in relation to the glycemic control and weight status., Methods: A retrospective longitudinal analysis was conducted among 354 Japanese patients with type 2 diabetes mellitus (T2DM) (mean follow-up duration: 5.8±2.5 years). The multivariable-adjusted hazard ratio (HR) for the cumulative incidence of DR was calculated using a Cox proportional hazard model. During the observation period, the longitudinal associations of the HNF1A diplotypes with the risk of DR and the clinical parameters were also analyzed using the generalized estimating equations approach., Results: The combination of risk variants, i.e., rs1169288-C, rs1183910-A and rs2464196-A, was defined as the H1 haplotype. The incidence of DR was higher in the H1/H1 diplotype cases than in the others (HR 2.75 vs. non-H1/non-H1; p=0.02). Only in normal-weight subjects, the risks of DR and poor glycemic control were higher in the H1/H1 diplotype cases than in the others [odds ratio 4.08 vs. non-H1/non-H1, p=0.02; odds ratio 3.03, p=0.01; respectively]., Conclusions: This study demonstrated that the common HNF1A diplotype of three risk variants may be an independent risk factor for the development of DR resulting from poor glycemic control in normal-weight patients with T2DM. These results need to be replicated in larger and more varied study populations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The lack of physical activity, along with obesity, smoking, hypertension and hyperglycaemia are considered as risk factors for the occurrence of diseases such as diabetes. Primary objective of the study was to investigate potential correlation between physical activity and diabetic retinopathy., Patients and Methods: Three hundred and twenty patients were included in the study: 240 patients with diabetes type 2 (80 patients with mild to moderate non-proliferative diabetic retinopathy, 80 patients with severe to very severe non-proliferative diabetic retinopathy and 80 ones with proliferative diabetic retinopathy) were compared with 80 non-diabetic patients (control group). Physical activity of patients was assessed by the international physical activity questionnaire (IPAQ, 2002). HbA1c and BMI were also measured in diabetic patients. Group comparisons were attempted for levels of physical activity and sedentary behavior., Results: Total physical activity was decreased in patients with severe to very severe non-proliferative diabetic retinopathy and proliferative diabetic retinopathy as compared to patients with mild to moderate non-proliferative diabetic retinopathy and to the control group (p<0.05). Significant negative correlation was detected between HbA1c levels, BMI and physical activity (both p<0.05). Moreover, significant negative correlation between the severity of diabetic retinopathy and physical activity has been demonstrated (p<0.05)., Conclusions: Increased physical activity is associated with less severe levels of diabetic retinopathy, independent of the effects of HbA1c and BMI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: This study aimed to evaluate the association between total bilirubin (TBiL) and major diabetic complications among Chinese senile diabetic patients., Methods: A cross-sectional study was conducted in all the cadre sanitariums in Beijing, between May 2012 and December 2014. All the diagnoses of diabetic complications were extracted from the medical records including chronic kidney disease, retinopathy, peripheral vascular disease, coronary heart disease, and ischemic stroke., Results: The mean age of the 1839 senile diabetic patients were 87.4±4.0 (80-102years) and mean TBiL level was 13.2±6.0μmol/L. The prevalence of chronic kidney disease, retinopathy, peripheral vascular disease, coronary heart disease and ischemic stroke was 13.8%, 17.8%, 5.8%, 62.5%, and 44.5%, respectively. TBiL level was negatively correlated with age, weight, SBP, TC, FBG, 2hPG, diabetic duration and positively correlated with HDL-C. Prevalence of all five diseases gradually decreased with the increase of TBiL level (p<0.05). Also, number of diabetic complications showed a decreasing trend along with TBiL tertiaries. After adjusted age, education, marital status, current smoking, current drinking, physical activity ≥0.5h/day, BMI, hypertension, dyslipidemia, treatment and control status of diabetes, patients with higher TBiL level were at significantly decreased ORs for prevalence of major diabetic complications. The ORs were 0.97 (95%CI: 0.96-0.99), 0.90 (95%CI: 0.87-0.93), 0.98 (95%CI: 0.97-0.99), 0.97 (95%CI: 0.95-.99) and 0.98 (95%CI: 0.97-0.99) for chronic kidney disease, retinopathy, peripheral vascular disease, coronary heart disease and ischemic stroke (p<0.005). Similar results were obtained when TBiL was used as tertiary variable., Conclusion: Higher TBiL was significantly associated with