Third Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer: Summary of the results of a questionnaire survey of oncologists and diabetologists-Secondary publication.

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and health-care providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Development and Validation of Prediction Models for the 5-year Risk of Type 2 Diabetes in a Japanese Population: Japan Public Health Center-based Prospective (JPHC) Diabetes Study.

BACKGROUND: This study aimed to develop models to predict the 5-year incidence of type 2 diabetes mellitus (T2DM) in a Japanese population and validate them externally in an independent Japanese population. METHODS: Data from 10,986 participants (aged 46-75 years) in the development cohort of the Japan Public Health Center-based Prospective Diabetes Study and 11,345 participants (aged 46-75 years) in the validation cohort of the Japan Epidemiology Collaboration on Occupational Health Study were used to develop and validate the risk scores in logistic regression models. RESULTS: We considered non-invasive (sex, body mass index, family history of diabetes mellitus, and diastolic blood pressure) and invasive (glycated hemoglobin [HbA1c] and fasting plasma glucose [FPG]) predictors to predict the 5-year probability of incident diabetes. The area under the receiver operating characteristic curve was 0.643 for the non-invasive risk model, 0.786 for the invasive risk model with HbA1c but not FPG, and 0.845 for the invasive risk model with HbA1c and FPG. The optimism for the performance of all models was small by internal validation. In the internal-external cross-validation, these models tended to show similar discriminative ability across different areas. The discriminative ability of each model was confirmed using external validation datasets. The invasive risk model with only HbA1c was well-calibrated in the validation cohort. CONCLUSION: Our invasive risk models are expected to discriminate between high- and low-risk individuals with T2DM in a Japanese population.

GWAS meta-analysis of kidney function traits in Japanese populations.

BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Association of body mass index and weight change with pneumonia mortality in a Japanese population: Japan Public Health Center-based Prospective Study.

BACKGROUND: Accumulating evidence suggests that pneumonia mortality is lower for individuals with high body mass index (BMI) compared to normal BMI, but it remains unclear whether weight change during adulthood influences subsequent mortality due to pneumonia in Asian populations, who have a relatively lean body mass. This study aimed to examine the association of BMI and weight change over 5 years with the subsequent risk of pneumonia mortality in a Japanese population. METHODS: The present analysis included 79,564 Japan Public Health Center (JPHC)-based Prospective Study participants who completed a questionnaire between 1995 and 1998 were followed for death through 2016. BMI was categorized into four groups: underweight (<18.5 kg/m2), normal weight (BMI: 18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (BMI: ≥30.0 kg/m2). Weight change was defined as the difference of body weight between questionnaire surveys with a 5-year interval. Cox proportional hazards regression was used to estimate hazard ratios of baseline BMI and weight change for pneumonia mortality. RESULTS: During a median follow-up of 18.9 y, we identified 994 deaths from pneumonia. Compared with participants with normal weight, an elevated risk was observed among those who were underweight (hazard ratio = 2.29, 95% confidence interval [CI]: 1.83-2.87), whereas a decreased risk was found among those who were overweight (hazard ratio = 0.63, 95% CI: 0.53-0.75). Regarding weight change, the multivariable-adjusted hazard ratio (95% CI) of pneumonia mortality for a weight loss of 5 kg or more versus a weight change of less than 2.5 kg was 1.75 (1.46-2.10), whereas that for a weight gain of 5 kg or more was 1.59 (1.27-2.00). CONCLUSION: Underweight and greater weight change was associated with an increase in the risk of pneumonia mortality in Japanese adults.

Association of chronic kidney disease with total and site-specific cancer incidence in participants of the Japan Public Health Center-based Prospective Study.

