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Since type 2 diabetes (DM) is a life-style related disease, life-style should be considered when association between genetic factors and DM are examined. However, most studies did not examine genetic associations in consideration with lifestyle. Glucagon-like peptide-1 (GLP-1) receptor (GLP1R) mediates the insulinotropic action of GLP-1 in β-cells. We here examined the association while taking into consideration of interactions between the gene polymorphism and various nutrient factors. Participants from the population-based Iwaki study of Japanese subjects held in 2014–2017 with information on nutritional intake evaluated by self-administered dietary history questionnaire, and GLP1R genotype (rs3765467: A/G), were included (n = 1,560). Although not significant, insulin secretion indices assessed by homeostasis model assessment of β-cell function (HOMA-β) in subjects with the GG genotype tended to be lower than in those with the AA+AG genotypes in most groups stratified into tertiles based on daily nutrient consumptions (high, middle, and low). Stratification also showed that the GG genotype was a significant risk for decreased insulin secretion (HOMA-β ≤ 30) even after adjustment for multiple factors (age, body mass index, alcohol consumption), but only in the highest tertiles of energy, protein and carbohydrate consumption in men [odds ratios (95% confidence interval) 3.95 (1.03–15.1), 15.83 (1.58–158.9), and 4.23 (1.10–11.2), respectively]. A polymorphism of the GLP1R gene was associated with decreased insulin secretion in a nutrient consumption-dependent manner in Japanese men, indicating an interaction between GLP1R and nutritional factors in the pathophysiology of DM.

Background Xylitol is an approved food additive that is widely used as a sweetener in many manufactured products. It is also used in pharmaceuticals. Secondary oxalosis resulting from high dietary oxalate has been reported. However, reported cases of oxalosis following xylitol infusion are rare. Case presentation A 39-year-old man with a 16-year history of organic psychiatric disorder was hospitalized for a laparoscopic cholecystectomy because of cholecystolithiasis. He had been treated with several antipsychotics and mood stabilizers, including lithium. The patient had polyuria (> 4000 mL/day) and his serum sodium levels ranged from 150 to 160 mmol/L. Urine osmolality was 141 mOsm/L, while serum arginine vasopressin level was 6.4 pg/mL. The patient was diagnosed with nephrogenic diabetes insipidus (NDI), and lithium was gradually discontinued. Postoperative urine volumes increased further to a maximum of 10,000 mL/day, and up to 10,000 mL/day of 5% xylitol was administered. The patient’s consciousness level declined and serum creatinine increased to 4.74 mg/dL. This was followed by coma and metabolic acidosis. After continuous venous hemodiafiltration, serum sodium improved to the upper 140 mmol/L range and serum creatinine decreased to 1.25 mg/dL at discharge. However, polyuria and polydipsia of approximately 4000 mL/day persisted. Renal biopsy showed oxalate crystals and decreased expression of aquaporin-2 (AQP2) in the renal tubules. Urinary AQP2 was undetected. The patient was discharged on day 82 after admission. Conclusions Our patient was diagnosed with lithium-induced NDI and secondary oxalosis induced by excess xylitol infusion. NDI became apparent perioperatively because of fasting, and an overdose of xylitol infusion led to cerebrorenal oxalosis. Our patient received a maximum xylitol dose of 500 g/day and a total dose of 2925 g. Patients receiving lithium therapy must be closely monitored during the perioperative period, and rehydration therapy using xylitol infusion should be avoided in such cases.

Association of the C825T G-protein β3 subunit (GNB3) gene polymorphism with cardiovascular disease (CVD) incidence was examined in a population-based longitudinal study of the Japanese individuals. The incidence of CVD (stroke and coronary heart disease (CHD)) was assessed in a cohort population (n=1524) consisting of participants of the 2001-2005 Funagata study through March 2008. Cumulative incidences according to genotype were compared with the Kaplan-Meier product-limit method. During the follow-up, 78 subjects experienced a CVD event (stroke: n=54; CHD: n=30; both consecutively: n=6). At the end of the follow-up (longest and median follow-up periods: 81 and 68 months, respectively), the cumulative incidence of CVD for the TT genotype was significantly higher than that of the C-carriers (0.077 vs 0.042, P=0.004). Blood pressures and the prevalence of hypertension were not different between the genotypes. Cox's proportional hazard analysis showed that the TT genotype is a significant risk factor for CVD (hazard ratio (HR)=1.82 (95% confidence interval (CI) 1.14-2.89); P=0.012) and stroke (HR=1.76 (95% CI: 1.01-3.07); P=0.048) incidences after adjustment for age, sex, hypertension, hyperlipidemia, diabetes, alcohol drinking and smoking at baseline. The TT genotype of the C825T GNB3 gene polymorphism was found to be a significant risk factor for the incidence of CVD and stroke independent of hypertension and other established CVD risk factors in a Japanese population.

