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In Asia, young-onset type 2 diabetes (YOD) is characterized by obesity and increased risk for cardiovascular disease (CVD). In a genome-wide association study (GWAS) of 99 Chinese obese subjects with familial YOD diagnosed before 40-year-old and 101 controls, the T allele of rs1408888 in intron 1 of DACH1(Dachshund homolog 1) was associated with an odds ratio (OR) of 2.49(95% confidence intervals:1.57-3.96, P = 8.4 × 10(-5)). Amongst these subjects, we found reduced expression of DACH1 in peripheral blood mononuclear cells (PBMC) from 63 cases compared to 65 controls (P = 0.02). In a random cohort of 1468 cases and 1485 controls, amongst top 19 SNPs from GWAS, rs1408888 was associated with type 2 diabetes with a global P value of 0.0176 and confirmation in a multiethnic Asian case-control cohort (7370/7802) with an OR of 1.07(1.02-1.12, P(meta) = 0.012). In 599 Chinese non-diabetic subjects, rs1408888 was linearly associated with systolic blood pressure and insulin resistance. In a case-control cohort (n = 953/953), rs1408888 was associated with an OR of 1.54(1.07-2.22, P = 0.019) for CVD in type 2 diabetes. In an autopsy series of 173 non-diabetic cases, TT genotype of rs1408888 was associated with an OR of 3.31(1.19-9.19, P = 0.0214) and 3.27(1.25-11.07, P = 0.0184) for coronary heart disease (CHD) and coronary arteriosclerosis. Bioinformatics analysis revealed that rs1408888 lies within regulatory elements of DACH1 implicated in islet development and insulin secretion. The T allele of rs1408888 of DACH1 was associated with YOD, prediabetes and CVD in Chinese.

Syntaxin 1A is a candidate gene for Type II (non-insulin-dependent) diabetes mellitus, because it plays an important role in insulin secretion from the islet beta cells. We aimed to scan this gene for mutations or genetic markers that correlate with Type II diabetes.We identified and characterized coding exons of the syntaxin 1A gene and scanned the newly identified 10 exons using direct sequencing.In the single nucleotide polymorphism (SNP) of exon 3 (D68D, T to C) among three newly identified SNPs, genotype frequency of the homozygote of C allele (CC) occurred more frequently in a Type II diabetic group than in a non-diabetic group (16.48 %, n = 182, vs 11.05 %, n = 181, p = 0.0499). Among the diabetic patients, age of onset in patients with CC genotype was lower than that in patients with the TT and TC genotypes [40.10 +/- 1.50 years old (means +/- SEM) vs 44.20 +/- 0.58, p = 0.005]. Patients with the CC genotype had a higher frequency of insulin treatment (78.30 % vs 46.80 %, p = 0.006) with a duration equal to, or longer than, 10 years. Multiple regression analysis confirmed that the genotype was significantly and independently associated with age at onset and mode of treatment, respectively.These data indicate that the SNP in the syntaxin 1A gene (D68D, T to C) correlates to the age of onset and insulin requirements of Type II diabetic Japanese patients.

The GNB3 825C/T polymorphism, which is common worldwide, is associated with enhanced G-protein activation. The frequency of 825-T allele was increased with body mass index (BMI) and finally had a high frequency in relatively mild obese (BMI >27 kg/m 2 ) subjects in some populations. In the present study, we investigated 208 severely obese [BMI ≥30 kg/m 2 (97th percentile)] Japanese subjects including 146 probands with diabetes. No increase in the 825-T allele frequency was observed in the 208 severely obese and even in a subgroup of the 55 most obese [BMI ≥35 kg/m 2 (99.7th percentile)] subjects compared with that in 150 controls (BMI 2 ) (0.48 and 0.48 vs 0.51, respectively). Also, the frequency was not increased in the 146 obese subjects with diabetes (0.48). We concluded that the 825-T allele is not associated with obesity or diabetes associated with obesity at least in the Japanese population.

