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Biomedical subjects

K Nanjo

Publications and source records attributed to K Nanjo.

At least 19 recordsLinked to original sources
PubMed2001

Analysis of 825C/T polymorphism of G proteinbeta3 subunit in obese/diabetic Japanese.

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 >or=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 >or=35 kg/m(2) (99.7th percentile)] subjects compared with that in 150 controls (BMI <25 kg/m(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.

Body Mass Index↗
PubMed2001

A suspected case of proximal diabetic neuropathy predominantly presenting with scapulohumeral muscle weakness and deep aching pain.

A 48-year-old man with a 14-year history of type 2 diabetes with proliferative diabetic retinopathy and distal symmetrical diabetic polyneuropathy visited our hospital. Eight months later, he subacutely developed difficulty in both shoulder movement and trouble standing up from a squatting position. This was accompanied by severe bilateral shoulder and thigh pain. Magnetic resonance imaging of the brain, cervical and lumbar spine, computed tomography of the shoulder and X-ray films of the cervical spine and shoulder revealed no abnormality. Cerebrospinal fluid showed a mild elevation of protein (0.93 g/l) without cell infiltration. Antiganglioside antibodies and point mutation of mitochondrial DNA at position 3243 were not found. Neuropathology of the sural nerve showed a moderate myelinated fiber loss, active axonal degeneration, but onion-bulb formation, endoneurial or epineurial vasculitis were not observed. Electromyography revealed neurogenic changes in the proximal upper limb muscles. Nerve conduction studies revealed mild bilateral slowing in nerve conduction velocity in both of the upper and lower limbs. The diagnosis of this patients was suspected to be a proximal diabetic neuropathy (diabetic amyotrophy). The pain and muscle weakness had persisted more severely in the shoulder than in the thigh throughout the clinical course. His unbearable symptoms could be partially alleviated by an administration of a selective serotonin reuptake inhibitor, fluvoxamine maleate. Proximal diabetic neuropathy is a rare disabling type of neuropathy, which is characterized with subacute bilateral muscle weakness and wasting in the proximal part of the lower limbs. The involvement of the scapulohumeral region observed in this case is very unusual in proximal diabetic neuropathy.

Anorexia↗
PubMed2001

The renal metabolism of insulin: urinary insulin excretion in patients with mutant insulin syndrome (insulin Wakayama).

Many studies have shown that the kidney plays an important role in the metabolism of many proteins and small peptides. To understand insulin handling in the kidney, we examined urinary insulin excretion under several conditions in patients with mutant insulin syndrome (MIS; insulin Wakayama). Urinary excretion of insulin was studied using high-performance liquid chromatography analysis in patients with MIS. In these patients, most of the insulin extracted from a 24-hour urine collection and from urine collected after stimulation of insulin secretion by glucose or glucagon was normal insulin, whereas 90% of serum insulin is structurally abnormal (Leu-A3 insulin). On the other hand, arginine, which is known as an inhibitor of renal tubular reabsorption, increased urinary excretion of Leu-A3 insulin. The ratio of Leu-A3 and normal insulin in urine after arginine was similar to that in serum. A large amount of Leu-A3 insulin is excreted in urine when reabsorption of insulin at renal tubules is inhibited by arginine. These data indicate that normal and Leu-A3 insulin are filtered through the glomerulus with relatively little restriction. Using the fact that basal urine has a high concentration of normal insulin and an extremely low concentration of Leu-A3 insulin, which has less receptor-binding affinity, we speculated some possibilities. One possibility is that both forms of insulin are reabsorbed by the tubular cells, but with different efficiencies. Leu-A3 insulin absorption in more complete, and this suggests differences in the uptake pathways that may account for the differences in response to arginine infusions. Another possibility is that only normal insulin is secreted from tubules into urine which is mediated by receptors. Our results provide new insight into renal metabolism of insulin and showed that MIS is a useful model for studying it.

Adult↗
PubMed2001

The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes.

