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The 3 Screen ICA ELISA is a novel assay capable of simultaneously measuring autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A), making it a valuable tool for screening type 1 diabetes. Despite its advantages, it cannot specify which individual autoantibodies are positive or negative. This study aimed to estimate individual positive autoantibodies based on the 3 Screen ICA titer. Six hundred seventeen patients with type 1 diabetes, simultaneously measured for 3 Screen ICA and three individual autoantibodies, were divided into five groups based on their 3 Screen ICA titer. The sensitivities and contribution rates of the individual autoantibodies were then examined. The study had a cross-sectional design. Sixty-nine percent (424 of 617) of patients with type 1 diabetes had 3 Screen ICA titers exceeding the 99th percentile cut-off level (20 index). The prevalence of GADA ranged from 80% to 100% in patients with a 3 Screen ICA over 30 index and 97% of patients with a 3 Screen ICA ≥300 index. Furthermore, the prevalence of all individual autoantibodies being positive was 0% for ≤80 index and as high as 92% for ≥300 index. Significant associations were observed in specific titer groups: the 20–29.9 index group when all the individual autoantibodies were negative, the 30–79.9 index group when positive for GADA alone or IA-2A alone, the 30–299.9 index group when positive for ZnT8A alone, the 80–299.9 index group when positive for both IA-2A and ZnT8A, the 300–499.9 index group when positive for both GADA and ZnT8A, and the ≥300 index group when positive for all individual autoantibodies. These results suggest that the 3 Screen ICA titer may be helpful in estimating individual positive autoantibodies. [ABSTRACT FROM AUTHOR]

Aim: Clinical trials showed the efficacy of sodium‐glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat‐AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium‐glucose cotransporter 2 inhibitor, ipragliflozin. Methods: Adults with T1D (n = 25) took 50‐mg open‐labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed‐meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C‐peptide, glucagon and β‐hydroxybutyrate. Results: The area under the curve from fasting (0 min) to 120 min (AUC0‐120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial β‐hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0‐120min) from baseline to 12 weeks were significantly correlated with those in β‐hydroxybutyrate levels. Conclusions: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied. [ABSTRACT FROM AUTHOR]

Aim/Introduction: This study aimed to investigate the clinical utility of 3 Screen ICA ELISA in identifying immune‐mediated type 1 diabetes in Japanese subjects. Methods: We compared the positivity of 3 Screen ICA were compared with autoantibodies against GAD, IA‐2, and ZnT8 in 638 patients with type 1 diabetes and 159 healthy control subjects. Results: With a cut‐off value of 20.0 index, 67.4% of acute‐onset type 1 diabetic patients, 71.8% of slowly progressive type 1 diabetic (SPIDDM) patients, and none of the fulminant type 1 diabetic patients showed 3 Screen ICA levels above this threshold. The prevalence of 3 Screen ICA was 14.2% higher in acute‐onset type 1 diabetes and 1.6% higher in SPIDDM than in GADA. 3 Screen ICA‐positive cases were found in 4.8% of cases of individual autoantibody‐negative acute‐onset type 1 diabetes and 3.8% of SPIDDM, indicating improved diagnostic sensitivity with the 3 Screen ICA. Among individual autoantibody‐negative patients, the sum of each autoantibody level was significantly lower in fulminant type 1 diabetes than in acute onset type 1 diabetes and in SPIDDM (P < 0.0001). Additionally, 84.2% of patients negative for individual autoantibodies but positive for 3 Screen ICA had a sum of individual autoantibody levels of ≥4.7 U/mL. Furthermore, 3 Screen ICA levels were significantly higher in patients with type 1 diabetes with other autoimmune diseases than in those without (P < 0.0001). Conclusion: Our findings suggest that the 3 Screen ICA ELISA may be a valuable screening tool for Japanese patients with type 1 diabetes, potentially increasing the diagnostic sensitivity and accuracy beyond the existing GADA, IA‐2A, and ZnT8A tests. [ABSTRACT FROM AUTHOR]

