The joint association of diabetes distress and depressive symptoms with all-cause mortality in Japanese individuals with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry in Tenri [DDCRT 20]).

AIMS/HYPOTHESIS: The independent association of depressive symptoms and diabetes distress with mortality risk in individuals with diabetes has not been evaluated. We examined the temporal joint association of diabetes distress and depressive symptoms at baseline and the subsequent risk of all-cause mortality. METHODS: The longitudinal data of 3118 individuals with type 2 diabetes were obtained from a large Japanese diabetes registry. To assess the joint association of diabetes distress and depressive symptoms at baseline with the subsequent risk of all-cause mortality, the Cox proportional hazards model was used with adjustment for potential confounders. RESULTS: The mean age, BMI and HbA1c levels were 64.7 years, 24.6 kg/m2 and 58.6 mmol/mol (7.5%), respectively, and 38.1% of the participants were women. In the multivariable-adjusted models evaluating the diabetes distress and depressive symptoms separately, the HRs for all-cause mortality were 1.67 (95% CI 1.14, 2.43; p = 0.008) and 1.40 (95% CI 1.05, 1.85; p = 0.020), respectively. In such models evaluating the joint association of diabetes distress and depressive symptoms, compared with individuals without diabetes distress or depressive symptoms (DD-/DS-), the HRs for all-cause mortality for the group without diabetes distress but with depressive symptoms (DD-/DS+), with diabetes distress but without depressive symptoms (DD+/DS-), and with diabetes distress and depressive symptoms (DD+/DS+) were 1.34 (95% CI 0.99, 1.86; p = 0.056), 1.96 (95% CI 1.10, 3.50; p = 0.023) and 1.71 (95% CI 1.06, 2.77; p = 0.029), respectively. We did not observe a significant interaction between diabetes distress and depressive symptoms with all-cause mortality risk (p = 0.2636). In the stratified analysis by sex, a significant joint association of diabetes distress and depressive symptoms with the risk of all-cause mortality was observed only in men. CONCLUSIONS/INTERPRETATION: Diabetes distress and depressive symptoms were independently associated with all-cause mortality risk in male participants with type 2 diabetes, but we did not observe a significant interaction between diabetes distress and depressive symptoms in relation to all-cause mortality. Graphical abstract.

Association between diabetes distress and all-cause mortality in Japanese individuals with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry in Tenri [DDCRT 18]).

AIMS/HYPOTHESIS: The absence of data on the direct association between diabetes-specific distress and all-cause mortality in individuals with diabetes prompted us to examine the temporal association between Problem Areas in Diabetes (PAID) survey scores and the subsequent risk of all-cause mortality in a cohort of individuals with type 2 diabetes. METHODS: Longitudinal data from 3305 individuals with diabetes were obtained from a large Japanese diabetes registry. Independent correlations between quintiles of PAID total scores or PAID scores of ≥40 and all-cause mortality (median follow-up of 6.1 years) were examined using Cox proportional hazards models with adjustment for potential confounders. RESULTS: The study population included 1280 women and 2025 men with a mean age of 64.9 years, BMI of 24.6 kg/m2 and HbA1c level of 58.7 mmol/mol (7.5%). In the multivariable-adjusted model, compared with the first quintile of PAID scores, the multivariable-adjusted HRs (95% CIs) for all-cause mortality for the second to fifth quintiles were 1.11 (0.77, 1.60; p = 0.56), 0.87 (0.56, 1.35; p = 0.524), 0.95 (0.63, 1.46; p = 0.802) and 1.60 (1.09, 2.36; p = 0.016), respectively. Compared with a PAID score of <40, the multivariable-adjusted HR for all-cause mortality of those with a score of ≥10 was 1.56 (95% CI 1.17, 2.08; p = 0.002). In subgroup analyses, the association between PAID score and all-cause mortality was found in men (HR 1.76; 95% CI 1.26, 2.46) but not in women (HR 1.09; 95% CI 0.60, 2.00), with a significant interaction between diabetes distress and sex (p = 0.0336). CONCLUSIONS/INTERPRETATION: We observed a significant positive association between high diabetes distress and all-cause mortality in men with diabetes.

Serum uric acid levels are associated with increased risk of newly developed diabetic retinopathy among Japanese male patients with type 2 diabetes: A prospective cohort study (diabetes distress and care registry at Tenri [DDCRT 13]).