Pro-opiomelanocortin (POMC)-derived peptides play a critical role in body weight regulation in the central nervous system. Mice deficient in POMC developed obesity. We sought mutations in the POMC gene in 50 morbidly obese (body mass index 35-60 kg/m(2)) Japanese subjects with diabetes by direct sequencing. Apart from two silent mutations (C6982T and C7285T), no other mutations were detected. Frequencies of these mutations were not significantly different between 100 obese subjects and 100 controls. Also, the frequencies did not differ in the subjects with or without diabetes. These results suggest that mutations in the POMC gene are unlikely to be a major factor of obesity or diabetes in Japanese subjects.

Human amylin, a major constituent of pancreatic amyloid deposits, may be a pathogenetic factor for noninsulin-dependent diabetes mellitus (NIDDM). We demonstrated that the human amylin S20G gene mutation (S20G) was associated with a history of early onset, more severe type of NIDDM, linking the amylin gene to this disease. Also, we demonstrated that expression of human wild-type (WT) amylin in COS-1 cells leads to intracellular amyloidogenesis and induction of apoptosis, suggesting a possible mechanism for disease induction. Therefore we compared the abilities of S20G and WT amylin to induce apoptosis in transfected COS-1 cells and form amyloid in vitro. We transfected the rat (RAT), mutated human (MUT), WT, and S20G amylin genes into COS-1 cells and measured apoptosis using fluorescent-activated cell sorting analysis at 48, 72, and 96 hours. At 96 hours apoptosis increased significantly (P < 0.01) in cells transfected with WT and S20G over RAT or MUT (WT, 19%; S20G, 25%; RAT, 13%; and MUT, 12%) and the difference between WT and S20G was significant (P < 0.05). Synthetic WT and S20G monomeric peptides were used to generate amyloid fibrils in vitro as measured by the thioflavin T binding assay. The S20G amylin formed approximately twofold more amyloid at a rate approximately threefold higher than WT. Electron micrography indicated that the in vitro amyloid generated by WT and S20G amylins were morphologically indistinguishable. The results suggest that increased cytotoxicity by S20G is because of increased amyloidogenicity, which may be a causative factor in the early development of NIDDM, possibly through loss of β cell mass.

Prohormone convertase 2 (PC2) is a member of a family of mammalian subtilisin-like endoproteases that are involved in the processing of prohormones, neuropeptides and many other precursor derived proteins. The expression of PC2 is restricted to neuroendocrine tissues such as pancreatic islets, the pituitary and the brain. To understand the regulation of the PC2 gene, we cloned and characterized the promoter region of the mouse PC2 gene. The transcriptional start site of the mouse PC2 gene is identical to that of the human. There is 79% identity in the sequences of the promoter regions between the mouse and human PC2 genes. The mouse PC2 gene, like the human, does not have a TATA-like motif in the region just upstream of the start of the transcription. Studies with promoter-reporter gene, chloramphenicol acetyltransferase (CAT), constructs showed that the region from -400 to -170 bp was necessary for high level expression of the mouse PC2 gene in the betaTC-3 insulinoma cells.

Islet amyloid polypeptide is a 37 amino acid hormone-like peptide which is the major protein component of islet amyloid deposits commonly found in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Recent studies indicate that a physiologically active form of this peptide appears to be carboxyamidated and secreted from the insulin-producing beta cell. In order to clarify the possible in vivo actions of islet amyloid polypeptide, we have studied the effects of synthesized islet amyloid polypeptide-amide on peripheral glucose utilization by performing hyperinsulinaemic euglycaemic glucose clamp studies on dogs. Exogenously administered islet amyloid polypeptide-amide (an infusion from 1.0 to 100 micrograms.kg-1.h-1, over 2 h) inhibited the insulin-stimulated glucose disposal rate in a dose dependent manner. Twenty-five micrograms.kg-1.h-1 of islet amyloid polypeptide-amide infused via a peripheral vein significantly lowered the glucose disposal rate by 20% (from 17.4 +/- 1.7 to 14.4 +/- 1.7 mg.kg-1.min-1, n = 5, p less than 0.01). These findings suggest that islet amyloid polypeptide-amide causes peripheral insulin resistance in vivo.