Abnormal fibroblast function underlies poor wound healing in patients with diabetes; however, the mechanisms that impair wound healing are poorly defined. Here, we evaluated fibroblasts from individuals who had type 1 diabetes (T1D) for 50 years or more (Medalists, n = 26) and from age-matched controls (n = 7). Compared with those from controls, Medalist fibroblasts demonstrated a reduced migration response to insulin, lower VEGF expression, and less phosphorylated AKT (p-AKT), but not p-ERK, activation. Medalist fibroblasts were also functionally less effective at wound closure in nude mice. Activation of the δ isoform of protein kinase C (PKCδ) was increased in postmortem fibroblasts from Medalists, fibroblasts from living T1D subjects, biopsies of active wounds of living T1D subjects, and granulation tissues from mice with streptozotocin-induced diabetes. Diabetes-induced PKCD mRNA expression was related to a 2-fold increase in the mRNA half-life. Pharmacologic inhibition and siRNA-mediated knockdown of PKCδ or expression of a dominant-negative isoform restored insulin signaling of p-AKT and VEGF expression in vitro and improved wound healing in vivo. Additionally, increasing PKCδ expression in control fibroblasts produced the same abnormalities as those seen in Medalist fibroblasts. Our results indicate that persistent PKCδ elevation in fibroblasts from diabetic patients inhibits insulin signaling and function to impair wound healing and suggest PKCδ inhibition as a potential therapy to improve wound healing in diabetic patients., INTRODUCTION Chronic foot ulcers are one of the most common and serious complications of diabetes, resulting in more than 80,000 amputations per year as well as high health care costs [...]

Diabetic kidney disease (DKD) is a key determinant of morbidity and mortality in patients with type 1 diabetes (T1D). Identifying factors associated with early glomerular filtration rate (GFR) decline in T1D is important in prevention or early intervention for DKD. This study investigated whether phosphate metabolism, including fibroblast growth factor 23 (FGF23) is associated with the kidney function of patients with T1D. We randomly recruited 118 patients with T1D with a normal or mildly impaired kidney function [chronic kidney disease (CKD) stages of G1/G2, A1/A2], and measured their serum FGF23 levels. Serum FGF23 was significantly negatively associated with the estimated GFR (eGFR) (r = -0.292, P = 0.0016), but not urinary albumin creatinine ratio (UACR), and positively associated with serum phosphate (Pi; r = 0.273, P = 0.0027). Serum FGF23 increased with decreasing eGFR quartiles (P for linear trend = 0.0371), while FGF23 was modestly higher in the higher quartiles of UACR (not statistically significant). The multiple linear regression analysis also showed a significant inverse association between FGF23 and eGFR (Model 1: β = -0.149, P = 0.0429; Model 2: β = -0.141, P = 0.0370). The association remained significant after adjustment for Pi. We identified that FGF23 was inversely associated with the eGFR in T1D patients with a normal or mildly impaired kidney function. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the intrarenal renin-angiotensin system may be involved in the progression of diabetic nephropathy. Chymase is a potent local angiotensin II-forming enzyme in several species, including humans and hamsters. However, the pathophysiological role of chymase is not fully understood. Here, we report a causal role of chymase in diabetic nephropathy and the therapeutic effectiveness of chymase inhibition. In the present study, renal chymase expression was markedly upregulated in streptozotocin-induced diabetic hamsters. Oral administration of a specific chymase inhibitor, TEI-F00806, completely ameliorated proteinuria, the overexpression of transforming growth factor-[beta] and fibronectin in glomeruli, and renal mesangial expansion, by normalizing the increase in intrarenal angiotensin II levels in diabetic hamsters independently of blood pressure levels. In contrast, ramipril did not show such sufficient effects. These effects occurred in parallel with improvements in superoxide production and expression of NAD(P)H oxidase components [NAD(P)H oxidase 4 and [p22.sup.phox]] in glomeruli. This study showed for the first time that chymase inhibition may protect against elevated intrarenal angiotensin II levels, oxidative stress, and renal dysfunction in diabetes. These findings suggest that chymase offers a new therapeutic target for diabetic nephropathy. angiotensin II; NAD(P)H oxidase doi: 10.1152/ajprenal.00337.2010