BACKGROUND: Although studies have found an association between chronic kidney disease (CKD) and cancer incidence, the results are inconsistent. METHODS: This study included participants in the Japan Public Health Center-based Prospective Study who had data on serum creatinine measurements. We assessed the association between estimated glomerular filtration rate (eGFR) and the risk of total and site-specific cancer incidence using a systematic survey in Japan. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for participant demographics and lifestyle factors. RESULTS: A total of 21 978 participants who met the inclusion criteria were followed up for a mean period of 12.9 years, during which a total of 2997 incident cancer cases were reported. In the multivariable adjusted models, an eGFR of <45 mL/min/1.73 m2 was not significantly associated with total cancer incidence (adjusted HR 1.22, 95% CI 0.94-1.60), compared with an eGFR of 60-89 mL/min/1.73 m2 (reference). The HR among those with eGFRs of ≥90 mL/min/1.73 m2 was 1.10 (95% CI 1.00-1.22). CONCLUSIONS: In this large prospective study, a low eGFR was not significantly associated with an increased risk of total cancer incidence in patients with CKD, which may be partly due to an underpowered sample size. This finding may be due to the many shared risk factors between CKD and cancer.

Vitamin D intake and all-cause and cause-specific mortality in Japanese men and women: the Japan Public Health Center-based prospective study.

While higher circulating 25-hydroxyvitamin D concentrations have been reported to be associated with decreased risk of all-cause mortality, evidence on dietary vitamin D intake is limited and inconsistent. We investigated whether vitamin D intake is associated with all-cause and cause-specific mortality among Japanese adults. Participants were 42,992 men and 50,693 women who responded to the second survey of the Japan Public Health Center-based Prospective Study (1995-1998) and who were followed up for mortality through 2018. Dietary intake was ascertained using a validated food frequency questionnaire. Hazard ratios of deaths from the second survey to December 2018 were estimated using Cox proportional hazard regression analysis. During follow-up, we identified 22,630 deaths. Overall, the third and fourth quintiles, but not the highest quintile, of vitamin D intake were each associated with a significantly lower risk of all-cause mortality. In subgroups characterized by low sunlight exposure, risk of all-cause mortality decreased linearly with increasing vitamin D intake. The multivariable-adjusted hazard ratios (95% confidence intervals) of all-cause mortality for the highest versus lowest quintile of vitamin D intake were 0.87 (0.79-0.95) in women and 0.88 (0.79-0.97) in residents of higher latitude areas. Lower risk was also observed for all-cause mortality in participants with hypertension and for heart disease mortality in those with higher calcium intake. Higher vitamin D intake was associated with decreased risk of ischemic stroke and pneumonia mortality. Higher dietary vitamin D was associated with a lower risk of mortality among individuals with low sunlight exposure or hypertension. Individuals with potentially low vitamin D may benefit from increasing dietary vitamin D intake for the prevention of premature death.

Validation Study of Diabetes Definitions Using Japanese Diagnosis Procedure Combination Data Among Hospitalized Patients.

BACKGROUND: Validation studies of diabetes definitions using nationwide healthcare databases are scarce. We evaluated the validity of diabetes definitions using disease codes and antidiabetic drug prescriptions in the Japanese Diagnosis Procedure Combination (DPC) data via medical chart review. METHODS: We randomly selected 500 records among 15,334 patients who participated in the Japan Public Health Center-Based Prospective Study for the Next Generation in Yokote City and who had visited a general hospital in Akita between October 2011 and August 2018. Of the 500 patients, 98 were linked to DPC data; however, only 72 had sufficient information in the medical chart. Gold standard confirmation was performed by board-certified diabetologists. DPC-based diabetes definitions were based on the International Classification of Diseases, 10th Revision codes and antidiabetic prescriptions. Sensitivity, specificity, and the positive and negative predictive values (PPV and NPV, respectively) of DPC-based diabetes definitions were evaluated. RESULTS: Of 72 patients, 23 were diagnosed with diabetes using chart review; 19 had a diabetes code, and 13 had both a diabetes code and antidiabetic prescriptions. The sensitivity, specificity, PPV, and NPV were 89.5% (95% confidence interval [CI], 66.9-98.7%), 96.2% (95% CI, 87.0-99.5%), 89.5% (95% CI, 66.9-98.7%), and 96.2% (95% CI, 87.0-99.5%), respectively, for (i) diabetes codes alone; 89.5% (95% CI, 66.9-98.7%), 94.3% (95% CI, 84.3-98.8%), 85.0% (95% CI, 62.1-96.8%), and 96.2% (95% CI, 86.8-99.5%) for (ii) diabetes codes and/or prescriptions; 68.4% (95% CI, 43.4-87.4%), 100% (95% CI, 93.3-100%), 100% (95% CI, 75.3-100%), and 89.8% (95% CI, 79.2-96.2%) for (iii) both diabetes codes and prescriptions. CONCLUSION: Our results suggest that DPC data can accurately identify diabetes among inpatients using (i) diabetes codes alone or (ii) diabetes codes and/or prescriptions.

