Association between urinary C-megalin levels and progressive kidney dysfunction: a cohort study based on the diabetes distress and care registry at Tenri (DDCRT 24).

AIMS: The aim of this cohort study was to evaluate the association between urinary levels of C-megalin, a full-length form of megalin, and kidney dysfunction progression and its dependence on the urinary albumin-creatinine ratio (UACR) in individuals with diabetes. METHODS: We enrolled 1,547 individuals with diabetes who visited the ambulatory clinic at Tenri Hospital, a regional tertiary-care hospital in Tenri City, Nara Prefecture, Japan, with an estimated glomerular filtration (eGFR) of ≥ 30 mL/min/1.73 m2. The hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox proportional hazard models to examine the association between urinary C-megalin levels and eGFR decline by ≥ 40% from baseline. RESULTS: Urinary C-megalin level was not associated with ≥ 40% eGFR decline in an age-, sex-, eGFR-, systolic blood pressure-, hemoglobin-, and UACR-adjusted model in the 1,547 patients enrolled in the study. However, urinary C-megalin levels were associated with a ≥ 40% decline in eGFR when accounting for the relationship between urinary C-megalin levels and UACR in the model. This association was UACR-dependent. CONCLUSIONS: High urinary C-megalin levels were associated with progressive kidney dysfunction in individuals with diabetes, and this association was attenuated by high UACRs.

Production of insulin antibody associated with relapsed hodgkin's lymphoma.

A 72-year-old man with type 2 diabetes mellitus with good glucose control for 20 years and maintained on oral hypoglycaemic agents was diagnosed with Hodgkin's Lymphoma (HL) and started on insulin glargine for glycaemic control. Despite increased doses of insulin, his blood glucose levels went up dramatically. The anti-insulin antibody test proved to be positive, and Scatchard plot analysis showed 2 binding sites with relatively low-affinity constants: K 1 = 0.0032, K 2 = 0.0002 (108/M); and high binding capacities: R 1 = 98.4, R 2 = 372 (10-8 M), which were compatible with the features of antibody of insulin autoimmune syndrome (IAS). However, hypoglycaemia was not noted throughout the course of treatment. Since the insulin binding ratio of the antibody decreased from 87.3% to 62% after the termination of insulin treatment, it was suggested that the antibody reacted mainly to exogenously injected insulin. Switching insulin preparations or introducing insulin secretagogues did not improve elevated blood glucose levels. The initiation of brentuximab vedotin (BV), a therapeutic agent for relapsed HL, resulted in a remarkable improvement in glycaemic control despite the absence of insulin therapy and partial remission of HL. This case suggested that HL triggered anti-insulin antibody production, which resulted in poor glycaemic control, and that BV could be a new treatment option for autoimmune diseases associated with HL. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00550-1.

Urinary C-megalin as a novel biomarker of progression to microalbuminuria: A cohort study based on the diabetes Distress and Care Registry at Tenri (DDCRT 22).

AIMS: Megalin is a multiligand receptor expressed in proximal tubular cells that reabsorbs filtered albumin and correlates cross-sectionally with albuminuria. We investigated the association between urinary C-megalin levels and the incidence of microalbuminuria in patients with diabetes mellitus. METHODS: This cohort study included 752 patients with type 1 or 2 diabetes mellitus and a urinary albumin-to-creatinine (Cr) ratio (UACR) within the normoalbuminuric range (<30 mg/g Cr). The association between urinary C-megalin and persistent microalbuminuria, accounting for the possible interaction between baseline UACR and urinary C-megalin, was estimated using a Cox proportional hazards model. RESULTS: During a median follow-up period of 1.99 years, 179 cases of persistent microalbuminuria were observed. The association between urinary C-megalin and persistent microalbuminuria was UACR-dependent (P for interaction < 0.001), with the highest association observed in the absence of UACR (per 100 fM/gCr of urinary C-megalin: adjusted hazard ratio, 1.13; 95% CI 1.07-1.19), gradually decreasing as UACR increased to 30 mg/g Cr. UACR dependence was confirmed by sensitivity analyses according to low-normal (<10 mg/gCr) or high-normal (10-<30 mg/gCr) UACR. CONCLUSIONS: Urinary C-megalin is associated with progression to microalbuminuria, especially in those with low-normal UACR levels, and its usefulness to identify high risk patients requires further investigation.

Association of urinary C-megalin with albuminuria and renal function in diabetes: a cross-sectional study (Diabetes Distress and Care Registry at Tenri [DDCRT 21]).