lower prevalence of major diabetic complication among senile diabetic patients, and this association was graded with TBiL level and independent of age and control status of diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to investigate the relationship between serum FGF21 level and all microvascular complication including cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM)., Methods: A total 227 T2DM patients were enrolled and serum FGF21 levels were assessed. Diabetic retinopathy, nephropathy, peripheral neuropathy (DPN), and CAN were evaluated., Results: The prevalence of retinopathy and nephropathy among the FGF21 tertiles was significantly different (p=0.001, p=0.006, respectively), whereas no difference was found in the prevalence of DPN and CAN. In multivariate analysis, the odds ratio (OR) for the presence of retinopathy was 0.08 for the FGF21 second tertile when compared with the first tertile (p=0.029). OR of retinopathy in third tertile group was lower than first tertile and higher than second tertile, but statistically insignificant. Crude OR for nephropathy was 0.34 for the second FGF21 tertile, when compared with the first tertile (p=0.015). However, FGF21 level was not significantly associated with nephropathy after multivariable adjustment., Conclusions: In the present study, there was no association between diabetic nephropathy, DPN, and CAN and serum FGF21 levels. However, we found a U-shaped relationship between both lower and higher serum FGF21 levels and diabetic retinopathy. This result suggests that the very low serum FGF21 level itself may associate with diabetic retinopathy and also relatively elevated serum FGF21 level may be a compensatory increase to protect against microvascular injury., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To examine the relationship between systolic blood pressure (SBP) variability and the risk of microvascular complications in a non-elderly diabetic population., Methods: This is a retrospective cohort study of individuals aged ≤60years treated for diabetes in 2003 in the US Department of Veterans Affairs healthcare system. Individuals were followed for five years for any new diagnosis of diabetic nephropathy, retinopathy, or neuropathy. In each year of follow-up, individuals were classified into quartiles based on their SBP variability., Results: We identified 208,338 patients with diabetes without diabetic nephropathy, retinopathy, or neuropathy at baseline. Compared to individuals with the least SBP variability (Quartile 1), those with most variability (Quartile 4) had 81% (OR=1.81; 95% CI, 1.72-1.91), 17% (OR=1.17; 95% CI, 1.13-1.21), 30% (OR=1.30; 95% CI, 1.25-1.35), and 19% (OR=1.19; 95% CI, 1.15-1.23) higher incidence of nephropathy, retinopathy, neuropathy, and any complication, respectively, after adjusting for mean SBP, demographic and clinical factors., Conclusions: We found a significant graded relationship between SBP variability and the incidence of each complication and of any combined endpoint. This is the first study showing a significant association between SBP variability and the risk of diabetic retinopathy and neuropathy., Competing Interests: There is no conflict of interest to declare., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To evaluate relationships between early alterations in blood pressure and the progression of microvascular complications of diabetes in clinically-normotensive patients with type 1 diabetes (T1DM)., Methods: In a prospective observational study of 85 normotensive T1DM patients without microalbuminuria, blood pressure (BP) was monitored over 24h using the ambulatory blood pressure monitoring (ABPM) system at baseline and 7years later. Development or progression of microalbuminuria, retinopathy and hypertension was evaluated., Results: Initially, 20 patients (24%) were diagnosed with masked hypertension and 31 (37%) with non-dipper pattern as the only pathological findings. At 7years: 1) twenty-seven patients (32%) had progression of retinopathy related to the nocturnal diastolic blood pressure (BPD) (OR:1.122; p=0.034) and final non-dipper pattern (OR:5.857; p=0.005); 2) seven patients (10%) developed microalbuminuria for which nocturnal systolic blood pressure (BPS) was a risk factor (OR:1.129; p=0.007); 3) five of the normotensive patients (9%) progressed to hypertension; historic HbA1c (OR:2.767; p=0.046) and nocturnal BPD (OR:1.243; p=0.046) being the related risk factors. BPD level ≥65mmHg was associated with an increase in progression of retinopathy and hypertension., Conclusions: In T1DM patients there is an elevated prevalence of BP alterations, detected using ABPM. Alterations in nocturnal BP predispose to development/progression of microvascular complications and overt hypertension., (Copyright © 2016. Published by Elsevier Inc.)

