Association between continuous glucose monitoring-derived glycemic control indices and urinary biomarkers of diabetic kidney disease: Hyogo Diabetes Hypoglycemia Cognition Complications study.

AIMS: Glomerular damage and proximal tubular damage play an important role in the pathogenesis of diabetic kidney disease. This study aimed to investigate the relationship between the urinary markers of proximal tubular injury, including urinary liver-type fatty acid-binding protein-to-creatinine ratio (uL-FABP/Cr) and urinary N-acetyl-ß-D-glucosaminidase-to-creatinine ratio (uNAG/Cr), and glycemic control status. METHODS: This cross-sectional study included 245 and 39 patients with type 2 diabetes mellitus (T2DM) and non-T2DM (NDM), respectively. The participants of this study were fitted with retrospective CGM, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated. RESULTS: The results were presented as medians (interquartile ranges). The uL-FABP/Cr was significantly higher in the microalbuminuria than in the normo-albuminuria group [4.2 (2.7-7.1) and 2.2 (1.4-3.4) µg/gCr, respectively, P < 0.001], while the uNAG/Cr in the normo-albuminuria group [6.3 (4.5-10.1) U/gCr] was significantly higher than that in the NDM group [5.3 (3.8-6.3) U/gCr, P = 0.048] but significantly lower than that in the microalbuminuria group [9.2 (6.4-11.1) U/gCr, P = 0.004]. The multivariate logistic regression analysis indicated that CGM-derived TIR was significantly associated with the urinary albumin-to-creatinine ratio [uAlb/Cr, odds ratio (OR) 0.985, 95% confidence interval (CI) 0.971-0.998, P = 0.029] and uNAG/Cr (OR 0.973, 95% CI 0.957-0.989, P = 0.001) independent of renal function. GRI was similarly associated with uAlb/Cr and uNAG/Cr. CONCLUSION: The findings of this study indicated that uNAG/Cr was elevated before albuminuria development and was associated with CGM-derived TIR and GRI.

Association between brain imaging biomarkers and continuous glucose monitoring-derived glycemic control indices in Japanese patients with type 2 diabetes mellitus.

INTRODUCTION: Although type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate the association between continuous glucose monitoring (CGM)-derived glycemic control indices and brain imaging biomarkers assessed by MRI. RESEARCH DESIGN AND METHODS: This cross-sectional study included 150 patients with T2DM. The severity of cerebral white matter lesions (WMLs) was assessed using MRI for deep and subcortical white matter and periventricular hyperintensities. The degree of medial temporal lobe atrophy (MTA) was assessed using voxel-based morphometry. Each participant wore a retrospective CGM for 14 consecutive days, and glycemic control indices, such as time in range (TIR) and glycemia risk index (GRI), were calculated. RESULTS: The proportion of patients with severe WMLs showed a decreasing trend with increasing TIR (P for trend=0.006). The proportion of patients with severe WMLs showed an increasing trend with worsening GRI (P for trend=0.011). In contrast, no significant association was observed between the degree of MTA and CGM-derived glycemic control indices, including TIR (P for trend=0.325) and GRI (P for trend=0.447). CONCLUSIONS: The findings of this study indicate that the severity of WMLs is associated with TIR and GRI, which are indices of the quality of glycemic control. TRIAL REGISTRATION NUMBER: UMIN000032143.

Association between low-carbohydrate diets and continuous glucose monitoring-derived time in ranges.

AIMS: Low-carbohydrate diets have become popular in the general community. The mutual relationship between the percentage of total energy intake from carbohydrates (CHO/E), glycemic control indices, and diabetes complications remains unclear. MATERIALS AND METHODS: This cross-sectional study included 177 patients with type 2 diabetes mellitus who regularly visited outpatient clinics. In this study, dietary questionnaires were used to assess the intake ratio of the three macronutrients, and the low-carbohydrate-diet score was calculated. We investigated the association between the low-carbohydrate-diet score, continuous glucose monitoring (CGM)-derived short-term glycemic control indices, and diabetes complications in patients with type 2 diabetes mellitus. RESULTS: The results are presented as medians (interquartile ranges) unless otherwise stated. Hemoglobin A1c was 7.1% (6.6-7.7%), CGM-derived time in range (TIR) was 75.3% (62.8-87.0%), body mass index (BMI) was 24.0 (22.1-26.3) kg/m2, and CHO/E was 49.8% (44.8-55.6%). BMI, triglycerides, and CGM-derived time above range decreased significantly with increasing low-carbohydrate-diet scores. However, no significant association was found between the low-carbohydrate-diet score and glycemic control indices, including TIR, mean amplitude of glycemic excursions, and vascular complications of type 2 diabetes mellitus. CONCLUSION: Moderate-carbohydrate diets positively impact weight control and lipid metabolism but may have a limited effect on short-term glycemic variability in Japanese patients with type 2 diabetes mellitus.

Xanthine oxidoreductase activity is correlated with hepatic steatosis.