We report a 31-year-old woman who developed myopathy and neuropathy during pregnancy. She was diagnosed as having mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). A T-to-C transition mutation at nucleotide position 3271 was detected in the mitochondrial gene. Her symptoms subsided spontaneously and she delivered a male infant at 38 weeks of gestation. Prior reports on mitochondrial diseases with pregnancy are very rare, probably because of the early onset of the disease. The metabolic changes during pregnancy increase the stress on the mitochondrial function, particularly in patients with impaired mitochondrial function. Therefore pregnancy can aggravate mitochondrial diseases.

Malignant mesothelioma is a clinically aggressive tumor and has a poor prognosis; therefore, the selection of therapeutic strategies is important to improve the prognosis. Two patients with intraperitoneal malignant mesothelioma received combination therapy as follows: (1) case-oriented chemotherapy according to the results of a chemosensitivity test, and (2) adoptive immunotherapy using cytotoxic T lymphocytes (CTL). The chemosensitivity test was assessed by an MTT colorimetric assay. CTL was generated by a mixed culture with autologous tumor cells, and activated by immobilized anti-CD3 monoclonal antibody and interleukin-2. The MTT assay indicated that cisplatin and adriamycin were sensitive drugs in both patients, and they thus received the case-oriented chemotherapy according to the MTT assay. The activated CTL exhibited a high cytotoxicity against autologous malignant mesothelioma cells, and were transferred intraperitoneally. The patients were controllable for ascites, and the tumor masses gradually vanished (partial response). Chemoimmunotherapy is thus considered to be an effective treatment for intraperitoneal malignant mesothelioma, especially to improve the quality of life.

Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese.

The respective effects of 6 month's administration of beta-blockers (atenolol, metoprolol, carteolol and arotinolol), calcium-channel blockers (nicardipine, diltiazem) and angiotensin converting enzyme inhibitor (enalapril) on hemoglobin A1c (HbA1c) levels were evaluated in hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM), using a retrospective method. NIDDM patients with stable HbA1c and body weight were selected for this study. The following results were obtained. (1) The administration of nicardipine or beta-blockers significantly elevated HbA1c levels. (2) The administration of diltiazem or enalapril did not have any influence on HbA1c levels. These findings suggest that not only beta-blocker but nicardipine (dihydropyridine type calcium-channel blocker) may cause deterioration in glucose metabolism in NIDDM patients.

The recent development of molecular biology enables us to identify three abnormal insulins (insulin Chicago, insulin Los Angeles and insulin Wakayama). In Japan, three pedigrees in which affected individuals secrete [LeuA3] insulin (insulin Wakayama) have been identified. In each family, hyperinsulinemia associated with an abnormally elevated insulin to C-peptide molar ratio was demonstrated to occur in an autosomal dominant pattern of inheritance. In accordance with in vivo observations, semisynthetic [LeuA3] insulin demonstrated reduced in vitro receptor binding and biological activity relative to the human standard. The development of diabetes mellitus in affected family members was not uniform, was influenced by aging, and was different among families. Patients with impaired glucose tolerance demonstrated reduced insulin secretory reserve. Some of these features are thought to resemble the nature of non-insulin dependent diabetes mellitus (NIDDM). Therefore, insulin Wakayama may be a useful model for the study of the development of NIDDM.

Two restriction fragment length polymorphisms (RFLPs) near the human islet amyloid polypeptide (IAPP) gene were examined in 50 Japanese patients with non-insulin-independent diabetes mellitus (NIDDM) and 54 non-diabetic controls. RFLPs were identified with the enzymes Pvu II (A1 = 21 kb and A2 = 18kb) and Bgl II (B1 = 9kb and B2 = 7kb). These RFLPs were in complete linkage disequilibrium with A1 which was in disequilibrium with B2, as was A2 with B1. Since these two RFLPs map to different locations in the 5′-flanking region of the IAPP gene, they are most likely due to changes in the sequence of the sites recognized by Pvu II and Bgl II rather than to an insertion/deletion-type DNA polymorphism. There were no differences in the genotypic or allelic frequencies of these RFLPs between Japanese subjects with NIDDM and non-diabetic controls implying that these RFLPs do not play a major role in the development of NIDDM in this population.