Objective: Previous reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD). Methods: A total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD. Results: Logistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point. Conclusions: Serum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Diagnosis of diabetic peripheral neuropathy (DPN) depends on subjective findings, certain investigations for DPN risks have not been performed enough. Bilirubin protects against vascular complications by reducing oxidative stress in diabetes, but is not fully tested for DPN. This study aimed to evaluate sural nerve conduction impairments (SNCI) as an objective DPN marker and the contribution of bilirubin to SNCI. Materials and methods: Using DPN‐Check®, SNCI was defined as a decline of amplitude potential or conduction velocity below the normal limit in 150 inpatients with diabetes. The correlations between SNCI and conventional DPN diagnosis criteria, the incidence of diabetic retinopathy/nephropathy, biomarkers for atherosclerosis, cardiac function by ultrasonic cardiogram, and bilirubin were statistically tested, followed by the comparison of logistic regression models for SNCI to find confounders with bilirubin. Results: The incidence of SNCI was 72.0%. The sensitivity and specificity of SNCI for DPN prediagnosis by simplified criteria were 54.6 and 90.5%, respectively, and similarly corresponded with diabetic retinopathy and nephropathy (sensitivity 57.4 and 50.0%, respectively). SNCI significantly related to diabetes duration, declined estimated glomerular filtration rate, albuminuria and total bilirubin. SNCI incidence was attenuated in the higher bilirubin tertiles (89.8/65.3/54.8%, P < 0.001). Bilirubin was an independent inverse risk factor for SNCI, even after adjustment by known risk factors for DPN and markers for microvascular complications. Conclusions: SNCI is a comprehensive marker for diabetic complications. We first showed the independent inverse relationship between bilirubin and SNCI through the independent pathway with other complications, provably reducing oxidative stress, as previously reported. [ABSTRACT FROM AUTHOR]

Endogenous protection: Diabetic retinopathy (DR) is one of the most common consequences of diabetes affecting more than 35% of patients. Endogenous protective factors could explain why only a fraction of patients with diabetes develop DR. In this study, Yokomizo et al. analyzed data from a large cohort of patients with diabetes (Mendalist cohort) and showed that retinol binding protein 3 (RBP3) expression was negatively correlated with DR severity. Intravitreal RBP3 injection or retinal RBP3 overexpression in rodents protected against vascular endothelial growth factor– and diabetes-induced vascular retinal permeability. The protective effects were mediated by inhibition of glucose uptake in retinal endothelial and Müller cells. The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF. [ABSTRACT FROM AUTHOR]

In this study, a depletion load pMOS inverter, which is called an enhancement/depletion (E/D) inverter, with a single organic semiconductor was demonstrated utilizing threshold voltage controlled pentacene-based organic field-effect transistor (OFET) realized by a nitrogen-doped (N-doped) LaB6 interfacial layer (IL). It was found that a N-doped LaB6 IL introduced in drive OFET realized the inverter characteristic with logic swing of 4.3 V at an operation voltage of −5 V. In addition, a common-gate electrode structure for drive and load OFETs was demonstrated, which would contribute to further scaling and high integration of organic devices. [ABSTRACT FROM AUTHOR]

Our study suggests that timing of type 1 diabetes onset might be important for estimating lifetime fracture risk in patients with type 1 diabetes. Onset of type 1 diabetes during bone growth period is associated with increased prevalence of bone fracture: A post-hoc analysis of a cross-sectional study In this single-center, cross-sectional study, we demonstrated that the prevalence of fracture was significantly higher in patients who onset type 1 diabetes during 0-4 years, and 10-14 years compared with adult-onset type 1 diabetes. [Extracted from the article]

