Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study.

Aims: We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center. Methods: We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history. Results: Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the GCK and WFS1 genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the HNF4A gene. Twelve variants remained as candidates associated with the development of diabetes. Conclusion: Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00669-3.

Bilateral Adrenal Infarction That Developed in Latent Essential Thrombocythemia.

Bilateral adrenal infarction is an extremely rare disease, and it has been reported that some coagulation abnormalities, including essential thrombocythemia (ET), exist in the background. We herein report a 76-year-old patient in whom the platelet count had been in the normal range at the onset of adrenal infarction but subsequently increased to 102×104/µL at 7 months later, leading to the diagnosis of JAK2V617F-positive ET. As the presence of the JAK2V617F mutation increases the risk of thrombosis, Janus kinase 2 (JAK2) genetic testing should be considered in some cases of nonspecific unknown thrombosis, even if there are no obvious hematological findings, such as clonal hematopoiesis of indeterminate potential (CHIP).

Associations between subjective well-being, number of teeth, and self-rated mastication in Japanese adults: A cross-sectional study.

This cross-sectional study aimed to investigate the risk factors for low levels of subjective well-being (SWB) in the general population of Japan, specifically, the impact of the number of teeth and self-rated mastication. The surveyed population consisted of individuals aged between 40 and 79 years from Yamagata prefecture, Japan. A postal self-administered questionnaire survey of respondents lifestyles, medical history, oral health, and dietary intake, was conducted from 2017 to 2021. We included 6846 participants to confirm the independent associations between SWB and several parameters using multivariate ordinal logistic regression analysis to estimate adjusted odds ratios and 95% confidence intervals. Individuals with < 20 teeth and poor mastication ability had a 1.3-fold risk for low levels of SWB compared with individuals with ≥ 20 teeth with good mastication ability (adjusted odds ratios = 1.300, 95% confidence intervals = 1.043-1.621, P = .020). There were no differences between individuals with good mastication ability, regardless of the number of remaining teeth. Our study emphasizes not only the importance of having ≥ 20 teeth and good mastication ability for high levels of SWB but also the importance of restoring mastication ability using some form of prosthesis, to facilitate a high level of SWB when the number of remaining teeth is < 20.

Association of health behaviors, dietary habits, and oral health with weight gain after 20 years of age in community-dwelling Japanese individuals aged 40 years and older: a cross-sectional study.

OBJECTIVES: This cross-sectional study investigated the factors associated with weight gain ≥ 10 kg after 20 years of age in the general Japanese population, with a focus on the number of teeth. MATERIALS AND METHODS: We included individuals aged ≥ 40 years from Yamagata prefecture, Japan from 2017-2021. A postal survey was conducted using a self-administered questionnaire; 5,940 participants were included in the final analysis. The questionnaire included items on lifestyle factors, medical history, physical and mental conditions, oral health, and dietary intake. A multivariate logistic regression analysis was used to identify independent associations between weight gain ≥ 10 kg after 20 years of age and various parameters; adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS: Less than 20 teeth, male sex, drinking habit frequency, eating very fast or fast, and a higher frequency of eating-away-from-home were significant factors associated with weight gain ≥ 10 kg after 20 years of age; individuals with < 20 versus > 20 teeth exhibited a 1.35-fold higher OR (95% CI 1.15-1.59; p < 0.01). CONCLUSIONS: Our results suggest that having < 20 teeth may affect weight gain ≥ 10 kg after 20 years of age. However, owing to the cross-sectional study design, causality could not be determined. Therefore, maintaining healthy lifestyle behaviors to avoid tooth loss may also affect weight gain ≥ 10 kg after 20 years of age. CLINICAL RELEVANCE: Having < 20 teeth has the potential to affect long-term weight gain after 20 years of age.

Association of the number of teeth and self-rated mastication with self-rated health in community-dwelling Japanese aged 40 years and older: the Yamagata cohort study.