Islet amyloid polypeptide (IAPP), a novel peptide isolated from islet amyloid deposits in patients with insulinoma and non-insulin-dependent diabetes mellitus (NIDDM), has been reported to be cosecreted with insulin from pancreatic beta cells and to inhibit glucose uptake and glycogen synthesis in muscle tissue in vitro. We investigated the effects of the synthesized, rat-amidated form of IAPP on hepatic glucose output, and IAPP extraction, using an in situ flow-through perfusion system in rats to elucidate the actions of IAPP on the liver. The IAPP (10(-8) mol/L) alone had no effects on the hepatic glucose release. Infusion of 6 x 10(-11) mol/L glucagon alone resulted in an expected elevation in glucose production (30.0 +/- 1.7 mumol/35 min/g liver). Insulin (3 x 10(-10) mol/L) submaximally decreased the glucagon-stimulated glucose production to 73% (from 30.0 +/- 1.7 to 22.0 +/- 1.4 mumol/35 min/g liver; n = 7, P less than .01). A simultaneous infusion of 10(-8) mol/L IAPP did not influence the glucagon-stimulated glucose production (27.6 +/- 1.2 mumol/35 min/g liver) or the insulin-dependent inhibition of glucagon-stimulated glucose production (22.6 +/- 1.3 mumol/35 min/g liver). IAPP extraction by the liver in a single passage was minimal, in contrast to approximately 50% hepatic insulin extraction. These results indicate that IAPP does not play any important role in modulating glycogen metabolism in the liver.

It has been reported that islet amyloid polypeptide (IAPP) has insulin antagonistic effects in vivo and in vitro. To determine whether IAPP affects glucose metabolism in skeletal muscle, we performed in situ rat hindlimb perfusion which is a near-physiological system. Forty min after the beginning of insulin infusion at 1000 microU/ml, the synthesized rat amide form of IAPP was infused at 1 nM or 10 nM for 50 min and glucose concentration in the effluent was measured to calculate glucose uptake (GU). The GU did not change during the 1 nM IAPP infusion, but significantly decreased during 10 nM IAPP infusion (554 +/- 24 to 445 +/- 29 nmol/g/min, P less than 0.01). Rat calcitonin gene-related peptide (CGRP), which has sequence homology with IAPP and has been reported to inhibit insulin action, was also administered. Similar to the effect of IAPP, the GU did not change during 1 nM CGRP infusion but significantly decreased during 10 nM CGRP infusion (507 +/- 7 to 323 +/- 15 nmol/g/min, P less than 0.01). In the experiments without insulin infusion, the GU was not changed even by 10 nM IAPP infusion. Therefore, IAPP directly reduced only the insulin-mediated GU in the skeletal muscle, and this effect of IAPP occurred at the same dose as that of CGRP. These data suggest that both IAPP and CGRP may cause insulin resistance in skeletal muscle not through a CGRP receptor but a yet unknown receptor, which has similar binding affinity for both IAPP and CGRP.

We investigated the relationship between non-insulin-dependent diabetes mellitus (NIDDM) and islet amyloid polypeptide (IAPP) gene by restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR)-direct sequencing analysis. Endonuclease BglII and/or PvuII RFLP analysis revealed no positive correlation of IAPP gene with NIDDM. In PCR-direct sequencing of 25 NIDDM patients, no nucleotide sequence differences were found. These data do not support the view that IAPP plays an important role in the pathogenesis of NIDDM. cDNAs encoding cat, rat, mouse, guinea pig and degu IAPP precursors were also cloned, and comparison of these predicted amino acid sequences clarified the species difference, especially between amyloid-forming and non-amyloid-forming species. Amino acid residues 25-28 of mature IAPP might be responsible for their amyloidogeneity. The alternative splicing transcripts of guinea pig IAPP gene were identified by using PCR. If these types of transcripts are translated, N-terminal mutated IAPP might be produced and act as an antagonist. The signal peptide cleavage site of rat IAPP precursor was also identified by an in vitro translation and processing system.