We conducted individual participant data meta-analysis to examine the validity of interarm blood pressure difference in simultaneous measurement as a marker to identify subjects with ankle-brachial pressure index <0.90 and to predict future cardiovascular events. We collected individual participant data on 13 317 Japanese subjects from 10 cohorts (general population-based cohorts, cohorts of patients with past history of cardiovascular events, and those with cardiovascular risk factors). Binary logistic regression analysis with adjustments identified interarm blood pressure difference >5 mm Hg as being associated with a significant odds ratio for the presence of ankle-brachial pressure index <0.90 (odds ratio, 2.19; 95% confidence interval, 1.60-3.03; P<0.01). Among 11 726 subjects without a past history of cardiovascular disease, 249 developed stroke during the average follow-up period of 7.4 years. Interarm blood pressure difference >15 mm Hg was associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke (hazard ratio, 2.42; 95% confidence interval, 1.27-4.60; P<0.01). Therefore, interarm blood pressure differences, measured simultaneously in both arms, may be associated with vascular damage in the systemic arterial tree. These differences may be useful for identifying subjects with an ankle-brachial pressure index of <0.90 in the overall study population, and also a reliable predictor of future stroke in subjects without a past history of cardiovascular disease. These findings support the recommendation to measure blood pressure in both arms at the first visit. [ABSTRACT FROM AUTHOR]

The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity. [ABSTRACT FROM AUTHOR]

Protein kinase C (PKC) activation, induced by hyperglycemia and angiotensin II (AngII), inhibited insulin-induced phosphorylation of Akt/endothelial nitric oxide (eNOS) by decreasing tyrosine phosphorylation of IRS2 (p-Tyr-IRS2) in endothelial cells. PKC activation by phorbol ester (phorbolmyristate acetate [PMA]) reduced insulin-induced p-Tyr-IRS2 by 46% ± 13% and, similarly, phosphorylation of Akt/eNOS. Site-specific mutational analysis showed that PMA increased serine phosphorylation at three sites on IRS2 (positions 303, 343, and 675), which affected insulin-induced tyrosine phosphorylation of IRS2 at positions 653, 671, and 911 (p-Tyr-IRS2) and p-Akt/eNOS. Specific PKCβ2 activation decreased p-Tyr-IRS2 and increased the phosphorylation of two serines (Ser303 and Ser675) on IRS2 that were confirmed in cells overexpressing single point mutants of IRS2 (S303A or S675A) containing a PKCβ2-dominant negative or selective PKCβ inhibitor. AngII induced phosphorylation only on Ser303 of IRS2 and inhibited insulin-induced p-Tyr911 of IRS2 and p-Akt/eNOS, which were blocked by an antagonist of AngII receptor I, losartan, or overexpression of single mutant S303A of IRS2. Increases in p-Ser303 and p-Ser675 and decreases in p-Tyr911 of IRS2 were observed in vessels of insulin-resistant Zucker fatty rats versus lean rats. Thus, AngII or PKCβ activation can phosphorylate Ser303 and Ser675 in IRS2 to inhibit insulin-induced p-Tyr911 and its anti-atherogenic actions (p-Akt/eNOS) in endothelial cells. [ABSTRACT FROM AUTHOR]

Increased white rice (WR) with parallel decreased brown rice (BR) consumption has been associated with increased prevalence of type 2 diabetes (T2DM). To test whether WR and BR have differential effects on energy and glucose metabolism, C57BL/6 mice were fed 6 different diets: control diet (CD, 10% Fat), high-fat diet (HFD, 46% Fat) with either no rice, WR or BR. BR and, surprisingly, WR activated PGC1α and UCP-1 expressions in brown adipose tissue (BAT) and increased energy expenditure as measured by oxygen consumption, CO2 release and heat production, resulting in reduced body weight (36%, 23%) and improvements of glucose tolerance and insulin sensitivity while on HFD after 18 weeks. To investigate the underlying mechanism, gut microbial analysis was performed. Gut microbiota composition showed clear differences between HFD vs. CD or vs. the addition of BR or WR. Ratio of Firmicutes to Bacteroidetes was 3.7-fold increased in HFD vs.CD, but decreased by the WR (46%) or BR (59%). Increased alpha diversity was observed by WR and BR on HFD. Heat map binary showed that several genera are different in HFD+BR vs. HFD or HFD+WR vs. HFD. Analysis of family abundance revealed that Lachnospiraceae, Ruminococcaceae and Streptococcaceae are 2.5, 1.2 and 2.6-fold increased in HFD, which were reduced by WR or BR. Analysis of genus abundance showed that Lactococcus, Dorea, Peptococcus, Clostridium XIVb, Johnsonella, Anaerovorax are 2.6, 3.7, 2.9, 2.7, 4.7 and 1.7-fold respectively, increased in HFD, which were reduced by WR or BR on HFD. In addition, mice on BR+HFD showed greater reductions than mice on WR+HFD in family and genus levels. Our results demonstrated that supplementation with BR or WR, to a lesser degree, changed HFD-induced gut microbial composition at family and genus levels, in parallel with improved systemic energy and glucose metabolism via activation of BAT and increased energy expenditure, resulting in reduced body weight and improved insulin sensitivity. Disclosure: H. Yokomizo: None. A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. K. Park: None. Y. Maeda: None. Q. Li: None. I. Wu: None. M. Matsumoto: Employee; Self; Sunstar Group. S. Devkota: None. A. Kostic: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. [ABSTRACT FROM AUTHOR]

