Masashi Honda

Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population.

AbstractVariation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and ≥50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis ≥50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.

Morphological analysis of pancreatic endocrine cells in newborn animals delivered by experimental diabetic rats

Rats with mildly impaired glucose tolerance (MIGT) were prepared by the administration of streptozotocin and subsequent islet-isotransplantation. Of pups born to these rats, 65% exhibited macrosomia that weighed over 6.8 g (average weight of control pups was 5.96 g). The morphological changes in the endocrine pancreas in pups born of MIGT and normal control rats were studied using immunohistochemical methods and quantitative morphological analysis. In macrosomic pups, the percentages of pancreatic tissue devoted to islet areas and B cell areas were significantly higher than in control pups. The percentage of pancreas devoted to A cell areas was also higher in macrosomic than normal pups, while the ratio of A/B cell areas was in normal range. In non-macrosomic pups born to MIGT rats, the percentages of pancreas devoted to islet tissues, B cell, and A cell areas were each lower than these in macrosomic pups. Moreover, increase in the proportions of islet and B cell areas in the pancreatic tissue in pups born of MIGT mothers was linearly correlated with increase in birthright. There were no significant differences in D cell area as a proportion of pancreas among macrosomic, non-macrosomic and control pups. These findings suggest that insulin secreted from B cells play important roles in the control of fetal growth.

Identification of three missense mutations in the peroxisome proliferator-activated receptor α gene in Japanese subjects with maturity-onset diabetes of the young

AbstractWe screened the protein-coding region of the peroxisome proliferator-activated receptor α gene (PPARA) and the flanking intron sequences for mutations in 57 unrelated Japanese subjects with maturity-onset diabetes of the young (MODY). We found three missense mutations, designated P22R, D140Y, and V227A. The D140Y and V227A mutations were found at similar frequencies in MODY and in nondiabetic Japanese subjects, suggesting that they were unlikely to be pathogenic. The P22R mutation was found in a single female subject with MODY. Two of her four siblings, all of whom were diagnosed with diabetes before age 35 years, also inherited the P22R mutation. However, two other diabetic siblings had not inherited the mutant allele, implying that the P22R mutation was not the cause of MODY in this family. Variation in the coding region of PPARA is unlikely to be a major cause of MODY in Japanese people.

Comparison of Diagnostic Criteria of IGT, Borderline, and GDM: Blood Glucose Curve and IRI Response

A 75-g oral glucose tolerance test (OGTT) was performed in 615 nonobese pregnant women (mean ± SD age 29.7 ± 4.3 yr) who were referred to the Division of Internal Medicine at our diabetes center because of glycosuria. Seventy-seven cases were found to have urinary glucose at the first trimester, 185 at the second trimester, and 353 at the third trimester. With their 75-g OGTT results, the diagnostic criteria of borderline (formulated by the Japan Diabetes Society), impaired glucose tolerance (IGT; defined by the World Health Organization [WHO]), and gestational diabetes mellitus (GDM; determined by the Japan Society of Obstetrics & Gynecology standards) were compared through blood glucose (BG) curves and immunoreactive insulin (IRI) responses. Borderline (fasting BG ≥6.1 and <7.8 mM and 2-h BG ≥6.7 and <11.1 mM) is neither diabetes nor normal. IGT is as referred to by the WHO. GDM exceeds two points of fasting BG ≥5.6 mM, 1-h BG ≥10.0 mM, or 2-h BG ≥8.3 mM. Diabetes mellitus (DM) is as referred to by the Japan Diabetes Society (same as the WHO). The prevalence of abnormal glucose tolerance among all 615 pregnant women was 54.6% in borderline, 24.5% in IGT, 7.3% in GDM, and 3.4% in DM. The 2-h BG levels in IGT during the first trimester were higher than in borderline (P< 0.01). The 1- and 2-h levels in GDM without DM in a given trimester were higher than in borderline (P< 0.001–0.05). However, there were low responses of IRI at the early phase in each group. The prevalence of low responders whose 30-min ΔIRI (pM)/ΔBG (mM) was < 54 was 47% in borderline, 52% in IGT, 83% in GDM, and 100% in DM at the first trimester. Moreover, among 7 cases who were low-IRI responders during their first pregnancy, 3 developed GDM or DM during their second pregnancy. Although it is difficult to clarify which criteria for GDM are better, these data indicate that a low 30-min ΔIRI/ΔBG on 75-g OGTT is an important piece of evidence predicting the future onset of non-insulin-dependent DM.

Analysis of the effect of seasonal administration on the efficacy of sitagliptin: Subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study

Hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus fluctuate throughout the year. However, there are few studies that have evaluated the therapeutic effect of hypoglycemic agents while considering such fluctuations. In a multicenter study (Januvia Multicenter Prospective Trial in Type 2 Diabetes Study), pretreatment patients with type 2 diabetes mellitus were divided into seven groups and given sitagliptin for 1 year. The aim of the present study was to evaluate the differences in the therapeutic effect, and the efficacy of sitagliptin in patients with type 2 diabetes mellitus based on the month the administration of the drug began as a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study.

Erratum to: Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus and comparison of hypoglycemic action of concomitant medications: a subanalysis of the JAMP study

Erratum to: Diabetol Int DOI 10.1007/s13340-017-0330-2.