We developed a sandwich enzyme immunoassay for intact type IV collagen (IV-C) using two monoclonal antibodies as a marker of basement membrane metabolism, and examined the relationship between serum IV-C and diabetic complications. Serum IV-C was measured in 186 diabetics with or without clinical signs of retinopathy, neuropathy, and/or nephropathy, and 328 healthy subjects. Serum IV-C was significantly (P less than .01) higher in diabetics (mean +/- SE: 124.83 +/- 2.94 ng/ml) than in healthy subjects (73.32 +/- 1.42 ng/ml). In diabetics with microangiopathy, serum IV-C became higher as clinical signs worsened. Especially in diabetics with nephropathy, serum IV-C became higher with the elevation of blood urea nitrogen (BUN), serum creatinine, and beta 2-microglobulin. Serum IV-C level seems to be a useful marker for assessment of the activity or progression of diabetic microangiopathy, and for evaluation of therapeutic effects.

The DNA polymerase chain reaction can be a powerful tool for amplifying selected segments of genomie DNA for investigation of point mutations that are inaccessible via classic restriction-fragment–length polymorphism analysis. We have applied this method to an analysis of the incidence of heterozygosity for the mutant insulin allele insulin Wakayama (A3 Val→Leu) in two unrelated Japanese families having the hyperinsulinemic mutant insulin syndrome. The results indicate that this method is simple, sensitive, and accurate and should be useful for screening larger (diabetic) populations to detect single-base substitutions in the insulin gene that lead to either altered (pro)insulin structure and/or insulin production.

We describe a family from Japan displaying the mutant insulin syndrome with hyperinsulinaemia and an increased insulin: C-peptide molar ratio. Serum insulin isolated from several family members showed reduced in vitro biological activity, and analysis by high performance liquid chromatography revealed a peak co-eluting with human insulin and a second species of increased hydrophobicity co-migrating with the previously reported Insulin Wakayama. The insulin genes from the propositus were cloned and sequenced, revealing one normal allele; the second allele, encoding a leucine for valine amino acid substitution at position 3 of the insulin A chain, was similar to that previously described for Insulin Wakayama. Synthesized [LeuA3] insulin showed 0.14% of receptor binding activity on rat adipocytes and a 10-fold prolonged half-life in a somatostatin-infused dog compared with human insulin. The finding of the same mutant gene in two unrelated Japanese families suggests that Insulin Wakayama may be discovered in additional Japanese families with hyperinsulinaemia and/or diabetes.

我々は慢性腎不全透析症例におけるglycosylated hemoglobinをYueらの方法に準じたアフィニティークロマトグラフィー法 (AC法) とイオン交換樹脂を用いた高速液体クロマトグラフィー法 (HPLC法) により測定し比較検討した.慢性腎不全透析症例45名 (HD群糖尿病症例22名, 非糖尿病症例23名) と腎障害のない非透析症例43名 (Non-HD群: 糖尿病症例21名, 健常者22名) を対象に, PBA30樹脂を用いたAC法によるglycosylated hemogbbin値 (G・Hb値), HPLC法によるHbA1a+b, A1c, A1値, ならびに血糖値 (PG) を測定した.成績は以下の通りである. 1) HD群, Non-HD群においてG・Hb値とHbA1a+b, A1c, A1各値との間に各々有意の正の相関関係 (P

Studies on the reliability of the HbA1 assay in mass surveys for diabetes mellitus were carried out with special reference to the preservation and transportation of blood samples. It is essential to confirm that the preservation and transportation of samples have no effect on values for HbA1, since most of the mass surveys are carried out as field works. In our experience the levels of HbA1 remained unchanged for one week, both in samples kept at 4 degrees C, and in frozen samples kept at -40 degrees C or -80 degrees C and transported on solid CO2. The levels of HbA1 in the samples transported from Manila to Wakayama by the above-mentioned methods did not differ from those obtained in corresponding fresh samples. There was a good correlation between levels of HbA1 and levels of plasma glucose obtained 1 or 2 hr after breakfast (PPG). It was concluded that the use of both criteria (HbA1 of more than 8.00% and PPG of more than 120 mg/100 ml) in the diagnosis of diabetes mellitus is more reliable than use of either one alone.