Aims: To compare metabolic control between males and females with type 1 diabetes during adolescence and as young adults, and relate it to microvascular complications., Methods: Data concerning 4000 adolescents with type 1 diabetes registered in the Swedish paediatric diabetes quality registry, and above the age of 18years in the Swedish National Diabetes Registry was used., Results: When dividing HbA1c values in three groups; < 7.4% (57mmol/mol), 7.4-9.3% (57-78mmol/mol) and >9.3% (78mmol/mol), there was a higher proportion of females in the highest group during adolescence. In the group with the highest HbA1c values during adolescence and as adults, 51.7% were females, expected value 46.2%; in the group with low HbA1c values in both registries, 34.2% were females, p<0.001. As adults, more females had retinopathy, p<0.05. Females had higher mean HbA1c values at diagnosis, 11.2 vs. 10.9% (99 vs. 96mmol/mol), p<0.03, during adolescence, 8.5 vs. 8.2% (69 vs. 66mmol/mol) p<0.01, but not as young adults., Conclusions: Worse glycaemic control was found in adolescent females, and they had a higher frequency of microvascular complications. Improved paediatric diabetes care is of great importance for increasing the likelihood of lower mortality and morbidity later in life., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Retinal hemorrhage is an important finding on fundus photography. Diabetes mellitus is a cause of retinal hemorrhage, although other causes exist. We sought to better characterize the association between retinal hemorrhage and HbA1c in the Japanese population., Methods: We conducted a prospective study of 11,644 Japanese men and women aged 30-78years between 2001 and 2011. Fundus photography was performed as part of an annual cardiovascular disease risk survey. HbA1c was determined by the latex coagulation method throughout the study. We used logistic regression models to examine the association between HbA1c and the risk of retinal hemorrhage and diabetic retinal hemorrhage., Results: During a median follow-up period of 4.6years, 509 retinal hemorrhages, including 96 diabetic retinal hemorrhages, were diagnosed. HbA1c was positively associated with the risk of retinal hemorrhage and diabetic retinal hemorrhage among subjects not taking medication for diabetes mellitus at baseline, but not among subjects who were taking medication at baseline., Conclusions: HbA1c was positively associated with the risk of retinal hemorrhage and the subcategory of diabetic retinal hemorrhage among subjects not taking medication for diabetes mellitus at baseline. The association was evident for diabetic retinal hemorrhage, compared with retinal hemorrhage., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to examine the associations between possible indices of obesity based on information on weight history and the incidence of microvascular complications., Methods: A cohort of individuals with type 2 diabetes from 59 institutes in Japan was followed for 8years. Patients were classified into three categories according to weight at entrance and past maximum weight: normal (BMI at baseline <25kg/m(2) and maximum BMI <25kg/m(2)), past obesity (BMI at baseline <25kg/m(2) and maximum BMI ≥25kg/m(2)), and current obesity (BMI at baseline ≥25kg/m(2)) groups. The outcomes were diabetic retinopathy and overt nephropathy., Results: BMI at maximum and baseline of the 1809 patients was 26.5±3.5 and 23.1±3.0kg/m(2) (p<0.01), respectively (23.0±1.6 and 20.6±1.9kg/m(2) for normal, 27.4±2.0 and 22.8±1.4kg/m(2) for past obesity, and 30.1±2.9 and 27.0±1.8kg/m(2) for current obesity). The hazard ratios of past and current obesity compared to normal were 1.92 (95% CI, 1.08-3.41; p=0.03) and 2.21 (1.16-4.22; p=0.02), respectively, for overt nephropathy and 1.38 (1.05-1.83; p=0.02) and 1.64 (1.18-2.28; p<0.01), respectively, for diabetic retinopathy after adjustment for confounders., Conclusions: Past obesity as well as current obesity were associated with increased risks of microvascular complications. Further identification of high-risk populations may be possible by classifying normal weight patients by past obesity., (Copyright © 2016 Elsevier Inc. All rights reserved.)