Self-rated health (SRH) is a predictive factor for health-related prognoses such as mortality. This study aimed to comprehensively investigate the risk factors for poor SRH in the general population of Japan, focusing on the combination of the number of teeth and self-rated mastication. Individuals aged at least 40 years in Yamagata Prefecture, Japan, were surveyed from 2017 to 2021. The participants answered a self-administered postal survey on lifestyle factors, medical history, physical and mental conditions, oral health, and dietary intake, and 6739 participants were included. Multivariate logistic regression analysis showed that individuals with less than 20 teeth and who bite tightly on one side or neither side were at a 1.422- and 1.952-fold significantly higher risk, respectively, of poor SRH than individuals with at least 20 teeth and who bite tightly on both sides. Moreover, individuals who had less than 20 teeth but could bite tightly on both sides did not have a significant risk compared to those who had at least 20 teeth and could bite tightly on both sides. Regarding individuals with more than 20 teeth, there was no difference between those who could and could not bite tightly on both sides, although the odds ratios for poor SRH tended to increase for those who could bite on one side or neither side. Our results emphasize the importance of having at least 20 teeth without periodontal disease and oral rehabilitation using a type of prosthesis for SRH, even with less than 20 teeth.

Fibrosis-4 Index Is Closely Associated with Arterial Damage and Future Risk of Coronary Heart Disease in Type 2 Diabetes.

This study evaluated the association between fibrosis-4 (FIB 4) index and arterial damage or future risk of coronary heart disease (CHD) in type 2 diabetes. The study subjects were 253 patients with type 2 diabetes. The FIB4 index, as a marker of hepatic fibrosis based on age, aspartate aminotransferase and alanine aminotransferase levels, and platelet count, was calculated for all subjects. Carotid intima-media thickness (IMT), carotid artery calcification (CAC), and aortic arch calcification (AAC) grade (0-2) were assessed as atherosclerotic variables. The Suita score was calculated as the future risk of coronary heart disease (CHD). We assessed whether the FIB4 index was associated with both atherosclerotic variables and the Suita score. FIB4 index was significantly associated with IMT (r = 0.241, P < 0.001) and Suita score (r = 0.291, P < 0.001). Subjects with CAC showed a significantly higher FIB4 index score compared to subjects without (1.70 ± 0.74 and 1.24 ± 0.69, respectively, P < 0.001), whereas the FIB4 index was significantly elevated with a higher grade of AAC (1.24 ± 0.74, 1.56 ± 0.66, and 1.79 ± 0.71, respectively, P < 0.001). Linear regression analysis adjusted for clinical characteristics indicated that the FIB4 index was positively associated with IMT, Suita score, CAC, and AAC grade (ß = 0.241, P=0.004; ß = 2.994, P < 0.001; ß = 0.139, P=0.001; and ß = 0.265, P < 0.001, respectively). FIB4 index is closely associated with arterial damage and future risk of CHD in type 2 diabetes.

Cardio-ankle vascular index is more closely associated than brachial-ankle pulse wave velocity with arterial damage and risk of cardiovascular disease in patients with diabetes.

BACKGROUND: This study aimed to compare the usefulness of arterial stiffness parameters, cardio-ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV), for evaluating arterial damage and risk of cardiovascular disease (CVD) in subjects with diabetes. METHODS: The study subjects were 277 patients with type 1 or type 2 diabetes. All subjects were evaluated for vascular stiffness using CAVI (n = 154) or baPWV (n = 123). Carotid intima-media thickness (IMT) and the Suita score were also measured because these are established risk factors for future CVD. Associations of both CAVI and baPWV with these established parameters were evaluated in all subjects, and then in 174 subjects with adjustment for covariates by using propensity score matching. RESULTS: In all subjects, CAVI and baPWV correlated significantly with both IMT (r = 0.462, P < 0.001, and r = 0.212, P = 0.019, respectively) and the Suita score (r = 0.573, P < 0.001, and r = 0.373, P < 0.001, respectively). The correlation between CAVI and IMT was more significant than that between baPWV and IMT (Z = 2.33, P = 0.020). Similarly, the correlation between CAVI and the Suita score was more significant than that between baPWV and the Suita score (Z = 2.13, P = 0.033). After adjustment by propensity score matching, significant correlations between CAVI and IMT (r = 0.432 P < 0.001) and between CAVI and the Suita score (r = 0.544, P < 0.001) were preserved, though only the association between baPWV and the Suita score was significant (r = 0.289, P = 0.007) while that between baPWV and IMT showed no significance. Again, CAVI showed a significant association with the Suita score than baPWV (Z = 2.02, P = 0.043). CONCLUSIONS: CAVI is more closely associated than baPWV with arterial damage and risk of CVD in patients with diabetes.

Aortic arch calcification with pericardial fat mass detected on a single chest X-ray image is closely associated with the predictive variables of future cardiovascular disease.