The allele frequencies for a Pro12-->Ala substitution in peroxisome proliferator-activated receptor-gamma differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes (n = 2,201) and normal control subjects (n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol (P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment (P = 0.007), and tended to possess a higher level of HbA1c. These data suggest that the Ala12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes.

Adult↗
PubMed2000

A polymorphic marker in the leptin gene associated with Japanese morbid obesity.

The prevaleance of morbid obesity (body mass index of 35.0 or greater) is low in Japan (0.2-0.3%), and little systematic investigation of its cause in this population has been carried out. Leptin plays a central role in regulation of body weight; mice deficient in leptin develop marked obesity. We sought mutations in the leptin gene in 53 morbidly obese Japanese (maximum body mass index 35-60) including 46 with type 2 diabetes. Direct DNA sequencing was performed following polymerase chain reaction amplification. Apart from a silent mutation at codon 25 (CAA/CAG, glutamine) detected in eight subjects, no mutations were detected. We found a significantly higher prevalence of the variant leptin 25CAG allele among the 53 obese subjects (0.085) studied than in 132 nonobese control subjects (0.011, P<0.001). In Japanese populations mutations in the protein coding sequence of the leptin gene are unlikely to be a major cause of morbid obesity. However, the leptin 25CAG allele may be linked to morbid obesity in this population. Specifically, genetic variation located near the leptin gene may be involved in pathogenesis. The leptin polymorphism 25CAG appears to be a new genetic marker for obesity susceptibility, at least in Japanese.

Body Mass Index↗
PubMed2000

S20G mutant amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild-type amylin.

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 ss cell mass.

Amyloid↗
PubMed2000

Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history.

Islet-1 (Isl-1) is one of the transcription factors that play an important role for the formation of the islet cells. We scanned the Isl-1 gene in 77 Japanese type 2 diabetic patients with a family history and found a heterozygous nonsense mutation (Q310X) in 1 diabetic patient. The mutation was not found in 180 nondiabetic subjects. This mutation is located in the putative transactivation domain and deletes 40 amino acids of the COOH-terminal lesion. The Q310X mutant exhibited a 50% reduction in activity compared with the wild-type when tested for stimulation of transcription of a human amylin promoter-linked luciferase reporter gene in betaTC3 cells. The patient was a 49-year-old nonobese man who was diagnosed as having type 2 diabetes at 32 years of age and has been treated with sulfonylureas. The mutation was found in his mother, who has type 2 diabetes, and in his 14-year-old daughter, who has normal glucose tolerance but a relatively low insulin response. This is the first reported finding of Isl-1 gene mutation in type 2 diabetes. Although Isl-1 is not a common predisposing gene for Japanese type 2 diabetes, the mutation in this gene may be a rare cause of diabetes in isolated families.

Adolescent↗
PubMed1999

Molecular scanning for mutations in the melanocortin-4 receptor gene in obese/diabetic Japanese.

Decreased function of the melanocortin-4 receptor (MC4R) was reported to cause late-onset obesity and insulin resistance in rodents. Thus mutations in the MC4R gene drew strong attention as a possible cause of obesity and diabetes. We screened for mutations in the MC4R gene in extremely obese [body mass index (BMI) > or = 35 kg/m2] Japanese with diabetes by direct sequencing. A heterozygous mutation (V103I) was detected in one case (2.0 %), however the frequency was not significantly different from that in non-obese (BMI < or = 24 kg/m2) and non-diabetic subjects (2.7 %). No other mutations were detected. These results suggest that mutations including V103I in the MC4R gene are not a major cause of obesity or diabetes in Japanese.

Animals↗
PubMed1999

[NIDDM susceptibility genes].

Non-insulin dependent diabetes mellitus (NIDDM) is a heterogeneous disorder and both genetic and nongenetic factors are associated with the development of diabetes. Until now five genes (HNF-4 alpha, glucokinase, HNF-1 alpha, IPF-1 and HNF-1 beta), whose mutation can result in MODY, insulin and insulin receptor genes, and mitochondria DNA have been reported to be responsible for diabetes. Furthermore the mutations in some genes which work for insulin secretion or action also have been reported. This review discusses our current knowledge of these NIDDM susceptibility genes.

