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Maturity-onset diabetes of the young type 4 (MODY4, PDX1-MODY) is a monogenic diabetes caused by the PDX1 gene. Here we detected two novel heterozygous missense variants, NM_000209.4(NP_000200.1):c.443G>T, p.(Arg148Leu) and c.442C>G p.(Arg148Gly), in two Japanese patients. Pathogenicity testing revealed a loss of function in both variants. Family members had severe diabetic complications, including proliferative retinopathy and overt nephropathy such as end-stage renal disease. Laboratory testing indicated persistently high glucose levels, at least partially caused by reduced postprandial insulin secretion.

Maturity-onset diabetes of the young (MODY) is a heterozygous monogenic diabetes; more than 14 disease genes have been identified. However, the pathogenesis of MODY is not fully understood because the patients' pancreatic beta cells are inaccessible. To elucidate the pathology of MODY, we established MODY3 patient-derived iPS (MODY3-iPS) cells using non-integrating Sendai virus (SeV) vector and examined the mutant mRNA and protein of HNF1A (Hepatocyte Nuclear factor 1A) after pancreatic lineage differentiation. Our patient had a cytosine insertion in the HNF1A gene (P291fsinsC) causing frameshift and making a premature termination codon (PTC). We confirmed these MODY3-iPS cells possessed the characteristics of pluripotent stem cells. After we differentiated them into pancreatic beta cells, transcripts of HNF1A gene were cloned and sequenced. We found that P291fsinsC mutant transcripts were much less frequent than wild ones, but they increased after adding cycloheximide (CHX) to the medium. These results suggested that mutant mRNA was destroyed by nonsense-mediated mRNA decay (NMD). Moreover, we were not able to detect any band of mutant proteins in pancreatic lineage cells which were differentiated from MODY3-iPSCs by western blot (WB) analysis. A scarcity of the truncated form of mutant protein may indicate that MODY3 might be caused by a haplo-insufficiency effect rather than a dominant negative manner.

Potassium inwardly rectifying channel, subfamily J, member 15 (KCNJ15) is a type 2 diabetes-associated risk gene, and Kcnj15 overexpression suppresses insulin secretion in rat insulinoma (INS1) cells. The aim of the current study was to characterize the role of Kcnj15 by knockdown of this gene in vitro and in vivo. Human islet cells were used to determine the expression of KCNJ15. Expression of KCNJ15 mRNA in islets was higher in subjects with type 2 diabetes. In INS1 cells, Kcnj15 expression was induced by high glucose-containing medium. Regulation of Kcnj15 by glucose and its effect on insulin secretion were analyzed in INS1 cells and in normal mice and diabetic mice by the inactivation of Kcnj15 using small interfering RNA. Knockdown of Kcnj15 increased the insulin secretion in vitro and in vivo. KCNJ15 and Ca(2+)-sensing receptor (CsR) interact in the kidney. Binding of Kcnj15 with CsR was also detected in INS1 cells. In conclusion, downregulation of Kcnj15 leads to increased insulin secretion in vitro and in vivo. The mechanism to regulate insulin secretion involves KCNJ15 and CsR.

Maturity‐onset diabetes of the young (MODY) is a heterozygous monogenic diabetes; more than 13 disease genes have been identified. However, the pathogenesis of MODY is not fully understood, because the pancreatic β‐cells of the patients are inaccessable. Therefore, we attempted to establish MODY patient‐derived induced pluripotent stem cells (MODY‐iPS) cells to investigate the pathogenic mechanism of MODY by inducing pancreatic β‐cells. We established MODY5‐iPS cells from a Japanese patient with MODY5 (R177X), and confirmed that MODY5‐iPS cells possessed the characteristics of pluripotent stem cells. In the course of differentiation from MODY5‐iPS cells into pancreatic β‐cells, we examined the disease gene, HNF1B messenger ribonucleic acid. We found that the amount of R177X mutant transcripts was much less than that of wild ones, but they increased after adding cycloheximide to the medium. These results suggest that these R177X mutant messenger ribonucleic acids are disrupted by nonsense‐mediated messenger ribonucleic acid decay in MODY‐iPS cells during the developmental stages of pancreatic β‐cells. We established Maturity Onsets Diabetes of Young (MODY) 5‐iPS cells from Japanese patient. R177X mutant mRNAs are disrupted by nonsense‐mediated mRNA decay in MODY‐iPS cells during the developmental stages of pancreatic beta cells.