This study evaluated the associations between aortic arch calcification (AAC) with pericardial fat (PF) mass detected on a single chest X-ray image and predictive variables of future cardiovascular disease (CVD). The subjects were 353 patients treated with at least one of the hypertension, dyslipidemia or diabetes. All subjects were evaluated for AAC; divided into 3 groups with AAC grades of 0, 1, or 2; and examined for the presence of PF. Carotid intima-media thickness (IMT, n = 353), cardio-ankle vascular index (CAVI, n = 218), the Suita score (n = 353), and cardiovascular risk points defined in the Hisayama study (n = 353), an assessment of the risk of future cardiovascular disease, were measured. The relationship of AAC grades, with or without PF, and CVD risks was evaluated. The IMT (1.62 ± 0.74 mm, 2.33 ± 1.26, and 2.43 ± 0.89 in patients with AAC grade 0, 1 and 2, respectively, p < 0.001), CAVI (8.09 ± 1.32, 8.71 ± 1.32, and 9.37 ± 1.17, respectively, p < 0.001), the Suita score (46.6 ± 10.7, 51.8 ± 8.3, and 54.2 ± 8.2, respectively, p < 0.001), and cardiovascular risk points (8.5 ± 2.6, 10.6 ± 2.3, and 11.5 ± 2.3, respectively, p < 0.001) were significantly elevated with AAC progression. Multinomial logistic regression analysis adjusted for clinical characteristics showed that the relative risk ratios of the Suita score or cardiovascular risk points were elevated according to the progress of AAC grade with PF. Therefore, aortic arch calcification with pericardial mass detected on a single chest X-ray image is closely associated with the predictive variables of future CVD.

High Parity Is an Independent Risk Factor for Tooth Loss in Women: A Community-Based Takahata Study in Japan.

Risk factors for tooth loss have been widely examined previously. However, no previous study has comprehensively investigated the risk factors, including lifestyle-related specific factors (parity, oral health habits, and socioeconomic status), for fewer than 20 teeth among women in the general population in Japan. This cross-sectional study explored the association of these risk factors, especially parity, with having fewer than 20 teeth among Japanese women. A self-reported questionnaire including items on lifestyle-related risk factors (parity, oral health, diet [e.g., alcohol and sucrose consumption]) and socioeconomic status was sent by post to female residents (age ≥ 40 years) of Takahata town, Yamagata Prefecture, in 2005. Multivariate logistic regression analysis including 3,854 eligible participants was performed to investigate the association between various factors (including parity) and having fewer than 20 teeth. The results indicated that, compared with nulliparous women, women with two, three, and four completed pregnancies had 2.485-, 2.844-, and 4.305-fold increased risk of having fewer than 20 teeth, respectively. Our study is the largest-scale study of the general female population in Japan and the first study to comprehensively investigate risk factors (parity, oral health status, and socioeconomic status) for fewer than 20 teeth. We thus found that higher parity, especially, two or more, was independent risk factors for having less than 20 teeth among Japanese women. In conclusion, the present study emphasizes the importance of good oral health habits in women, especially, during pregnancy and in the postpartum period, to maintain 20 or more teeth.

Association between presence of 20 or more natural teeth and all-cause, cancer-related, and cardiovascular disease-related mortality: Yamagata (Takahata) prospective observational study.

BACKGROUND: Several studies have surveyed the relationship between the presence of ≥ 20 natural teeth and mortality. However, very few have evaluated this association over a long-term follow-up of more than ten years within a large population in Japan. This study aimed to prospectively confirm the associations between mortality and the presence of ≥ 20 natural teeth within a community-based population in Japan. METHODS: A prospective observational study including 2208 participants aged ≥ 40 years was conducted in Takahata Town, Japan, between May 2005 and December 2016. All participants answered a self-administered questionnaire to provide their background characteristics, including their number of teeth. The participants were classified into two categories based on their self-reported number of teeth (< 20 and ≥ 20 teeth). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional-hazards regression model to assess risk factors for all-cause, cancer-, and cardiovascular disease-related mortality. RESULTS: The total follow-up period was 131.4 ± 24.1 months (mean ± SD). After adjusting for covariates, the risk of all-cause mortality was significantly higher in the group with < 20 teeth than in those with ≥ 20 teeth (HR = 1.604, 95% CI 1.007-2.555, p = 0.047). However, the risk of cancer- and cardiovascular disease-related mortalities was not statistically significant between the two groups. CONCLUSION: In this study, participants with < 20 teeth had a significantly higher risk of all-cause mortality, although the difference was borderline significant. These results emphasize the importance of having ≥ 20 natural teeth for a healthy life expectancy.