OBJECTIVE: We assessed the prospective association between baseline serum uric acid levels and consequent risk of developing diabetic retinopathy. RESEARCH DESIGN AND METHODS: Data for 1839 type 2 diabetes patients without diabetic retinopathy were obtained from a Japanese diabetes registry. A Cox proportional hazards model with time-varying exposure information by sex was used and adjusted for potential confounders to assess the independent correlations between baseline serum uric acid levels and incidence rate of diabetic retinopathy. RESULTS: Newly developed diabetic retinopathy was recognized in 188 patients (10.2%) during the observation period of 2 years. Compared to the first serum uric acid quartile level, the multivariate adjusted hazards ratio for diabetic retinopathy development in male patients was 1.97 (95% CI, 1.14-3.41; P = .015), 1.92 (95% CI, 1.18-3.13; P = .008), and 2.17 (95% CI, 1.40-3.37; P = .001) for the second, third, and fourth serum uric acid quartile levels, respectively. But this was not the case with female patients. CONCLUSION: Higher serum uric acid levels were associated with increased risk of developing diabetic retinopathy in male patients with type 2 diabetes, but not in female patients. Serum uric acid may be a useful biomarker for predicting the future risk of developing diabetic retinopathy in male patients with type 2 diabetes.

The Japanese version of Problem Areas in Diabetes Scale: a clinical and research tool to assess emotional functioning among people with diabetes.

Introduction: The purpose of this study was to develop the Japanese version of the Problem Areas in Diabetes (PAID) scale, a measure of emotional adjustment to diabetes that has been translated into Japanese by our group. Materials and methods: A total of 418 Japanese people with diabetes attending our outpatient clinic participated (n = 65 type 1 and n = 353 type 2). We assessed the internal reliability of the PAID, examined correlations of the PAID with conceptually related psychosocial constructs, evaluated mean differences in the PAID between diabetes treatment groups, and examined correlations of the PAID with diabetes self-care behaviours and selected treatment outcomes. Results: Results showed that the PAID had excellent reliability (Cronbach alpha = 0.934). The PAID correlated significantly with the Diabetes Treatment Satisfaction Questionnaire (r = -0.593, p < 0.0001) and the positive wellbeing (r = -0.396, p < 0.0001), negative wellbeing (r = -0.640, p < 0.0001) and energy (r = -0.444, p < 0.0001) subscales of the Wellbeing Questionnaire. Adherence to diet was negatively correlated with PAID score (r = -0.263, p < 0.0001). The frequency of recent hypoglycemia and number of chronic complications (retinopathy, nephropathy and neuropathy) were positively correlated with PAID scores. PAID was weakly correlated with HbA1c (r = 0.13, p = 0.01). Conclusions: In conclusion, the Japanese version of the PAID demonstrated good internal reliability and evidence of concurrent and discriminant validity. The PAID measures the impact of diabetes, diabetes treatment and treatment outcomes on the emotions of people with diabetes. The results provide encouraging evidence for the clinical utility of the PAID in Japanese people with diabetes.

Diabetes Distress Is Associated With Future Risk of Progression of Diabetic Nephropathy in Adults With Type 2 Diabetes: A Prospective Cohort Study (Diabetes Distress and Care Registry at Tenri [DDCRT23]).

OBJECTIVES: Our aim in this study was to investigate the prospective association between diabetes distress assessed with Problem Areas in Diabetes (PAID) survey scores at baseline and the subsequent risk of development or progression of diabetic nephropathy in people with type 2 diabetes. METHODS: Longitudinal data were acquired from 2,845 individuals with type 2 diabetes registered in a Japanese diabetes registry. A Cox proportional hazards model was used to adjust for possible confounders to examine the prospective association between baseline diabetes distress (PAID score ≥40) and the development or progression of albuminuria. RESULTS: Mean patient age, body mass index, and glycated hemoglobin level were 64.8 years, 24.5 kg/m2, and 57.4 mmol/mol (7.5%), respectively. We did not observe a significant association between diabetes distress and the subsequent risk of diabetic nephropathy development from normoalbuminuria to microalbuminuria/macroalbuminuria (multivariable-adjusted hazard ratio [HR]=0.95 over 4.2 years, 95% confidence interval [CI] 0.77 to 1.17, p=0.640); however, we identified a significant association for progression from microalbuminuria to macroalbuminuria (multivariable-adjusted HR=1.34 over 7.0 years, 95% CI 1.01 to 1.80, p=0.045). Stratification by sex revealed a significant association between diabetes distress and the subsequent risk of progressing diabetic nephropathy (HR=1.45, 95% CI 1.06 to 1.98, p=0.019) in males, but not females (HR=1.42, 95% CI 0.95 to 2.14, p=0.087). CONCLUSIONS: Diabetes distress at baseline, assessed using the PAID survey, was associated with a subsequent risk of progressing diabetic nephropathy independent of possible confounders in males, but not females, with type 2 diabetes.

