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Introduction: Arteriolar hyalinosis (AH) has been shown to be associated with albuminuria and GFR. In this study, we investigated whether or not index of AH (IAH) is a predictor of the onset of macroalbuminuria and impaired renal function (eGFR <60 mL/min/1.73 m2 [eGFR <60]) in type 2 diabetic patients with early diabetic nephropathy., Methods: The study population consisted of 35 patients with type 2 diabetes (25 men; age: 47 ± 9 years; eGFR: 92.7 ± 18.0 mL/min/1.73 m2) with normo- or microalbuminuria who underwent percutaneous renal biopsy. These patients were followed for at least 5 (18 ± 6, range: 6-28) years. The study endpoint was the onset of macroalbuminuria or eGFR <60. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes., Results: During the observation period, 9 out of the 35 patients progressed to macroalbuminuria, and 15 out of the 35 patients developed eGFR <60. The annual rate of eGFR decline was significantly correlated with IAH (r = -0.40, p = 0.016). Kaplan-Meier analysis demonstrated that AH was associated with a significantly higher risk of onset of macroalbuminuria and eGFR <60, and microalbuminuria is associated with the onset of macroalbuminuria but not the onset of eGFR <60., Conclusions: Aggravated AH is a histological risk factor which predicts the onset of macroalbuminuria and eGFR <60 in patients with type 2 diabetes. These findings provide novel insights into the mechanism of progression of diabetic nephropathy., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Continuous glucose monitoring (CGM) improves glycemic fluctuation and reduces hypoglycemic risk. Whether CGM-guided glycemic control favorably modulates coronary atherosclerosis in patients with type 2 diabetes (T2DM) remains unknown., Methods: The OPTIMAL trial was a prospective, randomized, single-center trial in which 94 T2DM patients with CAD were randomized to CGM- or HbA1c-guided glycemic control for 48 weeks (jRCT1052180152). The primary endpoint was the nominal change in total atheroma volume (TAV) measured by serial IVUS. The secondary efficacy measure was the nominal change in maxLCBI 4mm on near-infrared spectroscopy imaging., Results: Among the 94 randomized patients, 82 had evaluable images at 48 weeks. Compared to HbA1c-guided glycemic control, CGM-guided control achieved a greater reduction in %coefficient of variation [-0.1 % (-1.8 to 1.6) vs. -3.3 % (-5.1 to -1.5), p = 0.01] and a greater increase in the duration with glucose between 70 and 180 mg/dL [-1.5 % (-6.0 to 2.9) vs. 6.7 % (1.9 to 11.5), p = 0.02]. TAV increased by 0.11 ± 1.9 mm 3 in the HbA1c-guided group and decreased by -3.29 ± 2.00 mm 3 in the CGM-guided group [difference = -3.4 mm 3 (95%CI: -8.9 to 2.0 mm 3 ), p = 0.22]. MaxLCBI 4mm , increased by 90.1 ± 25.6 in the HbA1c-guided group and by 50.6 ± 25.6 in the CGM-guided group (difference = -45.6 (95%CI: -118.1 to 26.7) p = 0.21]. A post-hoc exploratory analysis showed a greater regression of maxLCBI 4mm in the CGM-guided group [difference = 20.4 % (95%CI:1.3 to 39.5 %), p = 0.03]., Conclusions: CGM-guided control for 48 weeks did not slow disease progression in T2DM patients with CAD. A greater regression of lipidic plaque under CGM-guided glycemic control in the post-hoc analysis requires further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yu Kataoka has received research support from Kowa, Nipro and Abbott, and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda and Daiichi-Sankyo. Stephen J. Nicholls is a recipient of a Principal Research Fellowship from the National Health and Medical Research Council of Australia and has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx and Sanofi-Regeneron and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron and Novo Nordisk. Other authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims/introduction: The discrepancy between HbA1c and glucose exposure may have significant clinical implications; however, the association between the hemoglobin glycation index (HGI) and clinical parameters in type 1 diabetes remains controversial. This study aimed to find the factors associated with HGI (laboratory HbA1c - predicted HbA1c derived from the continuous glucose monitoring [CGM])., Materials and Methods: We conducted a cross-sectional study of adults with type 1 diabetes (n = 211, age 50.9 ± 15.2 years old, female sex = 59.2%, duration of CGM use = 2.1 ± 1.0 