Differences in metabolic characteristics between Metabolically Healthy Obesity (MHO) and Metabolically Unhealthy Obesity (MUO) in weight reduction therapy.

Metabolically Healthy Obesity (MHO) is generally recognized as the absence of any metabolic disorders and cardiovascular diseases, including type 2 diabetes, dyslipidemia, and hypertension, in obese individuals; however, it is not clearly defined. Therefore, the present study investigated differences in metabolic characteristics between individuals with MHO and Metabolically Unhealthy Obesity (MUO) during weight reduction therapy. The key factors defining MHO and the importance of weight reduction therapy for MHO were also examined. Cohort data from the Japan Obesity and Metabolic Syndrome (JOMS) study were analyzed. Subjects were divided into the MHO (n = 25) and MUO (n = 120) groups. Prior to weight reduction therapy, serum adiponectin levels were significantly higher in the MHO group than in the MUO group. Serum adiponectin levels also negatively correlated with the area of subcutaneous adipose tissue (SAT) and Homeostasis model assessment (HOMA)-R in the MHO group, but not in the MUO group. Collectively, the present results suggest the importance of adiponectin for maintaining metabolic homeostasis in the MHO group. On the other hand, no significant differences were observed in inflammatory markers between the MHO and MUO groups, suggesting the presence of chronic inflammation in both groups. Furthermore, a positive correlation was noted between changes in serum cystatin C levels and waist circumference in the MHO group, which indicated that despite the absence of metabolic disorders, the MHO group exhibited anti-inflammatory responses during weight reduction therapy. These results underscore the significance of weight reduction even for individuals with MHO.

Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes.

To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care.

Association of sugary drink consumption with all-cause and cause-specific mortality: the Japan Public Health Center-based Prospective Study.

BACKGROUND: Few epidemiologic studies have assessed the associations of sugary drink consumption with mortality outcomes among Asian populations. METHODS: This study included 70,486 participants in the Japan Public Health Center-based Prospective Study at the age of 45-74 years in 1995-1999. A validated food frequency questionnaire was used to assess the consumption of sugary drinks. We estimated the risk of total and cause-specific mortality associated with sugary drink consumption using Cox proportional hazards regression model. RESULTS: Mean follow-up was 17.1 years, during which 11,811 deaths were documented. Sugary drink consumption was associated with higher total mortality, with multivariate HR of 1.06 (95% CI 1.00-1.13) for quintile 3, 1.07 (95% CI 1.01-1.13) for quintile 4, and 1.15 (95% CI 1.09-1.22) for quintile 5, compared with quintile 1 (P < 0.001 for trend). Additionally, positive associations with cause-specific mortality were observed, including death from circulatory system diseases (quintile 5 vs quintile 1; HR, 1.23; 95% CI 1.09-1.38) and heart disease (quintile 5 vs quintile 1; HR, 1.35; 95% CI 1.14-1.60). CONCLUSION: In this large Japanese prospective study, sugary drink consumption was associated with all-cause and cause-specific mortality.

Dietary glycemic index, glycemic load and mortality: Japan Public Health Center-based prospective study.