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.

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.

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.

Prevention of type 2 diabetes in a primary healthcare setting: three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance.

BACKGROUND: A randomized control trial was performed to test whether a lifestyle intervention program, carried out in a primary healthcare setting using existing resources, can reduce the incidence of type 2 diabetes in Japanese with impaired glucose tolerance (IGT). The results of 3 years' intervention are summarized. METHODS: Through health checkups in communities and workplaces, 304 middle-aged IGT subjects with a mean body mass index (BMI) of 24.5 kg/m2 were recruited and randomized to the intervention group or control group. The lifestyle intervention was carried out for 3 years by public health nurses using the curriculum and educational materials provided by the study group. RESULTS: After 1 year, the intervention had significantly improved body weight (-1.5 ± 0.7 vs. -0.7 ± 2.5 kg in the control; p = 0.023) and daily non-exercise leisure time energy expenditure (25 ± 113 vs. -3 ± 98 kcal; p = 0.045). Insulin sensitivity assessed by the Matsuda index was improved by the intervention during the 3 years. The 3-year cumulative incidence tended to be lower in the intervention group (14.8% vs.8.2%, log-rank test: p = 0.097). In a sub-analysis for the subjects with a BMI > 22.5 kg/m2, a significant reduction in the cumulative incidence was found (p = 0.027). CONCLUSIONS: The present lifestyle intervention program using existing healthcare resources is beneficial in preventing diabetes in Japanese with IGT. This has important implications for primary healthcare-based diabetes prevention. TRIAL REGISTRATION NUMBER: UMIN000003136.

Predictive Validity of Each Item of the 8-Item Short-Form Health Survey for All-Cause Mortality in Japanese patients with type 2 diabetes: A prospective Cohort Study (Diabetes Distress and Care Registry at Tenri [DDCRT 19]).

AIMS: While health-related quality of life (HRQOL) is reported to be associated with mortality, this assessment was made using surveys with a large number of questions, not specifically focused on populations with diabetes, or in western countries alone. We thus evaluated the predictive validity of summary scores, and each item score of the 8-Item Short-Form Health Survey in Japanese individuals with type-2 diabetes. MATERIALS AND METHODS: Longitudinal data from 3269 individuals with diabetes were obtained from a large Japanese diabetes registry. To assess the independent correlation between the 10-point scores of the SF-8 physical component summary (PCS) and mental component summary (MCS), each item score, and all-cause mortality, the Cox proportional hazards model was used with adjustment for potential confounders. RESULTS: Mean cohort parameters included age (64.9 years [SD 11.2]), body mass index (24.6 kg/m2 [SD, 3.9]), and HbA1c level (7.5% [SD, 1.2]; or 58.6 mmol/mol [SD, 12.7]). We recorded 248 deaths during the median follow-up of 7.2 years (incidence ratio, 12.2 per 1000 person-years). Multivariable-adjusted HRs for all-cause mortality were 0.780 (95%CI, 0.674-0.902; p=0.001) and 0.776 (95%CI, 0.656-0.917; p=0.003), respectively, for 10-point increment of PCS and MCS scores. Higher score of any single item of SF-8 was associated with lower risk of all-cause mortality even after adjusting for possible confounders. CONCLUSIONS: As assessed by the SF-8, higher PCS, MCS, and any single 1-item scores were associated with lower risk of all-cause mortality in Japanese individuals with type 2 diabetes.

Association of diabetes therapy-related quality of life and physical activity levels in patients with type 2 diabetes receiving medication therapy: the Diabetes Distress and Care Registry at Tenri (DDCRT 17).