years). All subjects wore the CGM for 90 days before HbA1c measurement. Data derived from the FreeStyle Libre sensor were used to calculate the glucose management indicator (GMI) and glycemic variability (GV) parameters. HGI was defined as the difference between the GMI and the laboratory HbA1c levels. The participants were divided into three groups according to the HGI tertile (low, moderate, and high). Multivariate regression analyses were performed., Results: The female sex ratio, HbA1c, and % coefficient of variation (%CV) significantly increased over the HGI tertile, while eGFR and Hb decreased over the HGI tertile. In multivariate analysis, the factors associated with HGI were %CV and eGFR, after adjusting for HbA1c level and sex (R 2  = 0.44)., Conclusions: This study demonstrated that HGI is associated with female sex, eGFR, and some glycemic variability indices, independently of HbA1c. Minimizing glycemic fluctuations might reduce HGI. This information provides diabetic health professionals and patients with personalized diabetes management for adults with type 1 diabetes., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: The relationship between diabetic microvascular complications and the incidence of two types of heart failure-heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] < 40%) and non-HFrEF (LVEF ≥ 40%)-in patients without prior heart failure has not been clarified. We herein examined the association between diabetic microvascular complications and HFrEF or non-HFrEF in patients with type 2 diabetes mellitus (T2DM) without prior heart failure., Methods and Results: In this retrospective cohort study, we assessed the relationship between the presence of diabetic microvascular complications or severity of diabetic retinopathy (no apparent, non-proliferative and proliferative retinopathy) and nephropathy (normoalbuminuria, microalbuminuria, and macroalbuminuria) at baseline, with the primary outcome of first heart failure hospitalization classified as HFrEF or non-HFrEF in patients with type 2 diabetes mellitus without prior heart failure. Among 568 patients (69.2% males, mean age 66.2 ± 9.6 years), 70 experienced heart failure hospitalization (HFrEF: 24 and non-HFrEF: 46). Non-HFrEF hospitalization but not HFrEF hospitalization was significantly associated with the presence of diabetic microvascular complications. The incidence of non-HFrEF hospitalization was significantly higher in the proliferative retinopathy group than that in the no apparent retinopathy group (adjusted hazard ratio [HR] 2.96, 95% confidence interval [CI]: 1.09-6.83, P = 0.035) and in those with macroalbuminuria than in those with normoalbuminuria (adjusted HR 4.23, 95% CI: 2.24-7.85, P < 0.001) even after adjustment for age and sex. When non-HFrEF was classified into heart failure with mildly reduced ejection fraction (HFmrEF) (40% ≤ LVEF < 50%) and heart failure with preserved ejection fraction (HFpEF) (50% ≤ LVEF), HFmrEF and HFpEF hospitalizations were also found to be associated with the progression of retinopathy and nephropathy., Conclusions: In patients with T2DM without prior heart failure, non-HFrEF hospitalization was more closely associated with the progression of diabetic microangiopathy than HFrEF. The development of non-HFrEF may be mediated through a mechanism similar to that of microvascular complications in these patients., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims/introduction: The aim of this study was to develop a scale to evaluate disease stigma in patients with lifestyle-related chronic non-communicable diseases (LCNCDs), which we named the Kanden Institute Stigma Scale (KISS), and to consider its possible clinical application for patients with diabetes., Materials and Methods: An initial 90 questions were drafted and categorized into six subscales according to the manifestations of stigma. The final version of the KISS was developed as a 24-item questionnaire comprising four items for each subscale., Results: A total of 539 outpatients including 452 patients with diabetes and 87 patients without diabetes were recruited. Construct validity was confirmed by assessing the correlation with previously established measures. Confirmatory factor analysis showed the KISS to have good model fitness (adjusted goodness-of-fit index = 0.856). Test-retest reproducibility analysis showed that the intraclass coefficient of the first and a second KISS was 0.843 (P < 0.001), indicating