PURPOSE: Long-term associations of dietary glycemic index (GI) and glycemic load (GL) with mortality outcomes remain unclear. METHODS: The present analysis included 72,783 participants of the Japan Public Health Center-based Prospective Study. Participants who responded to the 5-year follow-up questionnaire in 1995-1999 were followed-up until December 2015. We estimated the risk of total and cause-specific mortality associated with GI and GL using Cox proportional hazards regression models. RESULTS: During 1,244,553 person years of follow-up, 7535 men and 4913 women died. GI was positively associated with all-cause mortality. As compared with the lowest quartile, the multivariable HR for those who had the highest quartile of GI was 1.14 (95% CI 1.08-1.20). The HRs for death comparing the highest with the lowest quartile were 1.28 (95% CI 1.14-1.42) for circulatory system diseases, 1.33 (95% CI 1.14-1.55) for heart disease, 1.32 (95% CI 1.11-1.57) for cerebrovascular disease, and 1.45 (95% CI 1.18-1.78) for respiratory diseases. GI was not associated with mortality risks of cancer and digestive diseases. GL showed a null association with all-cause mortality (highest vs lowest quartile; HR 1.04; 95% CI 0.96-1.12). However, among those who had the highest quartile of GL, the HRs for death from circulatory system diseases was 1.24 (95% CI 1.05-1.46), cerebrovascular disease was 1.34 (95% CI 1.03-1.74), and respiratory diseases was 1.35 (95% CI 1.00-1.82), as compared with the lowest quartile. CONCLUSION: In this large prospective cohort study, dietary GI and GL were associated with mortality risks.

Diabetes and cancer risk: A Mendelian randomization study.

Earlier cohort studies using conventional regression models have consistently shown an increased cancer risk among individuals with type 2 diabetes. However, reverse causality and residual confounding due to common risk factors could exist, and it remains unclear whether diabetes per se contributes to cancer development. Mendelian randomization analyses might clarify the true association between diabetes and cancer risk. We conducted a case-cohort study with 10,536 subcohort subjects and 3,541 newly diagnosed cancer cases derived from 32,949 eligible participants aged 40-69 years within the Japan Public Health Center-based Prospective Study. With 29 known type 2 diabetes susceptibility variants, we used an inverse variance-weighted method to estimate hazard ratios for the associations of diabetes with risks of total and site-specific cancers. The hazard ratios of cancer per doubling of the probability of diabetes were 1.03 (95% confidence interval [CI], 0.92-1.15) overall, 1.08 (95% CI: 0.73-1.59) for the pancreas, 0.80 (95% CI: 0.57-1.14) for the liver and 0.90 (95% CI: 0.74-1.10) for the colorectum. Additional analyses, using publicly available large-scale genome-wide association study data on colorectal cancer in Japan, resulted in a narrower CI (hazard ratio: 1.00; 95% CI: 0.93-1.07). In this prospective Mendelian randomization study with a large number of incident cancer cases, we found no strong evidence to support associations between diabetes and overall and site-specific cancer risks. Our findings suggest that there is little evidence to support the genetic role of type 2 diabetes in cancer development in the Japanese population.

Soy food and isoflavones are not associated with changes in serum lipids and glycohemoglobin concentrations among Japanese adults: a cohort study.

PURPOSE: It is unclear whether habitual intake of soy or isoflavones induces long-term changes in the concentrations of blood lipids and glycaemia. We examined the associations of soy food and isoflavone consumption with changes in blood lipids and HbA1c concentrations over 5 years among Japanese adults. METHODS: This cohort study included 7252 subjects with no known history of major chronic disease at baseline. Soy intake was measured using a food frequency questionnaire; while the concentrations of serum lipids and HbA1c were measured using standard laboratory methods. We used multivariable linear mixed-effects models to examine the associations of changes in lipids and HbA1c concentrations with intakes of soy food and isoflavones. RESULTS: Among the participants, mean age was 61 years, 67% were females and median intakes of soy and isoflavones were 95.3 g/day and 47.4 mg/day, respectively. Soy food and isoflavone intakes were not associated with 5-year changes in blood lipids or HbA1c concentrations. However, stratified analyses showed inverse associations between fermented soy intake and serum lipids among obese/overweight subjects. In particular, intake of 20 g/day of natto was associated with a reduction of 1.4 (95% CI 0.3, 2.5) mg/dL in TC, 1.5 (95% CI 0.4, 2.6) mg/dL in non-high-density lipoprotein cholesterol, 1.0 (95% CI - 0.0, 2.0) mg/dL in low-density lipoprotein cholesterol and 4.0 (95% CI 0.6, 7.5) mg/dL in triglycerides. CONCLUSIONS: Overall, habitual consumption of soy or isoflavones was not associated with changes in serum lipids or HbA1c concentrations. The negative associations between intake of natto and changes in serum lipids among overweight/obese subjects deserve further investigation.