糖尿病性腎症23名を含む慢性腎不全透析症例48例より透析前後に採血し, 血清 (S) および血漿 (P) フルクトサミン値 (Fr) を測定し以下の成績を得た. 1) 透析前後とも, S-Frに比しEDTA-2Na採血後測定されたP-Frは有意の低値を示したが, 両者の間に有意の正相関が認められた. 2) S-Fr, P-Frとも透析前後の値に差異は認められなかった. その一因に, 透析前に比し除水により高値となった透析後のFrが, 透析中に添加されたheparinの影響により, 測定法上, 低下をきたしたことが考えられる. また, 透析前のS-Frにおいて, 3) 糖尿病性腎症のS-Frは非糖尿病性腎不全症例に比し高値を示した. 4) S-Frは, 同時測定された血糖値よりも過去2週間の平均透析前血糖値 (PG) との方が相関性が強く, affinity chromatography法によるglycated albumin and Hb値やHbA1and HbA1c値とも有意の正相関を示した. しかし, 尿素窒素, 尿酸クレアチニン, アセト酢酸, 3ヒドロキシ酪酸などの各値とは相関性を示さなかった. 5) PGは, S-Fr/総蛋白のA/G ratio>S-Fr/アルブミン値>S-Fr>S-Fr/総蛋白値, の順に強い有意の正相関を示した. 従って, Frの測定は糖尿病を含む慢性腎不全透析症例における過去2週間の長期的な血糖コントロール状態の指標として有用であることが実証された. また, S-Frを総蛋白のA/G ratioにより除すことにより, S-Frのみ, またはアルブミン値により除すFr補正値に比し, PGとの相関がより一層強くなることが示唆された. さらに, 一回の血液透析過程がFrに及ぼす影響としては, 主として透析中に添加されるheparinが, 測定法上, 透析後のFrの低下をきたすことも分かった.

A 47-yr-old woman who had previously received methimazole (MMI) treatment for hyperthyroidism was found to have glucagon binding autoantibodies in plasma. She had never received glucagon. The binding substances were detected in plasma at the time of a glucagon RIA. [125I]Glucagon binding was inhibited only by porcine glucagon and porcine glicentin, and dissociated at acid pH. The substances proved to be glucagon binding antibodies (immunoglobulin G, L-chain K-type), as determined by ammonium sulfate and radioprecipitation. There were no clinical manifestations related the presence of these autoantibodies. In a survey of 91 patients with thyroid disease, 3 patients whose plasma bound [125I]glucagon were identified among 41 with hyperthyroidism who were receiving MMI treatment. Such binding was not found in plasma from untreated hyperthyroid patients, those receiving propylthiouracil or those with chronic thyroiditis. These findings suggest that the development of glucagon antibodies in hyperthyroidism may be associated with MMI treatment.

糖尿病性腎不全透析症例におけるglycosylated hemoglobinを, mini-column法, macro-column法, チオバルビツール酸法により検索し第1報において報告したが, 今回は非糖尿病性慢性腎不全透析症例のHbA1値についてイオン交換樹脂を用いた高速液体クロマトグラフィー (HPLC) 法により検討を加えた.非糖尿病性慢性腎不全透析症例 (HD群) 32名と健常者 (N群) 22名においてHPLC法によりHbA1a+b, HbA1c分画測定を行い, HbA1a+b/HbA1, HbA1c/HbA1各ratioを算出した. また, HD群において血糖 (PG), 尿素窒素 (BUN), クレアチニン (Cr), 尿酸 (UA) の各値を測定し, HbA1値と同時採血した各値, ならびに各々の過去1ヵ月間 (3-4回測定) の透析前後における測定平均値とHbA1a+bまたはHbA1c値との相関性を調べた.その結果, N群に比しHD群の方がHbA1a+b値, HbA1a+b/HbA1 ratioは有意の高値 (p