excellent reproducibility. The KISS showed higher scores for patients with diabetes than for patients without diabetes (12.23 ± 0.49 vs 5.76 ± 0.73, P < 0.05). The KISS score was significantly higher in type 1 and type 2 diabetes patients taking insulin therapy than in type 2 diabetes patients not taking insulin (P < 0.05)., Conclusion: The KISS is a validated and reliable questionnaire for assessment of stigma among patients with diabetes as well as other lifestyle-related chronic non-communicable diseases, and might contribute to identifying and rectifying diabetes stigma, as well promoting awareness among health care professionals of this very consequential health problem., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: A high urinary albumin excretion (UAE) and low glomerular filtration rate (GFR) are risk factors for progressive renal function loss in type 2 diabetic patients. In addition, diabetic retinopathy (DR) is also a risk factor for progressive renal function decline in microalbuminuric type 2 diabetic patients. We aimed to elucidate the factors, including DR, associated with a more severe situation of diabetic nephropathy, i.e., hemodialysis (HD) induction in normo- and microalbuminuric type 2 diabetic patients without renal dysfunction., Methods: Normo- and microalbuminuric type 2 diabetic patients with normal renal function whose GFRs had been measured by iohexol injection in 1995-1997 and had been followed for over 5 years were analyzed (n = 199). HbA1c levels was divided into HbA1c ≥ 7.0 (n = 146) and <7.0 (n = 53) groups. The UAE levels were classified as normoalbuminuria (NA, n = 114) and microalbuminuria (MA, n = 85). Seventy-two patients had DR, and 96 had hypertension. Patients were followed up for 15.7 ± 6.0 years and frequency of and duration to the HD induction were evaluated., Results: During the study period, 8 patients received HD induction. There were no remarkable differences in the rates of HD induction between patients with and without HbA1c ≥7.0, microalbuminuria, DR or hypertension. A Kaplan-Meier analysis revealed that HbA1c ≥7.0 (p = 0.037) and DR (p = 0.037) were associated with a significantly higher risk of HD induction than HbA1c <7.0 and no DR, respectively while albuminuria grade and hypertension were not associated with the risk of HD induction. There was significant negative correlation between HbA1c and annual decline rate of eGFR and annual decline rate of eGFR in the patients with prepro-proliferative DR (PDR) was significantly higher than that in the patients without DR. In the multivariate analysis, HbA1c and PDR showed significant relationships with the annual decline rate of eGFR., Conclusions: It was reasonable that poorer glycemic control affected HD induction for 16 years follow-up. However, DR, especially PDR, should also be considered a substantial risk factor for HD induction although microalbuminuria and hypertension did not predict it at the early stage of diabetic nephropathy in type 2 diabetic patients with normal renal function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The impact of glucose fluctuation on intracranial artery stenosis remains to be elucidated. This study aimed to investigate the association between glucose fluctuation and intracranial artery stenosis. This was a cross-sectional study of type 2 diabetes mellitus (T2DM) patients equipped with the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories) between February 2019 and June 2020. Glucose fluctuation was evaluated according to the standard deviation (SD) of blood glucose, coefficient of variation (%CV), and mean amplitude of glycemic excursions (MAGE). Magnetic resonance angiography was used to evaluate the degree of intracranial artery stenosis. Of the 103 patients, 8 patients developed severe internal carotid artery (ICA) siphon stenosis (≥70%). SD, %CV, and MAGE were significantly higher in the severe stenosis group than in the non-severe stenosis group (<70%), whereas there was no significant intergroup difference in the mean blood glucose and HbA1c. Multivariable logistic regression analysis adjusted for sex showed that SD, %CV, and MAGE were independent factors associated with severe ICA siphon stenosis. In conclusion, glucose fluctuation is significantly associated with severe ICA siphon stenosis in T2DM patients. Thus, glucose fluctuation can be a target of preventive therapies for intracranial artery stenosis and ischemic stroke.