Risk factors for tooth loss in community-dwelling Japanese aged 40 years and older: the Yamagata (Takahata) study.

OBJECTIVES: The aim of the present study was to investigate comprehensively the risk factors, including some lifestyle-associated factors, oral health habits, and socioeconomic status, for having less than 20 teeth in cross-sectional study in the general population of Japan. MATERIALS AND METHODS: The survey population was the general population of individuals aged greater than or equal to 40 years in Takahata town, Japan in 2005. A postal survey with a self-administered questionnaire was distributed, and 7542 participants were entered into the final statistical analysis. The self-administered questionnaire contained items regarding some lifestyle-associated factors, oral health, and dietary intake, including alcohol and sucrose consumption. To confirm the independent association between the number of teeth and several parameters, a multivariate logistic regression analysis was used to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A low educational status, no dental check-ups, low frequency of brushing, older age, and smoking habit were independent risk factors for less than 20 teeth. A low educational status was a particularly significant risk factor for less than 20 teeth (OR = 1.352, 95% CI = 1.125-1.624). CONCLUSION: These results emphasize the importance of good oral health habits, such as frequent tooth brushing, routine dental check-ups, and no smoking, and indicate that more appropriate and compulsory education regarding oral health is needed to lessen the education level-derived differences in oral health. CLINICAL RELEVANCE: Poor oral health habits and low educational status are the independent risk factors for having less than 20 teeth.

Fewer teeth are a risk factor for being underweight in community-dwelling Japanese aged 40 years and older: The Yamagata (Takahata) Study.

OBJECTIVE: The aim of the present study was to investigate comprehensively, the risk factors for underweight in cross-sectional study in the general population of Japan. METHODS: The survey population was the general population of individuals aged >40 years in Takahata town, Japan in 2005. A postal survey in the form of a self-administered questionnaire was distributed, and 6084 individuals were entered into the final statistical analysis. The self-administered questionnaire contained items regarding lifestyle, oral health status, socio-economic status and dietary intake. To examine the independent relationships between an underweight status and several parameters, a multivariate logistic regression analysis was used to estimate adjusted odds ratios (ORs). RESULTS: The number of teeth, age, alcohol consumption, hypertension, spousal status, smoking habit, appetite, body weight at 20 years of age, habit of going out and physical activity were independently associated with an underweight status compared with the normal weight group. Individuals with fewer than 10 teeth were especially more likely to be underweight than individuals with more than 20 teeth (OR = 1.956, 95% CI = 1.261-3.035). CONCLUSION: This study showed an independent association between the number of teeth and an underweight status, indicating that fewer teeth can increase the risk of being underweight.

Corneal vesicles accumulate collagen VI associated with tissue remodeling in apolipoprotein a-I deficiency: a case report.

BACKGROUND: Apo A-I deficiency clinically shows low serum levels of HDL cholesterol and corneal opacity at a young age. Histopathological evaluations of affected corneas are not enough, and the mechanism of corneal opacity is still unclear. CASE PRESENTATION: A 61-year-old woman suffered from blurred vision with a corneal opacity. She had significantly reduced serum levels of high-density lipoprotein cholesterol and Apo A-I, stenosis of the coronary arteries, and ischemic heart failure. On genetic examination, a homozygous mutation of Apo A-ITsukuba was identified. Histopathological examination of the corneal button after PKP showed numerous vesicles in the corneal stroma, which were more prominent in the deep stroma than in the shallow stroma. Collagen VI was observed in some of those vesicles. CONCLUSION: We experienced a rare case of corneal opacity due to Apo A-I deficiency. Our histopathological findings indicated that structural changes in corneal collagen fibrils contribute to the formation of stromal vesicles.

Transient Worsening of Photosensitivity due to Cholelithiasis in a Variegate Porphyria Patient.

