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Biomedical subjects

T Sanke

Publications and source records attributed to T Sanke.

At least 55 records · Page 3Linked to original sources
PubMed1994

Nicardipine may impair glucose metabolism in hypertensive diabetic patients.

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.

Adult↗
PubMed1994

Abnormal insulinemia.

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.

Adult↗
PubMed1994

[Review for clinical molecular genetics of mutant insulin].

Three types of structurally abnormal insulin "Insulin Chicago, Los Angeles and Wakayama" has been identified in 6 families by the recent development of molecular biology. It has been clarified that a point mutation in the coding region of each patient's insulin gene allele give rise to a substitution of one amino acid of each insulin, resulting in reduced biological activities of these insulins. These abnormal insulin have slow metabolic clearance rate which cause typical hyperinsulinemia accompanying normal level of plasma C-peptide. In this paper, we review insulin gene mutations and discuss its participation to the pathogenesis of NIDDM.

Diabetes Mellitus, Type 2↗
PubMed1994

[Glycogen synthase gene-glycogen synthase gene in Japanese patients with NIDDM].

As glycogen synthase is a key enzyme of the non-oxidative pathway of glucose metabolism in the skeletal muscle, and reduced activity of this enzyme is related to insulin resistance, it seems likely that this enzyme is a candidate gene for contributing to the pathogenesis of NIDDM. In this paper, we review recent findings of polymorphism of the human glycogen synthase gene, XbaI restriction enzyme length polymorphism and simple tandem repeat DNA polymorphism, and discuss the possible association between the glycogen synthase gene and NIDDM.

Asian People↗
PubMed1994

[Role of IAPP in the pathogenesis and development of NIDDM].

Islet amyloid deposits are the characteristic lesions of the pancreas of the patients with non-insulin-dependent diabetes mellitus (NIDDM). Islet amyloid polypeptide (IAPP or amylin) is a 37 amino acid peptide, which was extracted and characterized from islet amyloid deposits in patients with NIDDM. Recent studies and characterization of IAPP cDNA suggest that IAPP is a normal islet hormone and is co-secreted with insulin from islet beta cells of the pancreas. In this paper, we review recent advance of the research for IAPP including our results, and discuss the role of IAPP in the development of NIDDM, and we propose a new type of diabetes, "amyloid diabetes".

Amino Acid Sequence↗
PubMed1992

Lack of effect of islet amyloid polypeptide on hepatic glucose output in the in situ-perfused rat liver.

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.

Amyloid↗
PubMed1992

Restriction fragment length polymorphisms near the islet amyloid polypeptide gene in Japanese subjects.

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 PvuII (A1 = 21 kb and A2 = 18 kb) and BglII (B1 = 9 kb and B2 = 7 kb). 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 PvuII and BglII 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.

Adult↗
PubMed1992

Molecular biology of islet amyloid polypeptide.

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.

Amino Acid Sequence↗
PubMed1992

Islet amyloid polypeptide (IAPP/amylin) causes insulin resistance in perfused rat hindlimb muscle.

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.

Amyloid↗
PubMed1992

Islet amyloid polypeptide (IAPP) secretion from islet cells and its plasma concentration in patients with non-insulin-dependent diabetes mellitus.

Islet amyloid polypeptide (IAPP/Amylin) is a novel peptide which was extracted from islet amyloid deposits in patients with non-insulin-dependent diabetes mellitus (NIDDM). However, its pattern of secretions and plasma concentrations under various conditions has not yet been made clear enough. In this study, we examined IAPP secretion from islet beta-cells in vitro using cultured islet cells of neonatal rat pancreas and plasma IAPP responses under various conditions in vivo in normal control subjects and patients with glucose intolerance. Our data revealed that (1) IAPP is co-secreted with insulin from islet cells of the rat pancreas by glucose and non-glucose stimuli; (2) fasting plasma IAPP levels in normal control subjects are 24.9 +/- 2.0 pg/ml and the molar ratio of IAPP/insulin is approximately 1/7; (3) fasting IAPP levels are high in obese patients and low in insulin-dependent diabetic patients, and the molar ratio of IAPP/C-peptide in NIDDM patients is lower than that in normal control subjects, suggesting the basal hyposecretion of IAPP relative to insulin in NIDDM; and (4) the obese patients who had a hyperresponsiveness of insulin relative to C-peptide had the hyperresponsiveness of IAPP relative to C-peptide during an oral glucose load, suggesting that IAPP may have some physiological effect in glucose metabolism.

Adult↗
PubMed1991

Plasma islet amyloid polypeptide (Amylin) levels and their responses to oral glucose in type 2 (non-insulin-dependent) diabetic patients.