Aims: Whether or not renal structural changes, especially arteriolar hyalinosis, are related to the rate of renal functional decline and increase in urinary albumin excretion (UAE) at the early stage of diabetic nephropathy in patients with type 2 diabetes is still unknown. Our previous study determined that arteriolar hyalinosis is an independent risk factor for low GFR. We sought to determine whether arteriolar hyalinosis is also a risk factor for rapidly progressive decline in GFR., Methods: We evaluated 22 type 2 diabetic patients with normo- or microalbuminuria who took part in the previous study, to clarify which renal histological factors were associated with changes in UAE and the glomerular filtration rate (GFR) during 11.0 ± 3.0 years of follow-up. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate the glomerular and interstitial structural changes., Results: In all 22 patients, the GFR was significantly decreased from baseline to follow-up, while the UAE did not change markedly between the 2 periods. After 11 ± 3 years of follow-up, the GFR was significantly lower in the rapid decliner group (annual rate of GFR decline ≥3.0%) than in the non-rapid decliner group (p = 0.017). The index of arteriolar hyalinosis (IAH) at baseline in the rapid decliners was significantly larger than in the non-rapid decliners (p = 0.015). The IAH showed a significant negative correlation with the GFR at follow-up (r = 0.50, p = 0.018) and the annual rate in the GFR decline (r = 0.47, p = 0.027) and significant positive correlations with UAE at follow-up (r = 0.46, p = 0.034) and the annual rate in the UAE increase (r = 0.57, p = 0.005). The GFR at follow-up in patients with IAH ≥2.0 was significantly decreased from baseline (p = 0.042) and significantly lower than that of the patients with IAH <2.0 (p = 0.026), which did not decrease significantly from baseline. The frequency of rapid decliners was larger in the IAH ≥2.0 than in the IAH <2.0 patients (p = 0.037)., Conclusions: Aggravated arteriolar hyalinosis was a risk factor for a rapid GFR decline. This finding might reflect initial changes in early diabetic nephropathy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: The aim of the present study was to explore the relationship between changes in renal structure in patients with type 2 diabetes at an early stage of diabetic nephropathy using serial renal biopsies, and change in renal function., Methods: The study population comprised 10 patients with type 2 diabetes with normo- or microalbuminuria at baseline. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. Urinary albumin excretion (UAE) and glomerular filtration rate (GFR) were measured annually. A second renal biopsy was performed after a mean of 6.1 ± 2.4 years of follow-up., Results: UAE, GFR, blood pressure and severity of diabetic retinopathy (DR) did not change between the baseline and follow-up. The annual decrease in the surface density of the peripheral glomerular basement membrane (GBM) (Sv[PGBM/glom]) was correlated with the rate of loss of GFR during the six-year follow-up period. The annual change in the Sv(PGBM/glom) was negatively correlated with the change in mesangial volume fraction., Conclusions: Decreases in the GFR in patients with type 2 diabetes with normo- or microalbuminuria at baseline were associated with a decreased glomerular filtration surface, as a result of mesangial expansion during a mean six years of observation. These findings confirm ongoing pathological progression of glomerulopathy despite no significant change in albuminuria or retinopathy status., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: This study investigated the association between renal histology, as assessed by morphometric analysis using light (LM) and electron (EM) microscopy, and changes in urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in Japanese people with type 2 diabetes in the early stages of diabetic nephropathy., Research Design and Methods: We performed percutaneous renal biopsies in 29 patients with type 2 diabetes (22 men, mean ± SD age 49 ± 10 years and GFR 119 ± 27 mL/min/1.73 m 2 , with 15 normoalbuminuric [UAE <20 μg/min] and 14 microalbuminuric [UAE 20-200 μg/min]) to clarify which histological factors were associated with changes in UAE and GFR during 8.0 ± 3.5 years' follow-up. Glomerular structural changes including mesangial volume fraction [Vv(Mes/glom)] were estimated using EM, whereas the index of arteriolar hyalinosis (IAH) score was assessed by LM. Patients underwent annual measurement of GFR using iohexol injection with simultaneous urine collections for UAE., Results: Vv(Mes/glom) was negatively correlated with baseline and follow-up GFR but not with UAE. The IAH score was positively correlated with UAE and negatively correlated with GFR at follow-up, but it was not correlated with either UAE or GFR at baseline. GFR at follow-up was significantly decreased from baseline in patients with IAH scores ≥2.0 and significantly lower than in patients with IAH scores <2.0. Patients with IAH scores <2.0 showed no significant change in GFR during follow-up., Conclusions: Arteriolar hyalinosis is an additional histological predictor for albuminuria increase and GFR decline in normo- and microalbuminuric Japanese people with type 2 diabetes., (© 2017 by the American Diabetes Association.)