Background The development of diabetic retinopathy is associated with the duration of diabetes and HbA1c levels. However, the familial aggregation of diabetic retinopathy is consistent with genetic susceptibility. Recently, a –634C/G polymorphism in the vascular endothelial growth factor (VEGF) gene was shown to be associated with diabetic retinopathy. To clarify the contribution of the VEGF gene in the development of diabetic retinopathy we analyzed variants in this gene among 469 Japanese patients with type 2 diabetes. Methods DNA from each patient was typed for –634C/G and –2578C/A polymorphisms using conventional polymerase chain reaction techniques. The vitreous fluid samples were obtained from 40 patients with PDR for measurement of VEGF levels. Results We found a significantly higher frequency of the A allele in the group with proliferative diabetic retinopathy (PDR) than in the control group at –2578C/A polymorphism ( p  = 0.036). Moreover, if the subjects were grouped according to the duration of diabetes and status of diabetic retinopathy (a first group consisting of subjects with longer duration (>20 y) of diabetes without any retinopathy ( n  = 102), and a second group of those with shorter diabetes (<15 y) but having retinopathy ( n =  35), the genotype distribution at -2578 C/A polymorphism was again significantly higher in the second group ( p  = 0.005) and differed significantly ( p =  0.002) in a recessive model. The risk of the AA for PDR was 7.7 (95%, CI: 1.8–30.9). Conclusions The AA genotype at –2578C/A polymorphism in the VEGF gene is associated with proliferative diabetic retinopathy. No significant association with –634 C/G polymorphism was confirmed.

Diabetes is a risk factor for osteoporosis, and glycemic control is critical during osteoporosis treatment in patients with type 2 diabetes (T2D). However, diabetic therapies have potentially adverse effects on bone metabolism. Additionally, biomarkers for bone metabolism are directly affected by drug therapies for osteoporosis. This study examined resting energy expenditure (REE) and respiratory quotient (RQ) as indices of bone metabolism in postmenopausal Japanese women with T2D. Forty-six postmenopausal Japanese women with T2D were examined. Procollagen type 1 N-terminal propeptide (P1NP, a fasting serum bone formation marker) and carboxy-terminal collagen cross-links-1 (CTX-1, a resorption marker) were evaluated, along with intact parathyroid hormone, 25-hydroxyvitamin D (25[OH]D), urine microalbumin, motor nerve conduction velocity, sensory nerve conduction velocity, R-R interval, body composition, REE, RQ, and bone mineral density at the nondominant distal radius. The mean T-score was low with high variance (−1.7 ± 1.6), and 18 patients (39%) met the criteria for osteoporosis. REE was positively correlated with body mass index (β = 0.517; r2 = 0.250), serum calcium (β = 0.624; r2 = 0.200), glycated hemoglobin A1C for the previous 6 mo (β = 0.395; r2 = 0.137), and the serum P1NP/CTX-1 ratio (β = 0.380; r2 = 0.144). RQ was positively correlated with serum 25(OH)D (β = 0.387; r2 = 0.131). The basal metabolic rate and diabetic pathophysiology are interrelated with bone turnover. •Basal metabolic rate and bone metabolism were evaluated in postmenopausal women with type 2 diabetes.•Bone metabolism was associated with resting energy expenditure.•Serum vitamin D was associated with respiratory quotient and insulin requirement.