The enzyme xanthine oxidoreductase (XOR) catalyzes the synthesis of uric acid (UA) from hypoxanthine and xanthine, which are products of purine metabolism starting from ribose-5-phosphate. Several studies suggested a relationship between hyperuricemia and hepatic steatosis; however, few previous studies have directly examined the relationship between XOR activity and hepatic steatosis. A total of 223 subjects with one or more cardiovascular risk factors were enrolled. The liver-to-spleen (L/S) ratio on computed tomography and the hepatic steatosis index (HSI) were used to assess hepatic steatosis. We used a newly developed highly sensitive assay based on [13C2, 15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry to measure plasma XOR activity. Subjects with the L/S ratio of < 1.1 and the HSI of < 36 had increased XOR activity and serum UA levels. Independent of insulin resistance and serum UA levels, multivariate logistic regression analysis revealed that plasma XOR activity was associated with the risk of hepatic steatosis as assessed by the L/S ratio and HSI. According to the findings of this study, plasma XOR activity is associated with hepatic steatosis independent of insulin resistance and serum UA levels.

Clinical impact of 11C-Pittsburgh compound-B positron emission tomography in addition to magnetic resonance imaging and single-photon emission computed tomography on diagnosis of mild cognitive impairment to Alzheimer's disease.

ABSTRACT: This study aimed to evaluated the clinical impact of adding [11C] Pittsburgh compound-B (11C-PiB) PET for clinical diagnosis of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia.Twenty six (mean age 78.5 ±â€Š5.18 years, 21 females) AD (n = 7), amnestic MCI (n = 12), non-amnestic MCI (n = 3), vascular dementia, progressive supranuclear palsy (PSP) with frontotemporal dementia (FTD), FTD (n = 1 each), and normal (n = 1) patients underwent 11C-PiB-PET, MRI, and SPECT scanning. 11C-PiB-PET was compared with MRI and SPECT for clinical impact.11C-PiB-PET showed positivity in 6, 9, and 0 of the AD, amnestic MCI, and non-amnestic MCI patients, respectively, and 0 of those with another disease. Parahippocampal atrophy at VSASD was observed in 5 AD patients, 6 amnestic and PiB-positive MCI patients, 1 amnestic and PiB-negative MCI patient, and 1 vascular dementia patient. Parietal lobe hypoperfusion in SPECT findings was observed in 6, 4, and 2 of those, respectively, as well as 1 each of non-amnestic MCI, vascular dementia, and normal cases. Sensitivity/specificity/accuracy for selecting PiB-positive patients among the 15 MCI patients for 11C-PiB-PET were 100% (9/9)/100% (6/6)/100% (15/15), for VSRAD were 66.7% (6/9)/83.3% (5/6)/73.3% (11/15), and for SPECT were 44.4% (4/9)/50.0% (3/6)/46.7% (7/15), while those were 88.9% (8/9)/33.3% (2/6)/66.7% (10/15)/for combined VSRAD and SPECT. 11C-PiB-PET accuracy was significantly higher than that of SPECT.11PiB-PET alone may be useful for selecting patients who will progress from MCI to AD in the future, although follow-up study is necessary to clarify the outcome of MCI patients.

Association of time in range with hemoglobin A1c, glycated albumin and 1,5-anhydro-d-glucitol.

AIMS/INTRODUCTION: Hemoglobin A1c (HbA1c), glycated albumin (GA) and 1,5-anhydro-d-glucitol (1,5-AG) are used as indicators of glycemic control, whereas continuous glucose monitoring (CGM) is used to assess daily glucose profiles. The aim of this study was to investigate the relationships between CGM metrics, such as time in range (TIR), and glycemic control indicators. MATERIALS AND METHODS: We carried out retrospective CGM and blood tests on 189 outpatients with impaired glucose tolerance (n = 22), type 1 diabetes mellitus (n = 67) or type 2 diabetes mellitus (n = 100). RESULTS: In type 1 diabetes mellitus and type 2 diabetes mellitus patients, HbA1c and GA were negatively correlated with TIR, whereas 1,5-AG was positively correlated with TIR. In type 1 diabetes mellitus patients, a TIR of 70% corresponded to HbA1c, GA and 1,5-AG of 6.9% (95% confidence interval [CI] 6.5-7.2%), 20.3% (95% CI 19.0-21.7%) and 6.0 µg/mL (95% CI 5.1-6.9 µg/mL), respectively. In type 2 diabetes mellitus patients, a TIR of 70% corresponded to HbA1c, GA and 1,5-AG of 7.1% (95% CI 7.0-7.3%), 19.3% (95% CI 18.7-19.9%) and 10.0 µg/mL (95% CI 9.0-11.0 µg/mL), respectively. TIR values corresponding to HbA1c levels of 7.0% were 56.1% (95% CI 52.3-59.8%) and 74.2% (95% CI 71.3-77.2%) in type 1 diabetes mellitus and type 2 diabetes mellitus patients, respectively. CONCLUSIONS: The results of this study showed that the estimated HbA1c corresponding to a TIR of 70% was approximately 7.0% for both type 1 diabetes mellitus and type 2 diabetes mellitus patients, and that the estimated 1,5-AG calculated from the TIR of 70% might be different between type 1 diabetes mellitus and type 2 diabetes mellitus patients.