Aims: To determine whether or not diabetic retinopathy (DR) in type 2 diabetic patients can predict the renal functional decline., Methods: We examined 32 normo-microalbuminuric type 2 diabetic patients by renal biopsy (23 men, age 49±10yrs) divided into two groups according to the presence (n=19) or absence (n=13) of DR. Electron microscopic morphometry including mesangial fractional volume [Vv(Mes/glom)] were performed and light microscopic tissues were categorized as: C1, normal/near normal renal structure; C2, typical diabetic glomerulopathy; C3, atypical injury patterns. Patients were followed up for 7.1±3.8years, and glomerular filtration rate (GFR) and urinary albumin excretion (UAE) measurements were taken annually., Results: Vv(Mes/glom) was larger in DR+ than that in DR-. Vv(Mes/glom) positively correlated with the UAE if patients had DR. The patients with DR had a significant higher rate of C2 pattern compared to those in DR-. Among patients with DR and C2, GFR in microalbuminuria (n=7) decreased while GFR in normoalbuminuria (n=5) did not change during the observation., Conclusions: Type 2 diabetic patients with DR and C2 showed progressive renal dysfunction after they had microalbuminuria. DR and albuminuria should be considered to determine renal function decline in type 2 diabetic patients., (Copyright © 2016. Published by Elsevier Inc.)

Objective: Despite the number of potential biomarker proteins for diabetes, very few of them have proven useful as clinically beneficial indicators, because of the technical difficulties associated with their identification among highly abundant serum proteins. We attempted to identify a protein with distinguishable expression in human diabetes., Methods: We applied a highly efficient strategy for the purification of endogenous low abundance proteins from diabetic and non-diabetic serum samples. Extracted sera were fractionated by SDS-PAGE and protein bands were isolated and analyzed by mass spectrometry using an ion-trap mass spectrometer. The identities of the proteins were confirmed by western blotting and the serum levels evaluated., Results: A significantly upregulated protein in diabetic patients was identified as monomeric α2-macroglobulin. Its tetramer, another dominant circulating molecular form, was only marginally increased in diabetes., Conclusion: Serum monomeric α2-macroglobulin is highly expressed in many diabetic subjects. It is identical to the human 'cardiac isoform of α2-macroglobulin' described in the literature, a well-known acute phase serum biomarker protein mechanistically involved in cardiac and atherosclerotic diseases., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Glomerular hyperfiltration (GHF) may be an important factor in the initiation of glomerular damage and in predisposing diabetic patients to the later development of diabetic nephropathy (DN). Previous reports show wide range of prevalence of GHF in type 2 diabetic patients. This cross-sectional study was designed to determine the prevalence of GHF at an early stage of DN in Japanese type 2 diabetic patients and to investigate the relationships between clinical variables and GHF. We measured the glomerular filtration rate (GFR) using the plasma clearance of iohexol in 56 control subjects and 93 type 2 diabetic patients without hypertension or overt proteinuria. We used Altman's method to calculate the age-adjusted 95% reference ranges for GFR from the data of control subjects and classified GHF in type 2 diabetics from the reference ranges. Hyperfiltrators (defined as GFR > mean GFR + 1.96 S.D. of control subjects) was found in 17% patients (16/93). Other 77 patients (83%) were normofiltrators (defined as GFR< or = mean GFR + 1.96 S.D. of control subjects). GFR values, both in hyperfiltrators and normofiltrators, were 140.5 +/- 14.6 and 98.8 +/- 14.0 ml/min/1.73 m2, respectively. Age, sex, BMI, blood pressure, albumin excretion rate, and frequency of microalbuminuria did not differ between the hyperfiltrators and normofiltrators. Fasting plasma glucose and hemoglobin A1c were significantly higher in the hyperfiltrators than the normofiltrators (P<0.001 and 0.004, respectively). GHF exists among Japanese type 2 diabetic patients with no evidence of overt proteinuria or hypertension. Glycemic control might be a significant determinant of GHF in these patients.