Fasting plasma islet amyloid polypeptide concentrations and their responses to an oral glucose load were determined in non-diabetic control subjects and patients with abnormal glucose tolerance in relation to the responses of insulin or C-peptide. Plasma islet amyloid polypeptide was measured by radioimmunoassay. In the non-diabetic control subjects, fasting plasma islet amyloid polypeptide was 6.4 +/- 0.5 fmol/ml (mean +/- SEM) and was about 1/7 less in molar basis than in insulin. The fasting islet amyloid polypeptide level rose in obese patients and fell in patients with Type 1 (insulin-dependent) diabetes mellitus. In non-obese patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetic patients without insulin therapy, the level was equal to that of the control subjects, but a low concentration of islet amyloid polypeptide relative to insulin or C-peptide was observed in the non-obese Type 2 diabetic group. The patterns of plasma islet amyloid polypeptide responses after oral glucose were similar to those of insulin or C-peptide. However, compared to non-obese patients, a hyper-response of islet amyloid polypeptide relative to C-peptide was noted in obese patients who had a hyper-response of insulin relative to C-peptide. This study suggests that basal hypo-secretion of islet amyloid polypeptide relative to insulin exists in non-obese Type 2 diabetes and that circulating islet amyloid polypeptide may act physiologically with insulin to modulate the glucose metabolism.

Adult↗
PubMed1991

[A case of so-called neoplastic angioendotheliosis with fever of unknown origin and temporary loss of consciousness].

A 65-year-old man was hospitalized with prolonged fever. The erythrocyte sedimentation rate was 62 mm/hour and the c-reactive protein was 5+. Serum lactic dehydrogenase was 1005 IU with elevation of isozyme types II and III. A computerized tomography scan of the abdomen showed large, bilateral adrenal masses. An aspirated specimen of the bone marrow revealed some clustered atypical cells. These findings suggested the patient had metastatic carcinoma, but the primary lesion could not be found. The patient had an episode of transient unconsciousness in mid course and died of bleeding from the gastrointestinal tract. A postmortem examination was performed. Microscopic examination showed an accumulation of neoplastic cells in the vascular system throughout the body and their extravascular proliferation in several organs. Immunohistochemical studies were performed on paraffin-embedded fixed tissues. The neoplastic cells were positive with the monoclonal antibodies LCA, LN 1, LN 2 and N 26 but did not show positive staining for factor VIII-related antigen, a marker for endothelial cells. These studies defined the neoplastic cells as being of a germinal-center B lymphocyte origin. On the basis of the above-mentioned results, we suggest that this case may be diagnosed as angiotrophic lymphoma.

Aged↗
PubMed1990

Islet amyloid polypeptide amide causes peripheral insulin resistance in vivo in dogs.

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.

Amyloid↗
PubMed1990

Lessons learned from molecular biology of insulin-gene mutations.

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate beta-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibits markedly altered subcellular sorting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Human islet amyloid polypeptide gene: complete nucleotide sequence, chromosomal localization, and evolutionary history.

The gene-encoding human islet amyloid polypeptide (hIAPP), a recently discovered 37 amino acid hormone-like polypeptide which is expressed in the insulin-producing beta-cells of the endocrine pancreas, has been isolated and characterized. The coding region of the gene is interrupted in the 5'-untranslated region and NH2-terminal propeptide by introns of 330 and 4808 base pairs (bp), respectively. Exon 1 (104 bp) encodes most of the 5'-untranslated region of the mRNA; exon 2 (95 bp) encodes 15 nucleotides of 5'-untranslated region, the putative 22 amino acid signal peptide and five residues of the NH2-terminal propeptide; exon 3 (1246 bp) encodes the remainder of the NH2-terminal propeptide (residues 6-9), the IAPP moiety and its processing signals and the 16 amino acid COOH-terminal propeptide, as well as the 3'-untranslated region of the mRNA (1059 bp). Analysis of the nucleotide and predicted amino acid sequence of intron 2 of the hIAPP gene did not reveal any homology with the structurally related calcitonin/calcitonin-gene-related peptide genes and indicated that, in contrast to these latter genes, the hIAPP gene apparently gives rise to only a single hormonal product. The transcriptional initiation site was identified about 28 bp downstream from a TATAA sequence. The hIAPP gene was localized to the p12.3 region of chromosome 12.

Amino Acid Sequence↗
PubMed1988

An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing.

Amyloid deposits occurring in the islets of Langerhans in patients with noninsulin-dependent diabetes mellitus and some insulinomas contain a 37-amino acid peptide that is structurally related to calcitonin gene-related peptide. We have identified three cDNA clones encoding islet amyloid polypeptide (IAPP) or diabetes-associated peptide (DAP) by oligonucleotide screening of a lambda gt10 human insulinoma cDNA library. Two of the three cDNAs contained a domain encoding IAPP/DAP but had an intron-like sequence in their 5' region. The other cDNA contained an open reading frame encoding an 89-amino acid precursor having a typical signal peptide followed by a small prohormone-like sequence containing within it the IAPP/DAP peptide bracketed at its NH2 and COOH termini by Lys-Arg and Gly-Lys-Arg, respectively. These data indicate that this amyloid peptide is generated by proteolytic processing similar to that for proinsulin and other islet prohormones and also that the peptide may be carboxyamidated. The isolation of cDNA clones having 5'-unprocessed intron-like sequences suggests that inefficient or alternative splicing of this mRNA occurred in the insulinoma.

Amino Acid Sequence↗