Diabetes Mellitus, Type 2↗
PubMed1999

[Complications of extraintestinal endocrine disease associated with ulcerative colitis--association of ulcerative colitis and autoimmune thyroid disease].

We experienced a rare case of Basedow's disease followed by ulcerative colitis (UC). The association of UC and autoimmune thyroid disease was reviewed and discussed. A high frequency of endocrine autoimmunity, especially autoimmune thyroid disease, was reported in patients with UC. But prevalence of autoimmune thyroid disease associated with UC varies widely in different studies. Some authors described that it was impossible to say that the observed numbers of UC associated with thyroid disease exceed to those to be expected in a random sample of the general populations. The hypothesis that autoimmunity is important in the pathogenesis of UC and thyroid disease continues to stimulate interest. But the evidence for autoimmunity acting in these diseases is not quite as convinced. Further investigation is warranted to clarify the exact relationships between UC and thyroid disease.

Adult↗
PubMed1998

Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity.

Insulin is synthesized in the pancreatic beta cell as a larger precursor molecule proinsulin which is converted to insulin and C-peptide by the concerted action of prohormone convertase 2 (PC2), prohormone convertase 3 (PC3) and carboxypeptidase E (CPE). One of the features of non-insulin-dependent diabetes mellitus (NIDDM) is an elevation in the proinsulin level and/or proinsulin/insulin molar ratio suggesting that mutations in these three proinsulin processing enzymes might contribute to the development of NIDDM. The identification of a mutation in the CPE gene of the fat/fat mouse which leads to marked hyperproinsulinaemia and late-onset obesity and diabetes is consistent with a possible role for mutations in CPE in the development of diabetes and obesity in humans. In order to test this hypothesis, we have isolated and characterized the human CPE gene and screened it for mutations in a group of Japanese subjects with NIDDM and obesity. The human CPE gene consists of 9 exons spanning more than 60 kb. Primer extension analysis identified the transcriptional start site at -141 bp from the translational start site. Single strand conformational polymorphism analysis and nucleotide sequencing of the promoter and entire coding region of the CPE gene in 269 Japanese subjects with NIDDM, 28 nondiabetic obese subjects and 104 nonobese and nondiabetic controls revealed three nucleotide changes, a G-to-T substitution at nucleotide -53, a G-to-A substitution at nucleotide -144 (relative to start of transcription) in the promoter region and a silent G-to-A substitution in codon 219. None of the nucleotide substitutions were associated with NIDDM or obesity. Thus, genetic variation in the CPE gene does not appear to play a major role in the pathogenesis of NIDDM or obesity in Japanese subjects.

Base Sequence↗
PubMed1998

Successful immunochemotherapy for patients with malignant mesothelioma: report of two cases.

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.

Adult↗
PubMed1998

A case of Albright's hereditary osteodystrophy-like syndrome complicated by several endocrinopathies: normal Gs alpha gene and chromosome 2q37.

We report a sporadic case of Albright's hereditary osteodystrophy (AHO)-like syndrome with several endocrinopathies. A 37-yr-old woman had an appearance of AHO but did not have renal PTH resistance. Her case was complicated by non-insulin-dependent diabetes mellitus with severe insulin resistance, central diabetes insipidus, and hyposecretion of GH. Most patients with AHO are found in a family of pseudohypoparathyroidism type-Ia and have a heterozygous mutation that inactivates the alpha-subunit of Gs (Gs alpha), the stimulatory regulator of adenylyl cyclase. Some sporadic cases occur in which patients with phenotype similar to AHO have a deletion of chromosome 2q37. However, in this patient, both the Gs alpha gene structure and the biological activity were normal. In addition, chromosome analysis revealed a normal pattern with no visible deletion of chromosome 2q37. Our findings suggest that one or more other factors may be involved in the pathogenesis of AHO-related disease.

Adult↗
PubMed1998

Characterization of the promoter of the mouse prohormone convertase PC2 gene.

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.

Animals↗