Variegate porphyria (VP) is an autosomal dominant disease caused by mutations of the protoporphyrinogen oxidase (PPOX) gene. This porphyria has unique characteristics which can induce acute neurovisceral attacks and cutaneous lesions that may occur separately or together. We herin report a 58-years-old VP patient complicated with cholelithiasis. A sequencing analysis indicated a novel c.40G>C mutation (p.G14R) in the PPOX gene. His cutaneous photosensitivity had been worsening for 3 years before the emergence of cholecystitis and it then gradually improved after cholecystectomy and ursodeoxycholic acid treatment with a slight decline in the porphyrin levels in his blood, urine and stool. In VP patients, a worsening of photosensitivity can thus be induced due to complications associated with some other disease, thereby affecting their porphyrin-heme biosynthesis.

Change of carotid intima-media thickness is associated with age in elderly Japanese patients without a history of cardiovascular disease.

AIM: The present study aimed to evaluate the relationship between the change of carotid intima-media thickness (CIMT) and clinical characteristics in Japanese patients without a history of cardiovascular disease. METHODS: The study participants were 149 Japanese patients without a history of cardiovascular disease treated in our outpatient department. The in all participants CIMT was measured with ultrasonography at baseline and after a mean interval of 2.4 years. Study participants were divided into a middle-aged group (younger than 65 years: n = 59) and an elderly group (65 years or older: n = 90). The annual CIMT change (ΔCIMT) was calculated, and the associations between ΔCIMT and clinical characteristics, including age, were evaluated in both groups. RESULTS: The ΔCIMT was significantly correlated with age in all participants (r = 0.222; P < 0.05) and in elderly participants (r = 0.234; P < 0.05), but was not correlated with other risk factors. The annual ΔCIMT was significantly higher in elderly participants (0.015 ± 0.096 mm) than in middle-aged participants (-0.018 ± 0.088 mm; P < 0.05). Multivariate linear regression analysis with ΔCIMT as a dependent variable and risk factors as independent variables showed that ΔCIMT was significantly associated with age in all participants (ß = 0.002; P < 0.05) and in elderly participants (ß = 0.004; P < 0.05), but not with other risk factors. CONCLUSIONS: Annual CIMT change is associated with age, rather than with other clinical characteristics, including traditional cardiovascular risk factors, such as diabetes and hypertension, in elderly Japanese patients without a history of cardiovascular disease.

Lower aldosterone-renin ratio is a risk factor for total and cancer death in Japanese individuals: the Takahata study.

OBJECTIVE: A higher plasma aldosterone-renin ratio (ARR) is an established marker for screening for primary aldosteronism (PA). The association between higher ARR and mortality in a general population has not been fully explored. We here examined whether higher ARR is a risk factor for total and cause-specific mortality in a Japanese population. SUBJECTS AND METHODS: A population-based, longitudinal study of 1,310 Japanese individuals (age: 63·9 ± 9·8 years) enrolled in the Takahata study between 2004 and 2006 and followed for up to 8 years. The incidence and causes of death were monitored annually until 10 January 2012 (median follow-up: 2691 days). RESULTS: During the follow-up period, 64 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total and cancer mortality in subjects with lower ARR (log-rank P < 0·001). Cox's proportional hazard model analyses with adjustment for age and gender showed that lower ARR was associated with increased total and cancer mortality in subjects with low (≦72) vs high (>72) ARR (hazard ratios and 95% confidential intervals: 2·56, 1·44-4·56 and 2·78, 1·16-6·65, respectively). CONCLUSIONS: Lower ARR was a significant and independent risk factor for increased total and cancer mortality in this Japanese population. Subjects with higher ARR were not-at-risk for total death in general. These findings increase the necessity for identifying people with PA from those with higher ARR. People with higher ARR without PA may be at very low risk for total and cancer death.

Lower physical activity is a risk factor for a clustering of metabolic risk factors in non-obese and obese Japanese subjects: the Takahata study.