BACKGROUND: A urinary biomarker sensitive to glomerular functional or structural changes in diabetic kidney disease is required. This study examined whether urinary C-megalin reflects renal function or albuminuria in diabetes. METHODS: This was a cross-sectional study involving 1576 patients with type 1 or 2 diabetes. The exposure variables were estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), and the outcomes were urinary C-megalin excretion and concentration. Two-part models were used to examine the associations between eGFR and UACR with urinary C-megalin excretion or concentration. RESULTS: The UACR was linearly associated with urinary C-megalin excretion (per 100 mg/gCr of UACR; 11.8 fM/gCr [95% CI 8.9-14.7]). There was no association between decreasing eGFR and increasing urinary C-megalin excretion. The UACR was also linearly associated with the urinary C-megalin concentration (per 100 mg/gCr of UACR, 7.7 fM/L [95% CI 5.8-9.6]). At eGFR values > 60 mL/min/1.73 m2, the eGFR and urinary C-megalin concentration were inversely linearly related (per 10 mL/min/1.73 m2 decline, 7.7 fM/L [95% CI 0.2-15.1]). CONCLUSION: Urinary C-megalin excretion as well as concentration levels are potentially useful biomarkers to detect early changes in diabetic kidney disease.

Reply to the comment of Wilbrink et al. on Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes: The association between remaining ß-cell function and the achievement of the HbA1c target 1 year after initiation.

We have reported that the HbA1c-lowering effects of liraglutide/basal insulin combination rely on remaining ß-cell function and that the cut-off value of the C-peptide immunoreactivity index (CPI), a ß-cell function-related index frequently used in Japanese clinical settings, is 1.103 for the achievement of HbA1c <7.0% at 54 weeks after initiating the liraglutide/basal insulin combination. Wilbrink et al claimed that glucose-lowering effects of glucagon-like peptide-1 receptor agonist liraglutide depend of duration of type 2 diabetes; while our resent study published in the Journal of Diabetes Investigation failed to detect such dependency. This discrepancy might be due to several reasons including co-administration of basal insulin with liraglutide in our study; ethnic difference in T2D pathophysiology between the two study; and difference in sample size (The Usui study on liraglutide/basal insulin, n = 38; the Usui study on liraglutide monotherapy or SU combination, n=88; and the Wilbrink study, n = 69).

Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining ß-cell function and the achievement of the glycated hemoglobin target 1 year after initiation.

AIMS/INTRODUCTION: The glucose-lowering effects of the glucagon-like peptide-1 receptor agonist, liraglutide, have been shown to rely on remaining ß-cell function. However, the possible associations of remaining ß-cell function with the glucose-lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation. MATERIALS AND METHODS: This was a single-center, retrospective, observational study carried out in a private hospital in Osaka, Japan. Type 2 diabetes patients who received a prescription change from insulin therapy, both multiple-dose insulin and basal insulin-supported oral therapy, to liraglutide and basal insulin combination and continued the therapy for 54 weeks without additional oral antidiabetic drugs or bolus insulin were retrospectively analyzed. RESULTS: Among the 72 participants who received a prescription change from multiple-dose insulin and basal insulin-supported oral therapy to liraglutide and basal insulin combination, 57 continued the therapy for 54 weeks. Of those who continued the therapy without receiving additional oral antidiabetic drugs or bolus insulin, seven participants achieved glycated hemoglobin < 7.0% at 54 weeks, but 30 participants did not. The participants who achieved glycated hemoglobin < 7.0% at 54 weeks had a significantly higher C-peptide immunoreactivity index, a ß-cell function-related index frequently used in Japanese clinical settings. The receiver operating curve analysis showed that the C-peptide immunoreactivity index cut-off value for the achievement of glycated hemoglobin <7.0% at 54 weeks is 1.103. CONCLUSIONS: The current findings show that the glucose-lowering effects of liraglutide rely on remaining ß-cell function, even when used with basal insulin; and suggest that liraglutide and basal insulin combination might require additional bolus insulin to fully compensate insulin insufficiency in individuals with reduced ß-cell function.

Polyfluorinated telomers in indoor air of Japanese houses.

The fluorotelomer alcohols (FTOHs) have been detected in various environmental compartments, including indoor and outdoor air, in North America and Europe. In our previous studies, FTOHs were detected at a relative higher concentration in outdoor air in the Keihan (Kyoto-Osaka, one of the major industrial zones) area, Japan compared to reported data. The exposure level of FTOHs in indoor air in the Keihan area remains unclear. In the present study, indoor air FTOH concentrations were investigated using a passive air sampler containing activated carbon felts. The indoor air sampling was conducted in 49 households of the Keihan area, during winter and summer 2008. Most samples contained 6:2 FTOH, 8:2 FTOH, 10:2 FTOH and 8:2 FTOAc. The median concentration of 8:2 FTOH (5.84 ng m(-3)) was highest among fluorotelomers, followed by those of 10:2 FTOH (1.12 ng m(-3)), 6:2 FTOH (0.29 ng m(-3)), and others. Significant correlations among fluorotelomers were observed in collected samples. The association between housing conditions and 8:2 FTOH concentrations showed that samples collected from bed rooms have higher 8:2 FTOH concentrations than those collected from other locations. In addition, samples collected in winter showed lower levels of 8:2 FTOH than those collected in summer. These findings suggest that 8:2 FTOH is the predominant component among fluorotelomers in indoor air, and that there are emission sources of fluorotelomers in indoor environments of the Keihan area. Further investigations into the origins of fluorotelomers are needed to evaluate indoor contamination with fluorotelomers.