AIM: To examine the association between diabetes therapy-related quality of life (DTR-QOL) and physical activity levels, and identify factors associated with high diabetes therapy-related quality of life. METHODS: Cross-sectional data from 2970 patients with type 2 diabetes in a Japanese diabetes registry were assessed for independent correlations between DTR-QOL (domains 1-4) and high physical activity levels. Data collected by the International Physical Activity Questionnaire were analyzed by logistic regression and adjusted for potential confounders. RESULTS: The mean patient age, BMI and HbA1c level were 65.8 years, 24.7 kg/m2 and 7.6% (58.7 mmol/mol), respectively. Univariate analysis showed that DTR-QOL domain 1, 2 and 4 scores were significantly associated with physical activity levels (p = 0.0046, p = 0.0004 and p < 0.001, respectively, but domain 3 score was not (p = 0.5073). In a multivariable-adjusted logistic regression model, odds ratios (ORs) of DTR-QOL domains 1, 3 and 4 were independently associated with high physical activity (ORs for 2nd to 4th quartile and p for trend; [domain 1] 1.16, 1.56, 1.22, p = 0.032; [domain 3] 1.45, 1.55, 1.38, p = 0.049; [domain 4] 1.09, 1.30, 1.51, p = 0.001, respectively), but domain 2 was not (ORs for 2nd to 4th quartile and p for trend; 1.19, 1.26, 1.23, p = 0.096). CONCLUSION: High diabetes therapy-related QOL scores were associated with high levels of physical activity in patients with type 2 diabetes. Because this is a cross-sectional study, further study is needed to evaluate the causal association between therapy-related QOL and physical activity.

Dipeptidyl peptidase-4 inhibitors as preferable oral hypoglycemic agents in terms of treatment satisfaction: Results from a multicenter, 12-week, open label, randomized controlled study in Japan (PREFERENCE 4 study).

AIMS/INTRODUCTION: To compare the treatment satisfaction of four classes of oral hypoglycemic agents (OHAs): dipeptidyl peptidase-4 (DPP-4) inhibitors, α-glucosidase inhibitors (αGI), biguanides (BG) and sulfonylureas (SU), which are common initial treatments for type 2 diabetes mellitus patients in Japan, and to identify the best oral hypoglycemic agent in terms of treatment satisfaction. MATERIALS AND METHODS: In this 12-week, randomized, controlled, open-label study, Japanese outpatients with type 2 diabetes mellitus who were naïve to pharmacological treatment were randomly assigned a DPP-4 inhibitor, a BG., an αGI or a SU. The primary end-point was the Oral Hypoglycemic Agent Questionnaire (OHA-Q) total and subscale scores (treatment convenience, somatic symptoms and satisfaction) at week 4. Adherence, glycated hemoglobin (HbA1c) level and safety were also evaluated. RESULTS: The DPP-4 inhibitor group scored highest in the OHA-Q total and all subscale scores at week 4. The total score was significantly higher in the DPP-4 inhibitor group than in the BG or αGI groups (P = 0.0084 and 0.0147, respectively). The mean total score at week 12 was also highest in the DPP-4 inhibitor group, with a significant difference compared with the αGI group (P = 0.0293). The mean HbA1c decreased from baseline to week 12 in all groups. The DPP-4 inhibitor group had the highest adherence at weeks 4 and 12. A total of 11 patients reported adverse events, including one hypoglycemic event in the SU group. CONCLUSIONS: The DPP-4 inhibitor was the most preferable option in terms of treatment satisfaction.

Association of proton pump inhibitor use with the risk of the development or progression of albuminuria among Japanese patients with diabetes: A prospective cohort study [Diabetes Distress and Care Registry at Tenri (DDCRT 16)].

AIMS: We aimed to determine the prospective association between proton pump inhibitor (PPI) use and the subsequent risk of the development or progression of albuminuria or eGFR. METHODS: Longitudinal data of patients with diabetes were obtained from a large Japanese diabetes registry. To assess the independent correlation between PPI use and the development or progression of urine microalbuminuria, the time-varying Cox proportional hazards model was used with adjustment for potential confounders. RESULTS: The mean patient age, body-mass index (BMI), and hemoglobin A1c (HbA1c) levels were 65.7 y, 24.5 kg/m2, and 7.5% (57.9 mmol/mol), respectively. In 1711 patients without albuminuria, we observed 599 cases with development of albuminuria over median follow-up of 4.0 years, and in 1279 patients with microalbuminuria, 290 cases with urinary albuminuria progression over 4.0 years, and 257 eGFR decline cases over 3.8 years. PPI use was not associated with the development of albuminuria (HR = 0.88; 95%CI, 0.77-1.01; p = .058), progression of albuminuria (HR = 1.24; 95%CI, 0.87-1.79; p = .236), nor eGFR decline (HR = 1.05; 95%CI, 0.81-1.34; p = .973) even in a propensity score-adjusted model with time-varyingly updating PPI use information. CONCLUSIONS: In conclusion, PPI use was not associated with the subsequent risk of development or progression of albuminuria, or eGFR decline in patients with diabetes.

