Third Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on diabetes and cancer: summary of the results of a questionnaire survey of oncologists and diabetologists-secondary publication.

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and healthcare 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 (JSCO) and the Japanese Society of Medical Oncology (JSMO), 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 demonstrated 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.

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.

Diagnosis and Treatment Course of Insulinoma Presenting as Hypoglycemia Unawareness Using a Factory-Calibrated Continuous Glucose Monitoring System.

BACKGROUND Insulinoma presenting only with postprandial hypoglycemia is difficult to diagnose. Repeated episodes of hypoglycemia can lead to "hypoglycemia unawareness", which can be even more dangerous and requires early detection and treatment. CASE REPORT We report the case of a 35-year-old man with an insulinoma presenting as postprandial hypoglycemia who was treated with diazoxide and monitored using a factory-calibrated continuous glucose monitoring (CGM) system until surgery. When the patient initially presented with hypoglycemia, relative hyperinsulinemia was present. There were no obvious abnormal findings on imaging examination. Hypoglycemia was not repeated on endocrinological examination, even while fasting. Four months later, asymptomatic postprandial hypoglycemia of 48 mg/dL was incidentally detected. Although none of the conventional 3 indicators of relative hyperinsulinemia were met, an insulinoma was suspected based on the results of a fasting test. Computed tomography and magnetic resonance imaging showed a mass in the pancreatic uncinate process, and selective intra-arterial calcium infusion revealed high insulin levels in the same area, leading to a diagnosis of insulinoma. The patient was treated medically with diazoxide, using a factory-calibrated CGM system until surgery. Subsequently, pancreatic mass enucleation was performed, and pathological examination confirmed the diagnosis. After surgery, the hypoglycemia resolved, and the blood glucose level remained within a range of 100 to 180 mg/dL, without the use of diazoxide. CONCLUSIONS A factory-calibrated CGM system is useful for evaluating the course of medical treatment, monitoring hypoglycemic episodes during the diagnostic period, detecting unconscious hypoglycemia, monitoring the response to medical treatment, and treating insulinoma after surgery.

Clinical significance of monitoring hypothyroidism in patients with autoimmune rheumatic disease: a retrospective cohort study.

We evaluated whether thyroid function test (TFT) screening is warranted for patients with autoimmune rheumatic diseases (ARD) by comparing the incidence of hypothyroidism requiring treatment (HRT) in ARD patients and healthy controls (HCs). Medical records of 2307 ARD patients and 78,251 HCs for whom thyroid-stimulating hormone (TSH) levels were measured between 2004 and 2018 were retrospectively reviewed. Cumulative incidence of HRT in ARD patients and HCs was compared. HRT development was evaluated with age- and sex-adjusted Kaplan-Meier curve. Risk factors were identified with Cox proportional hazard models. HRT was significantly more common in ARD patients than in HCs (6.3% vs. 1.9%, P < 0.001). After adjusting for age, sex, and baseline TSH level, hazard ratios for HRT were significantly higher in overall ARD patients (hazard ratio [95% confidence interval] 3.99 [3.27-4.87]; P < 0.001), particularly with rheumatoid arthritis and antinuclear antibody-associated diseases in female, and antinuclear antibody-associated diseases, spondyloarthritis, and vasculitis in male patients. Baseline high TSH level, thyroid-related autoantibody positivity, high IgG, and renal impairment were significant risk factors for hypothyroidism development in ARD patients; 20% of high-risk patients developed HRT during follow-up. HRT was significantly more frequent in ARD patients. Careful TFT screening and follow-up could help detecting clinically important hypothyroidism.

Correction to: Japanese Clinical Practice Guideline for Diabetes 2016.

[This corrects the article DOI: 10.1007/s13340-018-0345-3.].

The association of repeatedly measured low-density lipoprotein cholesterol and all-cause mortality and cardiovascular disease in dyslipidemic patients: A longitudinal study.