Clinical studies have suggested that loss of insulin's action and excessive IGF-1 levels in the glomeruli elevate the risk for diabetic kidney disease (DKD). To define the potential pathogenic role of IGF-1 and insulin signaling in DKD, we generated mice with selective loss of insulin receptor (IR) or IGF-1 receptor (IGF-1R) in the mesangial cells (MCs) by cross breeding IRflox/flox mice with Sm22α-Cre mice (SMIRKO) or IGF-1Rflox/flox mice with Myh11-Cre mice (SMIGF1RKO), and examined urinary albumin excretion (ACR) and mesangial expansion with 6 month duration of streptozotocin (STZ)-induced diabetes. IGF-1 levels were significantly increased by 1.5 fold in the renal cortex, but not in the plasma of all three types of diabetic mice. Diabetes induced elevation of ACR (2.0 fold), glomerular size and mesangial expansion (2.1 fold), in parallel with increased glomerular expressions of fibrosis-related (Tgfβ1, fibronectin and Col3a) and matrix (Has2) genes by 2-3 fold, significantly, in Wt and SMIRKO mice, but were prevented in diabetic SMIGF1RKO mice. In cultured MCs, IGF-1, at physiological levels, and insulin, only at supra-physiological levels, induced the expressions of Has2 (3.8 fold) and Tgfβ1 (1.7 fold). Deletion of IGF-1R, but not IR, in MCs inhibited both IGF-1 and insulin-induced expressions of Has2. Inhibitor of MAP kinase pathway, but not inhibitor of PI3 kinase reduced insulin or IGF-1-induced expressions of Has2 in MCs. IGF-1-induced phosphorylations of IGF-1R (39 fold), Akt (34 fold) and Erk/MAPK (8 fold) were significantly inhibited in both IR or IGF-1R-deleted MCs. Insulin-induced phosphorylations of IR-β (11 fold) and Akt (27 fold) were also decreased in IR-deleted MCs, but surprisingly increased in IGF-1R-deleted MCs. Thus, MAPK activation by elevated glomerular IGF-1 levels via IGF-1R, but not IR, on MCs, may contribute to the pathogenesis of DKD through induction of Has2 and fibrotic genes. Disclosure: A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. H. Yokomizo: None. Y. Maeda: None. K. Park: None. W. Qi: None. R. St-Louis: None. Q. Li: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. [ABSTRACT FROM AUTHOR]