Real-life glycemic control in patients with type 2 diabetes treated with insulin therapy: A prospective, longitudinal cohort study (Diabetes Distress and Care Registry at Tenri [DDCRT 9]).

AIMS/INTRODUCTION: We investigated the association between four insulin regimens, and increase in glycated hemoglobin (HbA1c) and insulin dose in a real-life clinical setting because there are no data about them among insulin regimens. MATERIALS AND METHODS: Participants included 757 patients with type 2 diabetes having been treated with insulin therapy for more than 1 year. The four insulin regimens were regimen 1 (long-acting insulin, once daily), regimen 2 (biphasic insulin, twice daily), regimen 3 (biphasic insulin, three times daily) and regimen 4 (basal-bolus therapy). Main outcomes were increases in HbA1c levels >0.5% and increases in daily insulin units after 1 year. We carried out multivariable analyses to examine differences in glycemic control and insulin dose with adjustment for possible confounders. RESULTS: Mean HbA1c level and duration of insulin therapy were 7.8% and 11.3 years, respectively. HbA1c levels increased by >0.5% at follow up in 22.8, 24.9, 20.7, and 29.3% of participants using regimen 1, 2, 3 and 4, respectively, with no significant differences between groups. Daily insulin doses increased in 62.3, 68.8, 65.3 and 38.6% of patients, respectively (P < 0.001). Multivariable regression analysis showed that patients who received regimen 4 had significantly lower odds of requiring future insulin dose increases than those who had received regimen 2 (adjusted odds ratio 0.24, 95% confidence interval 0.14-0.41; P < 0.001). CONCLUSIONS: Many patients receiving insulin therapy showed increases in HbA1c levels and insulin doses 1 year later. The smallest increase in insulin dose was observed in the basal-bolus therapy group compared with other regimens.

Imbalanced Expression of IGF2 and PCSK4 Is Associated With Overproduction of Big IGF2 in SFT With NICTH: A Pilot Study.

Context: Nonislet cell tumor hypoglycemia (NICTH) is a rare but serious paraneoplastic syndrome associated with large tumors. The high molecular weight IGF2, known as "big" IGF2, is produced by culprit tumors and leads to severe hypoglycemia. The detailed mechanism of its production in NICTH, however, remains unclear. Objective: To clarify the mechanism of production of big IGF2 in light of the processing of pro-IGF2 in patients with solitary fibrous tumor (SFT) and NICTH. Design: We enrolled 14 patients with SFT and divided them based on the presence or absence of hypoglycemia. In light of the processing of pro-IGF2 in SFT with hypoglycemia, we, retrospectively, compared the production levels of big IGF2 and the expression levels of IGF2 and proprotein convertase subtilisin/kexin type 4 (PCSK4), a proteolytic enzyme of pro-IGF2. Results: In all patients with NICTH, big IGF2 was detected in serum by western immunoblotting analysis. Moreover, we showed that two patients without hypoglycemia also had a small amount of big IGF2 in their serum. By immunohistochemical analysis, the protein expression level of IGF2 was significantly higher in the NICTH group than in the non-NICTH group (P = 0.043). The IGF2/PCSK4 protein expression-level ratio in the NICTH group was significantly higher than that in the non-NICTH group (P = 0.021). Conclusion: In patients with SFT and hypoglycemia, an imbalance of IGF2 and PCSK4 expression could lead to increased serum levels of big IGF2.

Higher levels of physical activity are independently associated with a lower incidence of diabetic retinopathy in Japanese patients with type 2 diabetes: A prospective cohort study, Diabetes Distress and Care Registry at Tenri (DDCRT15).