Clinical characterization of patients with primary aldosteronism plus subclinical Cushing's syndrome.

BACKGROUND: Primary aldosteronism (PA) plus subclinical Cushing's syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled. METHODS: A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans. RESULTS: The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p <  0.05), without a significant difference between the PASCS and SCS groups. Serum potassium concentration was significantly lower in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01), without a significant difference between the PASCS and PA groups. Among the 3 study groups of patients who had a unilateral adrenal tumor, MTD was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.4 ± 0.1 cm; p <  0.001), without a significant difference between the PASCS and SCS groups. CONCLUSIONS: Any reference criteria were not obtained that surely distinguish patients with PASCS from those with PA or SCS. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting a relatively large adrenal tumor on the CT scans.

Association Between Okinawan Vegetables Consumption and Risk of Type 2 Diabetes in Japanese Communities: The JPHC Study.

BACKGROUND: Some Okinawan vegetables have been reported to have anti-diabetic activity; however, no prospective cohort study has clarified whether consumption of Okinawan vegetables is associated with a risk of type 2 diabetes. This study aimed to determine the association between consumption of Okinawan vegetables and risk of type 2 diabetes through a large-scale, population-based, prospective study in Japan. METHODS: We examined 10,732 participants (4,714 men and 6,018 women) aged 45-74 years who resided in Okinawa. Participants were asked to answer a 147-item food frequency questionnaire. We calculated the overall amount of Okinawan vegetables consumed and the amount of seven specific kinds of Okinawan vegetables consumed. The odds ratios (ORs) for self-reported type 2 diabetes during 5 years of follow-up were estimated via multivariate logistic regression analysis. RESULTS: During the 5-year period, 216 new cases (123 men and 93 women) of type 2 diabetes were reported. Comparing the highest tertile to the lowest tertile of intake, the overall amount of Okinawan vegetables consumed was not associated with risk of type 2 diabetes in men (OR 1.22; 95% confidence interval [CI], 0.74-2.01, P-trend = 0.53) or in women (OR 0.96; 95% CI, 0.57-1.62, P-trend = 0.89). The consumption of seven specific kinds of Okinawan vegetables was also not associated with the risk of type 2 diabetes. CONCLUSIONS: The consumption of total Okinawan vegetables was not associated with the risk of type 2 diabetes.

Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

Plasma C-peptide and glycated albumin and subsequent risk of cancer: From a large prospective case-cohort study in Japan.

To elucidate the individual impacts of insulin and blood glucose on cancer risk, we investigated the association of plasma C-peptide, a surrogated marker of insulin and glycated albumin (GA), a more stable marker of blood glucose, with all-site and site-specific cancer risk by mutually accounting for their confounding effects. The study was prospectively conducted with nearly 4,000 cancer cases arising in our population-based cohort of 33,736 subjects who answered the baseline questionnaire and supplied blood samples. After exclusion of subjects with apparent DM, analysis was done in 3,036 cancer cases and 3,667 subcohort subjects. Among men and women combined, highest levels of C-peptide were statistically significantly associated with an increased risk of all-site [Hazard ratio (HR): 1.21; 95% confidence interval: 1.02-1.42], colon [1.73; 1.20-2.47], liver [3.23; 1.76-5.91], kidney, renal pelvis and ureter cancers [2.47; 1.07-5.69], compared to the respective lowest levels, after adjustment for GA levels. Among these C-peptide-related cancers, colon and liver cancers also showed an increased risk associated with elevated GA levels independently of C-peptide levels. The corresponding HRs for colon and liver cancers compared to the highest and lowest GA levels were 1.43 [1.02-2.00] and 2.02 [1.15-3.55], respectively. Effect modification by gender was only evident for the association between C-peptide and colon cancer (p for interaction = 0.04). Higher insulin levels, independently of higher blood glucose levels, may be relevant to DM-related carcinogenesis for several cancer sites. Examination of circulating insulin levels is a plausible option in evaluating cancer risk even in individuals who have not developed DM.

Significance of peripheral mononuclear cells producing interferon-γ in response to insulin B:9-23-related peptides in subtypes of type 1 diabetes.