BACKGROUND AND AIMS: This study aimed to evaluate the association between very low levels of low-density lipoprotein (LDL) cholesterol and subsequent clinical outcomes among dyslipidemic patients. METHODS: A retrospective longitudinal study was conducted at a large teaching hospital in Tokyo, Japan, from 2005 to 2018. We included all dyslipidemic adult patients who were followed up at the department of endocrinology. The primary outcome was all-cause mortality and the secondary outcome was cardiovascular disease. We compared the development of these outcomes according to LDL cholesterol categories through longitudinal analyses adjusting for potential confounders. RESULTS: We included total of 4485 dyslipidemic patients. The mean patient age (standard deviation) was 58.4 (12.2) years, and 2286 patients were men. During a median follow-up of 5.3 (interquartile range 2.2-9.6) years, 252 (5.7%) patients died (25[0.6%] were cardiovascular deaths) and 912 (20.3%) patients developed cardiovascular diseases. Multivariable longitudinal analyses showed that the very low LDL cholesterol group (<60 mg/dl) had significantly higher all-cause mortality than the normal LDL cholesterol group (100-140 mg/dl) (odds ratio[OR] 1.96, 95%confidence interval [CI]:1.22-3.16). Among high-risk patients for atherosclerotic cardiovascular disease (ASCVD), very low LDL cholesterol was significantly associated with increased all-cause mortality (OR 2.61, 95%CI: 1.12-6.10) but decreased incidence of cardiovascular disease (OR 0.47, 95%CI: 0.23-0.93). CONCLUSIONS: Very low LDL cholesterol is associated with increased all-cause mortality but not statistically associated with cardiovascular disease incidence among dyslipidemic patients, regardless of risk. When patients were stratified according to ASCVD risk, this association was more obvious among high-risk patients.

Dawn of a new era of diabeto-oncology.

Pathways of the mutual relationship between diabetes and cancer.

Development of malignancies and changes in time-dependent hemoglobin A1c among a nondiabetic population: longitudinal analysis.

BACKGROUND: The fluctuation of hemoglobin A1c (HbA1c) and changes in health habits over time was not considered in previous studies. The aim of this study was to evaluate the time-sequenced association between malignancy incidence and HbA1c with a longitudinal study design using repeated measurements of HbA1c. METHODS: A retrospective longitudinal study was conducted at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. All participants who underwent voluntary health check-ups at the hospital were included. Our outcomes were the development of malignancy. We compared these outcomes using HbA1c categories. Longitudinal analyses were conducted with a mixed effects model in which time-dependent HbA1c measurements were applied to consider fluctuations in HbA1c levels, adjusted for covariates. RESULTS: A total of 77,385 nondiabetic participants were included in the study; the mean age was 44.7 and 49.4% of participants were male. During a median follow-up of 1588 (interquartile range 730-2946) days, 4506 (5.8%) participants developed malignancies. The relationship between future malignancies and HbA1c was U-shaped; both the lower HbA1c groups (OR 1.31, 95% CI 1.17-1.46 for < 5.0%) and the higher HbA1c group (OR 1.87, 95% CI 1.03-3.39 for ≥ 7.5%) had significantly higher odds ratios compared to the 5.5-5.9%. The lowest HbA1c was associated with higher odds of breast cancer (OR 1.5, 95% CI 1.21-1.86) and female genital cancer (OR 1.57, 95% CI 1.04-2.37). CONCLUSIONS: Our study found a U-shaped association between HbA1c and future malignancies among nondiabetic people but did not find additional risk at the prediabetic level. Low HbA1c may be associated with the incidence of breast cancer and female genital cancer.

Glycemic variability and subsequent malignancies among the population without diabetes.

BACKGROUND: Glycemic variability has been suggested to be related to some unfavorable outcomes, but malignancy development has not been evaluated. The aim of this study was to evaluate the association of glycemic variability with malignancy development among the population without diabetes. METHODS: We conducted a retrospective cohort study at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all participants without diabetes who underwent voluntary health check-ups. Our outcome was the development of any malignancy. As a measure of glycemic variability, we calculated the quotient of CV in HbA1c and categorized subjects into quartile groups. A Cox proportional hazard model was applied, adjusting for patient demographics and social and family histories. RESULTS: A total of 42,731 participants were included in this study; the mean age was 53.8 and 48.3% were male. During the median follow up of 2639 (interquartile range (IQR):1787-3662) days, 2435 participants (5.7%) developed malignancies. Participants who had larger glycemic variability (CV in HbA1c; hazard ratio (HR) 1.15, 95%confidence interval (CI):1.02-0.31 for the second quartile group; HR 2.20, 95%CI:1.95-2.48 for the third quartile group, HR 4.66, 95%CI:4.16-5.21 for the fourth quartile group, compared to first quartile group) had a significantly higher risk of malignancies. CONCLUSION: We found an association between large glycemic variability and a high risk of future malignancies in a dose-dependent manner among people without diabetes. This finding suggests that maintaining a constant level of glucose may have favorable effects on cancer prevention in people without diabetes.

Repeated measures of extremely high levels of high-density lipoprotein cholesterol and subsequent all-cause mortality and cardiovascular events: A longitudinal study.