Daily glucose profile (DGP) involves various factors contributing to diabetic complications: diet, physical activity, insulin dose, social context and stressors. We aimed to identify specific DGPs susceptive to microvascular complication in T1D, exploring endpoint-oriented CGM metrics. First, cluster analysis with 5,584 pooled DGPs from 102 T1D subjects detected 4 major clusters characterized as aligned control (A), biphasic dysglycemia (B), continuous nocturnal hyperglycemia (C) and dyscontrol (D) (Figure 1). The presence of neuropathy and nephropathy was significantly associated with the increase of cluster B (+76%, p=0.002) and C (+69%, p=0.002), respectively. Next, we determined metric ∫B/∫C as the integration of loge (glucose excursions from 70-180 mg/dL):0-12am/:0-6am to represent cluster B/C. To evaluate ∫B/∫C, the retrospective study investigated 18,457 DGPs from 231 adults with T1D (steroid users and available DGPs <10 days were excluded; age 21-78, female 68%, A1c 5.5-12%). The higher ∫B/∫C (Q4) were independent risk factors for retinopathy (OR=3.18), neuropathy (OR=4.69) and the increase of albuminuria (t=2.11) after adjustment for age, gender, duration, smoking, BMI, A1c, HT, HL and T. bilirubin. New CGM metrics ∫B/∫C derived from vulnerable DGP clusters may support risk assessment and early intervention for diabetic complications. Disclosure: Y. Maeda: Research Support; Self; Abbott, Arkray, Inc. Speaker's Bureau; Self; Abbott, Arkray, Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Terumo Medical Corporation. M. Morita: None. A. Tamura: None. K. Takasu: None. Y. Kurogi: None. I. Nimura: Speaker's Bureau; Self; Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co., Ltd. R. Yoshioka: None. M. Minami: Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Medtronic, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Terumo Medical Corporation. Funding: Kondou Kinen Medical Foundation [ABSTRACT FROM AUTHOR]

The Joslin Medalist study reported that after having type 1 diabetes (T1D) for > 50 years, over 35% of Medalists exhibit no to mild diabetic retinopathy (DR) independent of glycemic control, suggesting presence of endogenous protective factors against DR. Proteomic analysis of Medalist retina and vitreous found that Retinol Binding Protein 3 (RBP3), secreted by photoreceptors, is elevated in individuals protected from DR. This finding was confirmed by RBP3 ELISA of replicate vitreous samples from Medalists and other T1D and T2D individuals. In contrast, vitreous VEGF concentrations increased with DR severity. Thus, elevated ratios of intravitreous RBP3/VEGF correlated with lack of progression to advanced DR. Intervention and prevention studies overexpressing RBP3 in retina/photoreceptors of nondiabetic and diabetic animals inhibited VEGF actions and normalized diabetes-induced retinal capillary permeability, neuro-retinal dysfunctions, expressions of VEGF and IL-6, and formation of acellular capillaries. Mechanistically, physiological levels of recombinant RBP3 (10-100nM), but not RBP4 or FGF, inhibited the increased in VEGFR2 tyrosine phosphorylation, hyperglycemia-induced expression of pro-inflammatory cytokines (VEGF and IL-6), and migration of retinal endothelial cells and Müller cells. RBP3, but not RBP4, physically bound to VEGFR2 in cross linkage studies. At physiological levels, RBP3 significantly inhibited glucose uptake into retinal endothelial and Müller cells, and subsequently decreased expression of VEGF and IL-6. These results suggest novel actions for RBP3 to slow glucose uptake in retinal cells and inhibit VEGF actions, thereby preventing, delaying and even arresting diabetes-induced neuro- and vascular retinal dysfunction, inflammatory abnormalities and DR pathologies. These findings strongly support therapeutic potential of RBP3 in DR. Disclosure: H. Yokomizo: None. K. Park: None. A. Clermont: Consultant; Self; KalVista Pharmaceuticals, Inc. Y. Maeda: Research Support; Self; Abbott, Arkray, Inc. Speaker's Bureau; Self; Abbott, Arkray, Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Terumo Medical Corporation. W. Fickweiler: None. A. Ishikado: Employee; Self; SunStar Inc. Employee; Spouse/Partner; SunStar Inc. Q. Li: None. C. Wang: None. D.M. Pober: None. I. Wu: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. L.P. Aiello: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Decision Resources Group, KalVista Pharmaceuticals, Inc., Mingsight, Retinal Solutions. Stock/Shareholder; Self; KalVista Pharmaceuticals, Inc. Other Relationship; Self; Optos. J.K. Sun: Research Support; Self; Adaptive Sensory Technology, Boston Micromachines Corporation, Genentech, Inc., KalVista Pharmaceuticals, Inc., Optovue, Incorporated. Other Relationship; Self; Genentech, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. G.L. King: Research Support; Self; Sanofi. Funding: National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; JDRF; Thomas J. Beatson, Jr. Foundation Inc.; Dianne Nunnally Hoppes Scholarship Fund [ABSTRACT FROM AUTHOR]