In several countries including Japan, people without obesity but with a clustering of metabolic risk factors (MetRFs) were not considered to have the metabolic syndrome (MetS). Here, we examined whether lifestyle characteristics differed between non-obese and obese subjects with or without a clustering of MetRFs. From a population-based cross-sectional study of Japanese subjects aged ≥ 40 years, 1,601 subjects (age: 61.9 ± 10.3 years; 710/891 men/women) were recruited. Physical activity status and daily nutritional intake were estimated using questionnaires. A clustering of MetRFs was defined based on the presence of at least two non-essential risk factors for the diagnosis of the MetS in Japan. Energy intake was not higher in subjects with a clustering of MetRFs compared with those without. Among men, energy expenditure at work was significantly lower in non-obese (9.0 ± 8.2 vs. 11.3 ± 9.3 metabolic equivalents (METs), P = 0.025) and obese (9.0 ± 7.9 vs. 11.6 ± 9.4 METs, P = 0.017) subjects with a clustering of MetRFs than in those without. Multiple logistic regression analysis showed that energy expenditure at work was significantly associated with a clustering of MetRFs after adjusting for possible confounding factors including total energy intake. The ORs (per 1 METs) were 0.970 (95% CI, 0.944-0.997; P = 0.032) in non-obese men and 0.962 (0.926- 0.999; P = 0.043) in obese men. Similar associations were not observed in women. In Japanese males, lower physical activity, but not excessive energy intake, is a risk factor for a clustering of MetRFs independent of their obesity status.

Thyroid dysfunction in patients treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, for metastatic renal cell carcinoma.

OBJECTIVE: Targeted drugs are generally associated with a lower toxicity than conventional systemic cytotoxic drugs and, thus, are administered for long periods. As a result, unusual adverse effects, including thyroid dysfunction, have become important clinical issues. METHODS: We retrospectively collected the data and compared the incidence and the time of onset of thyroid dysfunction in 33 patients (M/F: 26/7, age: 34-77) with metastatic renal cell carcinoma treated with the small-molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib and axitinib in Yamagata University Hospital, Japan, from 2005 to 2010. RESULTS: The incidence of thyroid dysfunction tended to be higher in patients treated with axitinib (6 of 6: 100%) than in those treated with sunitinib (9 of 15: 60%) or sorafenib (6 of 12: 50%) (P= 0.1113). The median thyroid dysfunction-free survival evaluated using the Kaplan-Meier product-limit method with the log-rank test was significantly shorter in patients treated with axitinib than in those treated with sunitinib/sorafenib (3 vs. 16 weeks, P=0.0198). A multivariate Cox regression model for thyroid dysfunction-free survival with several probable confounding factors as co-variables showed that patients treated with axitinib were more likely to have thyroid dysfunction than the others (hazard ratio: 4.53, 95% confidence interval: 1.40-14.63, P=0.0116). CONCLUSIONS: Patients treated with the tyrosine kinase inhibitors developed thyroid dysfunction frequently. Furthermore, those treated with axitinib developed thyroid dysfunction significantly more and at a faster rate than the others. Therefore, when the tyrosine kinase inhibitors, especially axitinib, are used, close monitoring of thyroid function is recommended, at least for the initial 1-2 months, to avoid clinical symptoms derived from thyroid dysfunction.

Serum glycerophosphate levels are increased in Japanese men with type 2 diabetes.

OBJECTIVE: To identify metabolites showing changes in serum levels among Japanese male with diabetes. METHODS: We performed metabolite profiling by coupling capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry using fasting serum samples from Japanese male subjects with diabetes (n=17), impaired glucose tolerance (IGT; n=5) and normal glucose tolerance (NGT; n=14). RESULTS: Other than the expected differences in characteristics related to abnormal glucose metabolism, the percent body fat was significantly different among subjects with diabetes, IGT and NGT (27.3±6.2, 22.2±4.5 and 19.2±6.0%, respectively, p=0.0022). Therefore, percent body fat was considered as a possible confounding factor in subsequent analyses. Of 560 metabolites detected using our platform, the levels of 74 metabolites were quantified in all of the serum samples. Significant differences between diabetes and NGT were observed for 24 metabolites. The top-ranked metabolite was glycerol-3-phophate (glycerophosphate), which was significantly higher in subjects with diabetes than in those with NGT, even after Bonferroni correction for multiple testing (11.7±3.6 vs. 6.4±1.9 µM, respectively; corrected p=0.0222). Stepwise multiple regression analyses revealed that serum glycerophosphate levels were significantly correlated with 2-h plasma glucose after a 75-g oral glucose tolerance test (r=0.553, p=0.0005), independently of other characteristics, including FPG and HbA1c. CONCLUSION: Serum glycerophosphate levels were found to be elevated in Japanese men with diabetes, and correlated with 2-h PG, independent of FPG and HbA1c. Namely, serum glycerophosphate level at fasting condition can be a marker for predicting glucose intolerance. These results warrant further studies to evaluate the relevance of glycerophosphate in the pathophysiology of diabetes.