Albuminuria is a known risk factor for cardiovascular events and premature deaths. However, the association between urinary albumin excretion and mortality is unknown in the Japanese population. To clarify this, we conducted a community-based longitudinal study.This study included 3,445 registered Japanese subjects (mean age 62.6 years), with a 7-year follow-up. Albuminuria was defined as a urine albumin-creatinine ratio (ACR) ≥30 mg/g in the morning spot urine.Subjects with albuminuria (n = 514, 14.9 %) were older and showed a higher prevalence of hypertension, obesity, and diabetes and lower values of estimated glomerular filtration rate (eGFR) than those without albuminuria (n = 2931, 85.1 %). During the follow-up, 138 subjects died. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in urine albumin excretion (log-rank test, P 0.001). The subjects with albuminuria showed a significantly higher mortality rate than those without albuminuria (7.4 vs. 3.4 %; log-rank test, P 0.001). A Cox proportional hazard model analysis after adjusting for possible confounders showed that albuminuria was an independent risk factor for all-cause and cardiovascular mortality (hazard ratio [HR] 1.69, 95 % confidence interval [CI] 1.12-2.56 and HR 2.27, 95 % CI 1.10-4.70, respectively) but not for noncardiovascular mortality. These associations were preserved after excluding subjects with high ACR (≥300 mg/g).Albuminuria was a risk factor for all-cause and cardiovascular mortality in the Japanese population. To detect subjects with a high risk for premature death, measuring urinary albumin excretion might be useful.

The lower cutoff limit used to define impaired fasting glucose (IFG) varies between countries/organizations and is usually 100 or 110 mg/dl. Therefore, we evaluated the cutoff value for IFG that predicted the development of type 2 diabetes among the participants of the Funagata Study, a Japanese population-based, longitudinal study. Overall, 3,413 individuals (age 56.2 ± 12.1 years) without diabetes at baseline and who attended follow-up examinations were included in this analysis. Diabetes was diagnosed based on 75-g oral glucose tolerance tests according to the 1998 World Health Organization criteria. Follow-up visits were completed in 2007 (mean follow-up 147 months). The development of diabetes was used as the endpoint. During the follow-up period, 156 individuals developed diabetes. Life-table method analysis showed significantly decreased diabetes-free survival in individuals with fasting plasma glucose (FPG) ≥ 96 mg/dl (p = 0.002). Cox’s proportional hazard model analyses showed a high risk for the development of diabetes in individuals with FPG ≥ 101 mg/dl. The hazard ratio for patients with an FPG of 101–105 mg/dl was 5.50 (95% confidence interval (CI) 2.12–14.25; p < 0.001). The 5-year incidence of diabetes was also substantially increased in individuals with FPG ≥ 101 mg/dl. The odds ratio for patients with FPG 101–105 mg/dl was 10.9 (95% CI 2.6–46.0; p < 0.001). Receiver operating characteristic curve analysis showed an optimal FPG cutoff value of 100 mg/dl. Based on these results, the optimal FPG cutoff value used to define IFG in Japanese individuals should be 100 mg/dl rather than 110 mg/dl.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease caused by a decreased activity of hydroxymethylbilane synthase (HMBS). Regarding the abnormalities of the HMBS gene, many different mutations have been reported worldwide; however, few families from Japan have been studied. In this work, we investigated the presence of mutations in two unrelated Japanese patients with AIP. Mutational analysis was performed using the polymerase chain reaction-single strand conformation polymorphism (SSCP) method, followed by DNA sequencing. Reliable restriction enzyme cleavage assays were also established for the pedigree analyses. Unique SSCP patterns were noted in exons 12 and 15 of the HMBS gene. Sequencing revealed different mutations in each patient: a two-base deletion of CT at nucleotide 730-731 (730delCT), and also a two-base deletion of CA at position 982-983 (982delCA). Both of the deletion mutations lead to truncated proteins with an abnormal C-terminus, which would be expected to decrease the stability and/or activity of HMBS. Using the cleavage assays, we were able to definitively identify gene carriers in the family. This study adds a novel mutation to those that have been previously reported, and emphasizes that molecular analysis would be very useful not only for the identification of asymptomatic gene carriers in the family but also for the detection of ancestral founders in porphyria families.

Acute intermittent porphyria (AIP) is an autosomal-dominant disease caused by a deficiency of porphobilinogen (PBG) deaminase. Patients with AIP present with neurological syndromes such as autonomic neuropathy, peripheral axonal neuropathy or central nervous system dysfunction. We report serial MRI of a patient with AIP who had cortical and subcortical cerebral changes. A 29-year-old woman with a 6-month history of AIP had an attack with severe hyponatraemia and generalised convulsions, treated with haem arginate and supportive therapy. MRI showed central pontine and extrapontine myelinolysis and cortical laminar necrosis. These are not common in AIP, but are likely to have been caused by rapid correction of hyponatraemia and by vasospasm, which could be induced by AIP.

Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease (CVD), includes elevated fasting plasma glucose (FPG) levels, elevated blood pressure (BP), elevated triglyceride (TG) levels, reduced highdensity lipoprotein cholesterol (HDL-C) levels, and obesity [1]. Obesity seems to be a central metabolic risk factor (MetRF) because insulin resistance, which is generally related to obesity, is a potential pathophysiologic link among MetRF. In this context, obesity, as measured by abdominal adiposity and increased waist circumference, is included as an essential factor for diagnosis of MetS by the International Diabetes Federation (IDF) and the Japanese Examination Committee for Criteria of Metabolic Syndrome [2, 3]. However MetRF were frequently clustered, even among non-obese subjects. Subjects with clustering of MetRF are often insulin-resistant compared with subjects without clustering of MetRF, even though they were not obese. Thus, non-obese subjects with a clustering of MetRF are at increased risk of CVD, as are obese subjects with a clustering of MetRF, or subjects with MetS. Thus, evaluation of MetRF seems to be important for finding such individuals. Recently, Hiraoka et al. reported an association of fatty liver with MetRF and such insulin-resistance indices as HOMA-R among non-obese subjects with normal waist circumference none of whom met the MetS criteria [4]. Blood pressure, serum triglyceride, and HOMA-R levels were significantly elevated among non-obese subjects with normal waist circumference and fatty liver compared to those without (males: 122/78 vs. 120/76 mmHg, 161.5 vs. 105.5 mg/dl, 1.9 vs. 1.3, respectively; females: 120/73 vs. 116/71 mmHg, 115.2 vs. 82.0 mg/dl, 1.7 vs. 1.3, respectively). This result indicated that those with fatty liver were at risk of clustering of MetRF and, thus, of developing MetS, even though they were not obese or did not meet the MetS criteria. Therefore, evaluation of fatty liver, which can be detected easily by ultrasonography in ordinary clinical settings, seems to be important for non-obese and obese individuals. Furthermore, because the authors excluded those who regularly drank 20 g or more alcohol per day from their study population, the fatty liver described in the report seems to be non-alcoholic fatty liver disease (NAFLD) [4]. Studies of MetS have revealed a J-shaped relationship between alcohol intake and the risk of MetS [5–7]. Indeed, light alcohol consumption was actually associated with a lower risk of MetS [6–8] whereas very heavy alcohol consumption was associated with a substantial increase in the risk of MetS [9]. However, the different relationships between alcohol intake and the risk of clustering of MetRF might be related to the different obesity of the subjects, i.e. non-obese versus obese. We recently reported that alcohol intake by non-obese males with a clustering of MetRF was significantly higher than by those without, but such differnce was not observed in obese males [10]. Furthermore, analysis of non-obese males stratified into the four groups on the basis of alcohol consumption (none, light (1–139 g/ week), heavy (140–279 g/week), and very heavy (]280 g/ week)) revealed a positive linear association between amount of alcohol intake and clustering of MetRF [10], i.e., increasing alcohol intake seemed to increase the risk of clustering of MetRF among non-obese Japanese males whereas non-obese individuals with no or light alcohol & Makoto Daimon mdaimon@hirosaki-u.ac.jp

Genomic DNA from a patient with acute intermittent porphyria were analyzed by the polymerase chain reaction (PCR)-direct sequencing method. The patient was heterozygote for a point mutation G to C at the last position of exon 12 of the porphobilinogen deaminase (PBG-D) gene. Analysis of the cDNA fragments amplified by PCR revealed that the patient has the abnormal PBG-D mRNA, which does not have exon 12 and exists in an approximately equal amount to the normal mRNA.

Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase (CPO). Only 11 mutations of the gene have been reported to date as the mutations responsible for HCP. We report here a novel mutation of the gene responsible for the disease in a Japanese family. Analysis of the polymerase chain reaction (PCR) amplified DNA fragments of the gene by direct-sequencing and/or cloning-based sequencing methods revealed the gene abnormality responsible for the disease. The mutation found was a single base deletion of T at nt position 526, which results in frame shift and truncation of coded protein at amino acid position 204. Screening of pre-symptomatic cases seemed to be possible by PCR restriction analysis using restriction enzyme Xcm I.

A single base insertion of C in exon 15 of the porphobilinogen deaminase (PBG-D) gene was observed in a patient with acute intermittent porphyria (AIP) by polymerase chain reaction (PCR)-direct sequencing analysis. The insertion locates between positions -22 and -21 from the translation termination codon TAA, causes a frame shift, and results in a stop codon located 4 codons downstream from the insertion (premature stopping of translation). The mutation generates an MspI recognition site, which can be used, in turn, to detect the mutant allele. Analysis of the cDNA fragments amplified by PCR revealed the existence of the abnormal PBG-D mRNA from the mutant allele in the patient.