To evaluate the function of the central nervous system of patients with occupational vibration disease, electroencephalograms and auditory brainstem responses (ABR) were recorded in 20 male subjects with occupational vibration disease whose age ranged from 46 to 67 years (mean 57.4 yr). All the subjects had operated chain saws from 10 to 25 yr (mean 15.2 yr) and had frequently complained of many subjective symptoms induced by central nervous system disturbances such as headache, head heaviness, tinnitus, vertigo, and insomnia, which corresponded to stage 3 in the diagnostic criteria of Andreeva-Galanina. Twenty-six healthy men whose age ranged from 40 to 67 yr (mean 53.0 yr) were selected as controls. Electroencephalograms were recorded with a 12-channel electroencephalograph, using unipolar and bipolar leads. Auditory brainstem responses were recorded by signal averaging technique using 100 μs alternating clicks. The stimuli were presented at 70 dB above threshold (SL) with a rate of 10 per second. The following results were obtained.1. By electroencephalography, the incidence of diffuse alpha pattern, slow alpha wave and drowsy pattern was 32%, 32%, and 42%, respectively.2. Click thresholds in the patients were obviously higher than those in the healthy controls.3. The occurrence rate of wave II of ABR in the patients (61.8%) was significantly lower than that in the healthy controls (85.0%) (p

我々は糖尿病性細小血管障害の末期状態である糖尿病性腎不全症例においてHbA1値を測定し, Macro column法やチオバルビツール酸法による検索を加えることにより腎不全状態ならびに透析療法がHbA1に及ぼす影響について検討を行った. 対象は, I群, 慢性透析患者 (糖尿病性) 31名, II群, 糖尿病性腎不全患者 (非透析) 10名, III群, 腎障害のない糖尿病患者46名, IV群, 慢性透析患者 (非糖尿病性) 22名, V群, 正常者17名で, I, IV群では透析開始前 (すなわち朝食後2時間) と透析終了時に, II, III, V群では朝食後2時間に採血した.その結果, 以下のことが判明した. 1) 透析群 (I, IV群) の方が非透析群 (III, V群) に比し血糖値が同程度であるにもかかわらずHbA1は低値で, その傾向は糖尿病群でより一層著明であった. 2) 腎不全状態はHbA1値を低下させ, 長期透析患者のHbA1値はさらに低値であった. 3) 1回の透析過程はHbA1値やHbの溶出像に影響を及ぼさなかった. 4) HbA1c/HbA1a+b+cの比率は同程度のHbA1a+b+c値を示す非透析患者 (III, V群) に比し透析患者 (I, IV群) で低値を示した. 5) 糖尿病群においてHbA1 高値域 (すなわち血糖高値域) では透析群 (I群) の方が非透析群 (III群) に比し, そのglycosylationの度合が過大評価されている.

Very little information is available related to possible differences in immunological characteristics of IDDM among Asian populations, though it has been reported that IDDM is associated with Bw54-DR4 and B17-DR3 in Japanese and Chinese, respectively. There is virtually no report related to comparative studies on Bf-DM association among Asian populations, while Bf-DM association is reported to be stronger than HLA-DM association in Caucasians. In the present paper, the results of our studies on anti-thyroid antibodies (ATA) of IDDM in Japanese, Chinese and Filipinos are presented. In Japanese, the incidence of ATA positive was higher in IDDM with a duration of less than one year (35.7%) than that in the patients with a duration of one year or more (12.5%). But, there was no such a duration dependent decrease in the incidences of ATA among Chinese or Filipino IDDM. The frequency of BfSS in Filipinos is lower than in Japanese or Chinese. However, no association was found between Bf phenotypes and IDDM in Asian populations. These results indicate that autoimmunity is transient in Japanese IDDM, but persistent in Chinese and Filipinos, and that it is too early to postulate in general that Bf-IDDM association in general populations is stronger than HLA-IDDM association.