Aims/Introduction Resting energy expenditure was associated with a serum bone turnover marker in postmenopausal women with type 2 diabetes (T2DMPW) in the present cross‐sectional study. To clarify the fundamental pathological factor for the correlation of bone metabolism and basal metabolism in type 2 diabetes, a 6‐month prospective follow‐up study was carried out with supplementation of vitamin D. Materials and Methods A total of 44 T2DMPW were enrolled. The following factors were evaluated at the beginning and the end of the summer: procollagen type 1 N‐terminal propeptide, carboxy‐terminal collagen crosslinks‐1, intact parathyroid hormone and 25‐hydroxyvitamin D (25[OH]D), as well as diabetic complications, body composition, respiratory quotient and resting energy expenditure. A total of 23 patients with low 25(OH)D levels (˂20 ng/mL) were instructed to increase vitamin D levels by lifestyle change. Among them, 15 patients with osteoporosis were also administered alfacalcidol. Results Serum 25(OH)D increased in 25 patients and decreased in 19 patients. Patients who did not receive the study intervention at the start tended to have a decreased 2525(OH)D level; therefore, the average 25(OH)D level of all patients was not changed. Changes in resting energy expenditure were positively correlated with those of procollagen type 1 N‐terminal propeptide/carboxy‐terminal collagen crosslinks‐1. Changes in the respiratory quotient correlated with the mean glycated hemoglobin levels; procollagen type 1 N‐terminal propeptide levels positively correlated with serum 25(OH)D after the intervention. These correlations were prominent in patients with increased 25(OH)D and those with alfacalcidol supplementation. Conclusions Restoration of vitamin D level might be a prerequisite for a normal correlation between bone and basal metabolism in T2DMPW. Lifestyle intervention for retention of vitamin D level is important even in summer, in T2DMPW. Basal metabolic rate and bone metabolism were evaluated in postmenopausal diabetic patients. Vitamin D may play an important role in the positive correlation between bone and basal metabolism. Respiratory quotient was associated with 25[OH]D as well as HbA1c after vitamin D supplementation.

Transcription factor 7-like 2 ( TCF7L2 ) has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups. Regarding the Asian population, Horikoshi et al. (Diabetologia 50:747–751, 2007) and Hayashi et al. (Diabetologia 50:980–984, 2007) reported that single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in the Japanese population, while contradictory results were reported for Han Chinese populations. The aim of this study was to investigate the associations of the TCF7L2 gene with type 2 diabetes using a relatively large sample size: 2,214 Japanese individuals with type 2 diabetes and 1,873 normal controls. The minor alleles of rs7903146, rs11196205, and rs12255372 showed significant associations with type 2 diabetes (OR = 1.48, P  = 2.7 × 10 −4 ; OR = 1.39, P  = 4.6 × 10 −4 ; OR = 1.70, P  = 9.8 × 10 −5 , respectively) in the combined sample sets. However, neither rs11196218 nor rs290487 showed a significant association. These results indicate that TCF7L2 is an important susceptibility gene for type 2 diabetes in the Japanese population.

Prediction of the disease status is one of the most important objectives of genetic studies. To select the genes with strong evidence of the association with type 2 diabetes mellitus, we validated the associations of the seven candidate loci extracted in our earlier study by genotyping the samples in two independent sample panels. However, except for KCNQ1 , the association of none of the remaining seven loci was replicated. We then selected 11 genes, KCNQ1 , TCF7L2 , CDKAL1 , CDKN2A/B , IGF2BP2 , SLC30A8 , HHEX , GCKR , HNF1B , KCNJ11 and PPARG , whose associations with diabetes have already been reported and replicated either in the literature or in this study in the Japanese population. As no evidence of the gene–gene interaction for any pair of the 11 loci was shown, we constructed a prediction model for the disease using the logistic regression analysis by incorporating the number of the risk alleles for the 11 genes, as well as age, sex and body mass index as independent variables. Cumulative risk assessment showed that the addition of one risk allele resulted in an average increase in the odds for the disease of 1.29 (95% CI=1.25–1.33, P =5.4 × 10 −53 ). The area under the receiver operating characteristic curve, an estimate of the power of the prediction model, was 0.72, thereby indicating that our prediction model for type 2 diabetes may not be so useful but has some value. Incorporation of data from additional risk loci is most likely to increase the predictive power.