BACKGROUND AND AIMS: Extremely high level high-density lipoprotein (HDL) cholesterol had been cautioned as risk factor for all-cause mortality and cardiovascular disease. However, both the physician and the patient may underestimate the risk due to the emphasis on "good cholesterol", resulting in passive treatment or adoption of a less healthy lifestyle. The aim of this study is to re-evaluate the association with longitudinal data to account for fluctuations in HDL cholesterol and covariates. METHODS: We conducted a retrospective longitudinal study at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all adults who participated in health check-ups. Outcomes were all-cause mortality and cardiovascular events. HDL cholesterol was repeatedly measured at each visit and categorized into five groups. The time-varying Cox model was applied to longitudinal analyses. RESULTS: We included a total of 83,100 participants; the mean age was 45.5 (standard deviation:12.4) years; 41,013 (49.4%) were male, and 4475 participants belonged to the extremely high level HDL cholesterol group (>90 mg/dl). During a median follow-up of 1746 (interquartile range:740-3112.5) days, 382 (0.5%) participants died, and 2023 (2.4%) experienced cardiovascular events. Although the extremely high level HDL cholesterol group had significantly lower hazard ratios (HRs) for all-cause mortality (HR:0.49, 95%confidence interval(CI):0.26-0.90) and cardiovascular events (HR:0.71, 95%CI:0.54-0.94) compared to the low group (<40 mg/dl), HRs were higher than in the very high level HDL cholesterol group. CONCLUSIONS: Our study demonstrated that extremely high level HDL cholesterol has significantly lower risks of all-cause mortality and cardiovascular events compared to low level, but higher risks compared to very high level, as previously reported.

Visit-to-Visit Hemoglobin A1c Variability Is Associated With Later Cancer Development in Patients With Diabetes Mellitus.

PURPOSE: Recent studies have shown that patients with diabetes mellitus have a higher risk of tumorigenesis. However, the effect of glycemic variability on tumorigenesis among diabetic patients has not been well investigated. Hence, we performed a retrospective cohort study to analyze the effect of visit-to-visit hemoglobin A1c (HbA1c) variability and later onset of malignancies. METHODS: This study included 2640 patients with diabetes mellitus 50 years or older. To analyze visit-to-visit glycemic activity, we calculated intrapersonal SD of all recorded HbA1c and used SD-HbA1c as a measure of glycemic variability. Because the number of individual visits varied, we divided SD-HbA1c by visit times in order to adjust for the potential influence of visit time difference between individuals. Patients were divided into quartiles according to their HbA1c variability, and Cox regression models were used to evaluate the association between glycemic variability and later onset of tumorigenesis. RESULTS: Three hundred thirty patients (12.5%) developed malignancy during follow-up. The median follow-up period was 1511 days (4.1 years; interquartile range, 2487.5 days). Relative to the group with the lowest glycemic variability (first quartile), the groups with higher glycemic variability showed a dose-dependent association with tumorigenesis. The odds ratios for the second, third, and fourth quartiles were 1.20 (95% confidence interval, 0.88-1.65), 1.43 (1.02-2.00), and 2.19 (1.52-3.17), respectively. The mean HbA1c and diabetes mellitus duration periods were not significantly associated with tumorigenesis. This result was consistent when limiting the number of covariates. CONCLUSIONS: These results demonstrated that visit-to-visit HbA1c variability is a potential risk factor for later tumorigenesis. The association may be mediated by oxidative stress or hormone variability. Routine cancer screening may be suggested for diabetic patients with unstable glycemic control.

Low level of hemoglobin A1c and the increased incidence of herpes zoster: longitudinal study.

Little is known about the association between glycemic status and herpes zoster. The aim of this study was to evaluate whether glycemic status, including both high and low hemoglobin A1c(HbA1c), is associated with subsequent herpes zoster. We conducted a retrospective longitudinal study in a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all participants who underwent voluntary health check-ups at the hospital. Our primary outcome was the incidence of herpes zoster in groups of individuals stratified by HbA1c levels, which were compared using the generalized estimating equation (GEE), adjusting for participants' demographic characteristics, social history, body mass index, and comorbidities. A total of 81,466 participants were included in this study. The mean age (standard deviation) was 46.5 (12.1), and 39,643 (48.7%) participants were male. Among them, 1751 (2.1%) were diagnosed with diabetes prior to their first visits. After a median follow-up of 1784 [interquartile range (IQR), 749-3150] days, 673 (0.8%) participants developed herpes zoster. The incidence of herpes zoster was 1.45 per 1000 person-years. Compared with the reference group (HbA1c of 5.0-6.4%), the lowest HbA1c group (HbA1c of < 5.0%) had a significantly higher adjusted odds ratio (OR) (OR 1.63; 95% confidence interval (CI), 1.07-2.48) of developing herpes zoster. The group with an HbA1c of ≥ 9.5% had a higher but nonsignificant OR than the reference group (OR 2.15; 95% CI, 0.67-6.94). Our longitudinal study demonstrated that individuals in the lowest (< 5.0%) HbA1c group had a significantly higher risk of developing herpes zoster than the reference group (HbA1c of 5.0-6.4%) after adjusting for covariates.

