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.

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.

Report of the Japan diabetes society/Japanese cancer association joint committee on diabetes and cancer, Second report.

The Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer published its first report in July 2013 on the epidemiological assessment of the associations of diabetes with cancer risk/prognosis, the common risk factors for diabetes and cancer, and cancer risk associated with diabetes treatment. The Joint Committee continued its work to assess the role of glycemic control in the development of cancer in patients with diabetes. This review shows that high-quality evidence examining the association between glycemic control and cancer risk is lacking.

Possible discrepancy of HbA1c values and its assessment among patients with chronic renal failure, hemodialysis and other diseases.

BACKGROUND: Glycated hemoglobin (HbA1c) and glycated albumin (GA) are frequently used as glycemic control markers. However, these markers are influenced by alterations in hemoglobin and albumin metabolism. Thus, conditions such as anemia, chronic renal failure, hypersplenism, chronic liver diseases, hyperthyroidism, hypoalbuminemia, and pregnancy need to be considered when interpreting HbA1c or GA values. Using data from patients with normal albumin and hemoglobin metabolism, we previously established a linear regression equation describing the GA value versus the HbA1c value to calculate an extrapolated HbA1c (eHbA1c) value for the accurate evaluation of glycemic control. In this study, we investigated the difference between the measured HbA1c and the eHbA1c values for patients with various conditions. METHODS: Data sets for a total of 2461 occasions were obtained from 731 patients whose HbA1c and GA values were simultaneously measured. We excluded patients with missing data or changeable HbA1c levels, and patients who had received transfusions or steroids within the previous 3 months. Finally, we included 44 patients with chronic renal failure (CRF), 10 patients who were undergoing hemodialysis (HD), 7 patients with hematological malignancies and a hemoglobin level of less than 10 g/dL (HM), and 12 patients with chronic liver diseases (CLD). RESULTS: In all the groups, the eHbA1c values were significantly higher than the measured HbA1c values. The median difference was 0.75 % (95 % CI 0.40-1.10 %, P for the difference is <0.001) in the CRF group, 0.80 % (95 % CI 0.30-1.65 %, P for the difference is 0.041) in the HD group, 0.90 % (95 % CI 0.90-1.30 %, P for the difference is 0.028) in the HM group, and 0.85 % (95 % CI 0.40-1.50 %, P for the difference is 0.009) in the CLD group. CONCLUSIONS: We found that the measured HbA1c values were lower than the eHbA1c values in each of the groups.

A newer conversion equation for the correlation between HbA1c and glycated albumin.

Glycated hemoglobin (HbA1c) and glycated albumin (GA) are frequently used as glycemic control markers. These markers are influenced by either altered hemoglobin metabolism or albumin metabolism. We investigated the correlation between HbA1c and GA by collecting only data that had not been affected by the turnover of either HbA1c or GA and proposed a novel equation for accurately estimating the extrapolated HbA1c (eHbA1c) value based on the GA value. Data sets for a total of 2461 occasions were obtained from 731 patients (including non-diabetes patients) whose HbA1c and GA values were simultaneously measured. Data sets obtained from patients undergoing hemodialysis, patients with hematological malignancies, pregnancy, chronic liver diseases, hyperthyroidism, steroid treatment or a blood transfusion during the past 3 months, or patients without albumin, hemoglobin, eGFR, or urinary protein measurements and data sets with an eGFR of less than 30 mL/min/1.73 m(2), a hemoglobin level of less than 10 mg/dL, an albumin level of below 3.0 g/mL, or a urinary protein level of 3+ were excluded. Finally, we selected 284 data sets. We then analyzed these data sets, performed a scatter plot to examine the correlation between HbA1c and GA, and established an equation describing the resulting correlation. Based on all the data points, the resulting equation was HbA1c = 0.216 × GA + 2.978 [R(2) = 0.5882, P < 0.001].

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.

Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer.

In recent years, diabetes has been shown to be associated with cancer risk, and this has led to a joint committee being formed, enlisting experts from the Japan Diabetes Society and the Japanese Cancer Association to address this issue. Epidemiological data in Japan provides evidence to demonstrate that diabetes is associated with increased risk for cancers, especially colorectal, liver, and pancreatic cancers. The mechanisms through which diabetes is assumed to promote oncogenesis include insulin resistance and associated hyperinsulinemia, hyperglycemia, and inflammation. Common risk factors for type 2 diabetes and cancer include aging, male sex, obesity, physical inactivity, inappropriate diet (excessive red/processed meat intake, inadequate vegetable/fruit/dietary fiber intake), excessive alcohol drinking, and smoking. Given that inappropriate diet/exercise, smoking and excessive alcohol drinking are common risk factors for diabetes and cancer, diet/exercise therapy, smoking cessation and alcohol moderation may be associated with decreased risk for cancer in diabetic patients. There is as yet limited evidence as to whether any particular antidiabetic agents may influence cancer risk.

Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age.

BACKGROUND: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age. METHODS: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4 ± 9.5 years, median 70 years; <65 years old, n = 1,261; 65 to 74 years old, n = 1,731; and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model. RESULTS: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P < 0.01 and 1.132, P < 0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65 years old (P < 0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P < 0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels. CONCLUSIONS: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease. TRIAL REGISTRATION: UMIN-CTR, UMIN00000516.

A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections.

A 73-year-old woman with malignant insulinoma was treated with 100 µg/day octreotide for unresected insulinoma and liver metastases. The daily administration of the drug induced hyperglycemia after dinner in addition to existing fasting hypoglycemia possibly because this drug suppressed both insulin and glucagon secretion and its blood concentration was unstable. After replacing a daily injection of octreotide with a monthly injection of octreotide long-acting repeatable (LAR), blood glucose levels stabilized within the normal range. The findings of the present study showed that octreotide LAR could be useful for the long-term treatment of unresectable insulinomas.

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.

Dawn of a new era of diabeto-oncology.

Pathways of the mutual relationship between diabetes and 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.

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.

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.

Correction to: Japanese Clinical Practice Guideline for Diabetes 2016.

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

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.

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.].