Summary We quantitatively assessed peripheral and autonomic nerve function in diabetic patients and compared them with various parameters of their diabetic status. Motor and sensory nerve conduction velocity (MCV, SCV), vibratory perception threshold (VPT) and the coefficient of variation of the ECG R-R interval (CV R-R) were measured in 85 diabetic patients aged 20–59 years. These values were compared with those of age-matched healthy subjects. Moreover, in 53 patients, MCV, SCV, VPT and CV R-R were investigated by multivariate analysis in relation to clinical parameters. In diabetics, MCV, SCV and CV R-R were significantly lower and VPT was higher than in age-matched healthy controls. The prevalence of impaired values in diabetics was 70% for VPT in the toe, 60% for SCV, and 55% for MCV, CV R-R and VPT in the finger. Impairments of MCV, SCV, CV R-R and VPT were closely correlated with diabetic retinopathy, proteinuria and duration of disease. Categorical regression analysis (multivariate analysis) revealed that the impairment of conduction velocity was closely related to diabetic retinopathy and to hypo- or areflexia, that the impairment of the vibratory perception threshold was related to ischemic changes in ECG and to hypo- or areflexia, and that the reduction of CV R-R was related to orthostatic hypotension and to proteinuria. These findings suggest that diabetic neuropathy progresses in parallel with other complications, and that it is a heterogeneous syndrome rather than a single entity.

The clinical usefulness of calcium antagonists was studied in four patients with reactive hypoglycemia including two with alimentary and two with idiopathic. All patients had hyperresponses of plasma insulin (IRI) and C-peptide (CPR) during an oral glucose tolerance test (OGTT). A calcium antagonist (diltiazem 90 mg/d, or nifedipine 30 mg/d, or nicardipine 60 mg/d) was administered orally for about two months. After two months of treatment, plasma IRI and CPR responses during the OGTT were clearly suppressed in all patients and symptomatic reactive hypoglycemia disappeared. One month after the discontinuation of the treatment in two patients, plasma IRI and CPR responses during the OGTT became higher again and symptomatic reactive hypoglycemia recurred. In addition, an intravenous glucose tolerance test was performed before and after two months of the treatment with calcium antagonists in the two patients with reactive hypoglycemia and seven patients with hypertension, who were free from glucose intolerance and were also treated with a calcium antagonist. In these patients, plasma IRI and CPR responses were also reduced after the treatment compared with those before the treatment. These results suggest that calcium antagonists are useful as therapeutic agents for the treatment of reactive hypoglycemia associated with hyperinsulinemia, and that one of the main mechanisms of action of calcium antagonists is a direct action on the pancreatic B-cell to inhibit glucose-induced insulin release.

The diet loading test (DLT), which measures the change in the blood sugar (BS) level after a loading diabetic diet (5 units = 400 kcal, including 50 g of carbohydrate), has been devised as a new diagnostic for diabetes. Twenty-seven and 253 patients classified as borderline type (G-B) and diabetic type (G-DM), respectively, from the results of 50 g-OGTT (GTT) were subjected to DLT to evaluate its clinical usefulness. Diagnostic criteria of DLT were established from the BS levels (mean +/- 2S.D.) in 46 normals as follows: normal type (D-N), lower than 100 mg/100 ml at baseline and than 120 mg/100 ml both 1 and 2 hr after loading; diabetic type (D-DM), higher than 120 mg/100 ml at both 1 and 2 hr; borderline type (D-B), neither of these patterns. According to these criteria, 253 patients of G-DM were divided into 249 D-DM and 4 D-B; 27 G-B were subclassified into 3 groups: 7 D-N (all of them were above 70 years old), 13 D-B and 7 D-DM (all of them were in a remission stage of diabetes). Furthermore, the results of DLT were more closely correlated with HbA1 levels, the daily profile of BS and the degree of retinopathy than those of GTT. The reproducibility of DLT was also better than that of GTT. In conclusion, DLT is a new system which makes it possible to differentiate physiological glucose intolerance in the aged and in patients in a remission state of diabetes from borderline cases diagnosed with GTT. Furthermore, it was proved that a better correlation existed between the state of BS control and the results of DLT than those of GTT. The usefulness of DLT in a population survey was also proved.