Correction to: Japanese Clinical Practice Guideline for Diabetes 2016.

[This corrects the article DOI: 10.1007/s13340-018-0345-3.].

Correction: Low-Carbohydrate Diets and All-Cause Mortality: A Systematic Review and Meta-Analysis of Observational Studies.

[This corrects the article DOI: 10.1371/journal.pone.0055030.].

Two Mutations in Thyroid Hormone Receptor Beta Gene (P453A and C36Y) in a Family with Resistance to Thyroid Hormone with Comorbid Myotonic Dystrophy.

The co-occurrence of resistance to thyroid hormone beta (RTHß) and myotonic dystrophy type 1 (DM1) was observed in a Japanese family. Two mutations, P453A and C36Y, were identified in the thyroid hormone receptor beta (THRB) gene. Whereas family members with THRBP453A exhibited RTHß, two members with THRBC36Y but without THRBP453A had normal thyroid function. Two members, one with RTHß and the other without, had a triplet expansion in the dystrophia myotonia protein kinase gene, a hallmark of DM1. The member with both RTHß and DM1 developed atrial fibrillation at the age of 16 years, suggesting a synergistic impact on the heart.

Malignancy incidences by glycemic control among diabetic patients.

BACKGROUND: The aim of this study was to evaluate the difference in malignancy incidence by evaluating time-dependent HbA1c levels among diabetic patients in a longitudinal study. METHODS: We conducted a retrospective longitudinal study at large academic hospital, Tokyo, Japan, from 2006 to 2016. We included all diabetic patients who were 50 years or older and who underwent health check-ups at the Center for Preventive Medicine. Those patients with a prior history of malignancies were excluded. We categorized patients into five groups on the basis of HbA1c measurements: <5.4, 5.5-6.4, 6.5-7.4, 7.5-8.5, >8.5%. Our primary outcome was the development of any types of malignancy. Longitudinal analyses by a mixed effect model with time-dependent HbA1c levels were applied in order to take into account fluctuations in HbA1c levels within the same patient. RESULTS: In total, 2729 participants were included in this study, where the mean age was 62.6 (standard deviation (s.d.): 7.8) and 2031 (74.4%) were male. The mean disease duration of diabetes was 7.6 (s.d.: 7.6) years, and 1688 (61.8%) were prescribed medications. Median follow-up was 1443.5 (interquartile range (IQR): 2508) days and 376 (13.8%) developed malignancies. Compared to the reference range of HbA1c (5.5-6.4%), the odds ratios for developing malignancies among the other HbA1c level groups were similar and not statistically different (OR: 0.98, 95% CI:0.31-3.15 (for HbA1c <5.4%); OR: 0.88, 95% CI: 0.69-1.12 (for HbA1c 6.5-7.4%); OR: 0.88, 95% CI: 0.64-1.22 (for HbA1c 7.5-8.4%); OR 1.07, 95% CI: 0.70-1.66 (for HbA1c >8.5%)). CONCLUSION: In our study, there was no association between glycemic control and the development of future malignancies. Compared to very strictly controlled HbA1c levels, both excessive control and good or bad control had a statistically similar risk of developing malignancies.

Dietary Approaches for Japanese Patients with Diabetes: A Systematic Review.

This study aimed to elucidate the effect of an energy restricted and carbohydrate restricted diet on the management of Japanese diabetes patients. Several databases including MEDLINE, EMBASE, and the Japan Medical Abstracts Society were searched for relevant articles published prior to June 2017. The articles identified were systematically reviewed. We identified 286 articles on an energy restricted diet, assessed seven and included two studies in our review. On a carbohydrate restricted diet, 75 articles were extracted, seven articles assessed and three included in the review, of which two were the studies that were selected for the energy restricted diet group, since they compared energy restricted diets with carbohydrate restricted diets. All selected studies were on Japanese patients with type 2 diabetes. No studies for type 1 diabetes were found in our search. Two randomized controlled trials on an energy restricted diet were also included in the three studies for a carbohydrate restricted diet. All the three randomized controlled trials showed better glucose management with the carbohydrate restricted diet. Our study revealed that there is very little evidence on diets, particularly in Japanese patients with diabetes, and that the energy restricted diet, which has been recommended by the Japan Diabetes Society in the sole dietary management approach, is not supported by any scientific evidence. Our findings suggest that the carbohydrate restricted diet, but not the energy restricted diet, might have short term benefits for the management of diabetes in Japanese patients. However, since our analysis was based on a limited number of small randomized controlled trials, large scale and/or long term trials examining the dietary approaches in these patients are needed to confirm our findings.