Type 1 diabetes is largely caused by ß-cell destruction through anti-islet autoimmunity. Reportedly, interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) specific to four insulin B-chain amino acid 9-23-related peptides (B:9-23rPep) were increased in type 1 diabetes participants. This study aimed to investigate the PBMC frequencies in subtypes of type 1 diabetes using enzyme-linked immunospot assay. In this cross-sectional study, peripheral blood samples were obtained from 148 participants including 72 with acute-onset type 1 diabetes (AT1D), 51 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 25 with type 2 diabetes. The frequency of B:9-23rPep-specific IFN-γ-producing PBMCs was significantly higher in AT1D participants than in SPIDDM and type 2 diabetes participants. Meanwhile, a significant inverse correlation was observed between the PMBC frequencies and insulin secretion capacity in SPIDDM participants. These findings suggest that the increased peripheral B:9-23rPep-specific IFN-γ immunoreactivity reflects decreased functional ß-cell mass and greater disease activity of type 1 diabetes.

Clinical characteristics of anti-glutamic acid decarboxylase antibody-positive fulminant type 1 diabetes.

This research aimed to examine the relationship between anti-glutamic acid decarboxylase antibody (GADA) titers and clinical parameters at onset and to clarify the association between clinical severity and GADA titers in GADA-positive fulminant type 1 diabetes. This cross-sectional observational study included 20 cases with GADA-positive fulminant type 1 diabetes (4 cases from our hospital and 16 from cases reported in the literature). The association between GADA titers and clinical parameters [age, sex, body weight, body mass index, period from appearance of any prodromal symptoms to diagnosis, period from development of hyperglycemic symptoms to diagnosis, GADA titer, HbA1c level, blood pH and HCO3- level, serum levels of ketone bodies and pancreatic exocrine enzymes] were analyzed. Spearman's rank correlation coefficient (rs) was used for the correlation analysis. The results showed that there was a significant inverse correlation between GADA titers and the "period from appearance of any prodromal symptoms to diagnosis" (rs = -0.559, p < 0.05). Moreover, GADA titers were inversely correlated with blood pH and HCO3- level (rs = -0.576, p < 0.05, rs = -0.578, p < 0.05, respectively), and positively correlated with serum levels of total ketone bodies, acetoacetate, and 3-hydroxybutyrate (rs = 0.661, p < 0.05; rs = 0.700, p < 0.05; and rs = 0.782, p < 0.01, respectively). These findings suggest that higher GADA titers may be linked to more severe clinical severity of GADA-positive fulminant type 1 diabetes at onset. This association may be attributed to possible pre-existence of autoimmunity-related ß-cell damage before the onset of fulminant type 1 diabetes.

Coffee Consumption and Lung Cancer Risk: The Japan Public Health Center-Based Prospective Study.

BACKGROUND: Many epidemiological studies have indicated a positive association between coffee intake and lung cancer risk, but such findings were suggested to be confounded by smoking. Furthermore, only a few of these studies have been conducted in Asia. Here, we investigated the association between coffee intake and lung cancer risk in one of the largest prospective cohort studies in Japan. METHODS: We investigated the association of coffee drinking and subsequent incidence of lung cancer among 41,727 men and 45,352 women in the Japan Public Health Center-based Prospective Study using Cox proportional hazards regression, with adjustment for potential confounders and by strata of smoking status. Coffee and other dietary intakes were assessed once at baseline with a food frequency questionnaire (FFQ). RESULTS: During 1,481,887 person-years of follow-up between 1990 and 2011, a total of 1,668 lung cancer cases were identified. In a multivariate regression model, coffee consumption was not associated with risk of lung cancer (HR 1.16; 95% CI, 0.82-1.63; Ptrend = 0.285 for men and HR 1.49; 95% CI, 0.79-2.83; Ptrend = 0.942 for women). However, there was a significant increase in the risk for small cell carcinoma (HR 3.52; 95% CI, 1.49-8.28; Ptrend < 0.001). CONCLUSION: Our prospective study suggests that habitual consumption of coffee is not associated with an increased risk of lung cancer incidence, despite observing a significant increase in the risk for small cell carcinoma.