We assessed the prospective association between baseline levels of physical activity (PA) and the incidence of newly developed diabetic retinopathy (DR) in patients with type 2 diabetes. Data from 1,814 patients with type 2 diabetes without DR were obtained from a Japanese diabetes registry at Tenri Hospital, Nara, Japan. To assess the independent correlations between baseline PA levels and newly developed DR, the participants were divided into five categories based on their PA levels. A Cox proportional hazards model with time-varying exposure information was used and adjusted for potential confounders to assess the independent correlations. At baseline, the mean age, BMI, and hemoglobin A1c levels of the patients were 65.5 years, 24.5 kg/m2, and 7.2% (54 mmol/mol), respectively. After 2 years, newly developed DR was confirmed in 184 patients (10.1%). Patients with newly developed DR had longer duration of type 2 diabetes (14.7 versus 11.0 years, p < 0.0001), higher systolic blood pressure (139.2 versus 135.1 mmHg, p = 0.0012), lower estimated glomerular filtration rate (74.0 versus 77.1 mL/min/1.73 m2, p = 0.0382), greater urinary albumin-creatinine ratio (4.00 versus 2.45 mg/mmol, p < 0.0039), and higher HbA1c levels (7.5 versus 7.2%, p = 0.0006) than those without newly developed DR. The multivariable-adjusted hazard ratios for DR development were 0.87 (95% CI, 0.53-1.40; p = 0.557), 0.83 (95% CI, 0.52-1.31; p = 0.421), 0.58 (95% CI, 0.35-0.94; p = 0.027), and 0.63 (95% CI, 0.42-0.94; p = 0.025)for the second, third, fourth, and fifth PA categories, respectively, compared with the reference category of patients with a mean PA of 0 metabolic equivalent of task-hours/week). Higher PA levels are independently associated with a lower incidence of DR in Japanese patients with type 2 diabetes.

Association between dipstick hematuria and decline in estimated glomerular filtration rate among Japanese patients with type 2 diabetes: A prospective cohort study [Diabetes Distress and Care Registry at Tenri (DDCRT 14)].

AIMS: To assess the association between dipstick hematuria and estimated glomerular filtration rate (eGFR) decline in Japanese patients with type 2 diabetes. METHODS: Longitudinal data were obtained from 3068 Japanese patients with type 2 diabetes. To assess the independent association between dipstick hematuria and eGFR decline, we used Cox proportional hazard model adjusted for potential confounders. RESULTS: Median follow-up period was 699.7days. Mean age, body mass index (BMI), and HbA1c level were 65.7years, 24.6kg/m2, and 7.5% (58.1mmol/mol), respectively. Positive dipstick hematuria was significantly associated with baseline eGFR and severity of albuminuria (p<0.001). The multivariable-adjusted hazard ratio for eGFR decline in patients with dipstick hematuria compared with those without dipstick hematuria was 2.19 [95% confidence interval (CI): 1.22-3.91]; this association remained significant even after the exclusion of patients who did not have diabetic retinopathy (hazard ratio: 2.39; 95% CI: 1.13-5.04). CONCLUSION: Positive dipstick hematuria was associated with severity of albuminuria and renal function. A significant association was found between dipstick hematuria and increased risk of eGFR decline among patients with type 2 diabetes. Therefore, our results suggest that dipstick hematuria is perhaps indicative of more severe diabetic nephropathy.

Determinants of Glycated Hemoglobin in Subjects With Impaired Glucose Tolerance: Subanalysis of the Japan Diabetes Prevention Program.

BACKGROUND: Limited evidence is available about the relationship of lifestyle factors with glycated hemoglobin (HbA1c) in subjects with impaired glucose tolerance. The aim of study was to identify such determinant factors of HbA1c in subjects with impaired glucose tolerance. METHODS: This cross-sectional study included 121 men and 124 women with impaired glucose tolerance, who were diagnosed based on a 75-g oral glucose tolerance test. Demographic and biochemical parameters, including the body mass index (BMI), fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and HbA1c, were measured. The pancreatic ß-cell function and insulin resistance were assessed using homeostasis model assessment (HOMA-ß). Dietary intake was assessed by a food frequency questionnaire. RESULTS: The levels of FPG, 2-h PG, and carbohydrate intake were correlated with the HbA1c level in men, while the FPG and 2-h PG levels were correlated with the HbA1c level in women. In multiple regression analyses, BMI, FPG, 2-h PG, and white rice intake were associated with HbA1c levels in men, while BMI, FPG, HOMA-ß, and bread intake were associated with HbA1c levels in women. CONCLUSIONS: The present findings suggest that a substantial portion of HbA1c may be composed of not only glycemic but also several lifestyle factors in men with impaired glucose tolerance. These factors can be taken into consideration as modifiable determinants in assessing the HbA1c level for the diagnosis and therapeutic monitoring of the disease course.