Relationships between time in range, glycemic variability including hypoglycemia and types of diabetes therapy in Japanese patients with type 2 diabetes mellitus: Hyogo Diabetes Hypoglycemia Cognition Complications study.

AIMS/INTRODUCTION: Continuous glucose monitoring (CGM) metrics, such as times in range (TIR) and time below range, have been shown to be useful as clinical targets that complement glycated hemoglobin (HbA1c) for patients with type 2 diabetes mellitus. We investigated the relationships between TIR, glycemic variability and patient characteristics in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We carried out continuous glucose monitoring in 281 outpatients with type 2 diabetes mellitus who participated in a multicenter cohort (Hyogo Diabetes Hypoglycemia Cognition Complications) study. RESULTS: The results are shown as the median (interquartile range). The age, disease duration and HbA1c were 68 years (62-71 years), 13 years (7-23 years) and 6.9% (6.5-7.5%), respectively. TIR and standard deviation obtained by continuous glucose monitoring worsened significantly with increasing disease duration. Multiple regression analyses showed that disease duration (standard partial regression coefficient, ß = -0.160, P = 0.003), diabetic peripheral neuropathy (ß = -0.106, P = 0.033) and urinary albumin excretion (ß = -0.100, P = 0.043) were useful explanatory factors for TIR. In contrast, HbA1c (ß = -0.398, P < 0.001) and the use of antidiabetic drugs potentially associated with severe hypoglycemia (ß = 0.180, P = 0.028), such as sulfonylureas, glinides and insulin, were useful explanatory factors for time below range in the elderly patients with type 2 diabetes mellitus. CONCLUSIONS: The results of this study suggest that disease duration and diabetic complications are associated with TIR deterioration. In addition, low HbA1c levels and the use of antidiabetic drugs potentially associated with severe hypoglycemia might worsen the time below range in the elderly.

Xanthine oxidoreductase activity correlates with vascular endothelial dysfunction in patients with type 1 diabetes.

AIMS: Xanthine oxidoreductase (XOR) is an enzyme regulating uric acid synthesis and generation of reactive oxygen species. Several studies suggested relationship between XOR and atherosclerotic diseases; however, few previous studies have directly examined the relationship between XOR and vascular endothelial dysfunction in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to evaluate the relationship between XOR activity and vascular endothelial function in patients with T1DM. METHODS: Seventy-one patients with T1DM participated in the study and underwent assessments, including plasma XOR activity and flow-mediated dilation (FMD), to measure vascular endothelial function. RESULTS: The natural logarithm value of XOR activity (ln-XOR) was 3.03 ± 0.99 pmol/h/mL, and FMD was 5.5% ± 2.4%. FMD was inversely and significantly correlated with ln-XOR (correlation coefficient: r = - 0.396, P < 0.001), UA (r = - 0.252, P = 0.034), and asymmetric dimethylarginine (ADMA) (r = - 0.414, P < 0.001). ln-XOR showed positive correlation with HbA1c (r = 0.292, P = 0.013), ALT (r = 0.658, P < 0.001), and ADMA (r = 0.363, P = 0.002). Stepwise multiple regression analysis showed that ln-XOR (standard partial regression coefficient: ß = - 0.254, P = 0.018) was an independent explanatory variable of FMD. CONCLUSIONS: The results of this study showed for the first time that XOR activity is associated with glycemic control in patients with T1DM and that XOR activity is associated with vascular endothelial dysfunction.

Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans.

BACKGROUND AND AIMS: The enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Besides the synthesis of UA, basic research has suggested that XOR is involved in the regulation of reactive oxygen species, adipogenesis, and peroxisome proliferator-activated receptor-γ (PPAR-γ). XOR activity has shown to be much lower in humans than in rodents, which makes its accurate measurement difficult. Recently, a novel human plasma XOR activity assay has been established using a combination of liquid chromatography (LC) and triple quadrupole mass spectrometry (TQMS) to detect [13C2,15N2]UA using [13C2,15N2]xanthine as a substrate. Using this novel assay, we for the first time determine plasma XOR activity in humans, and evaluate its association with insulin resistance, high-sensitivity C-reactive protein (hsCRP) levels, and other parameters. METHODS: Of the 29 volunteers who wished to participate in the study, 3 were excluded; of the remaining, 11 were female and 15 were male with a mean age of 25.9±3.3years. Blood samples were collected under fasting conditions in the early morning to measure XOR activity and other parameters. RESULTS: The natural logarithmic value of XOR activity (ln-XOR) in plasma was 3.4±0.8pmol/h/mL. Ln-XOR had a positive correlation with UA and body mass index (BMI) and a negative correlation with quantitative insulin sensitivity check index (QUICKI) and adiponectin. In addition, ln-XOR had a positive correlation with hsCRP levels, which serves as a marker of chronic inflammation. CONCLUSIONS: The present study has shown that XOR activity is correlated with serum UA levels in humans. Furthermore, even in young subjects, XOR activity is correlated with insulin resistance, BMI, and subclinical inflammation. Thus, XOR activity may be potentially involved in adiposity and subclinical inflammation in humans.