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K C Chiu

Publications and source records attributed to K C Chiu.

At least 37 records · Page 2Linked to original sources
PubMed1997

The insertion allele at the angiotensin I-converting enzyme gene locus is associated with insulin resistance.

Plasma angiotensin I-converting enzyme (ACE) levels are genetically predetermined and are correlated with a deletion (D) insertion (I) polymorphism at the ACE gene locus. A subset of diabetic patients are noted to have elevated ACE levels. Treatment with ACE inhibitors has been shown to improve insulin sensitivity in both diabetic and nondiabetic subjects. We examined the relationship of D/I polymorphism and insulin sensitivity in 24 glucose-tolerant subjects by an oral glucose tolerance test (OGTT) and glucose clamps. Subjects with the I allele had higher insulin levels at 90 minutes (515 +/- 69 v 250 +/- 43 pmol/L, P = .008) and higher insulin area under the curve (56,200 +/- 8,148 v 33,300 +/- 8,114, P = .022) after glucose challenge compared with subjects without the I allele. During the euglycemic clamp, subjects with the I allele require less glucose infusion to maintain euglycemia than subjects without the I allele (5.343 +/- 0.743 v 8.944 +/- 1.272 mg/kg/min, P = .020). We conclude that the I allele is associated with insulin resistance in glucose-tolerant and normotensive African-Americans.

Alleles↗
PubMed1997

Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients with hypertension, non-insulin-dependent diabetes mellitus, and coronary heart disease in Taiwan.

An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been identified that determines most of the plasma ACE activity genetically. Association of the D allele with insulin sensitivity and of the D/D genotype with coronary heart disease (CHD) has been reported in various ethnic populations. To study the role of this genetic polymorphism in patients with hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and NIDDM with CHD in a Taiwanese population, we used a polymerase chain reaction (PCR)-based genotyping technique with an insertion-specific primer for confirmation of the I allele. One hundred ninety-seven unrelated normal controls, 67 subjects with hypertension, 107 subjects with NIDDM, and 70 subjects with NIDDM and CHD were recruited for this study; all were Han Chinese. Subjects without a history of diabetes were studied by a standard 75-g oral glucose tolerance test. Hypertension was diagnosed according to the Fifth Joint National Committee criteria, and CHD was confirmed by a history of acute myocardial infarction and coronary angiographic intervention. The frequency of the I allele of the ACE gene in the normal population was 64.2%, which was higher than reported in white populations. The prevalence of the I allele of the ACE gene was not significantly increased in subjects with hypertension (73.1%), NIDDM (62.1%), and NIDDM with CHD (65%) compared with healthy controls. The I allele of the ACE gene did not correlate with demographic and metabolic variables. I/D polymorphism of the ACE gene is not a marker for hypertension, NIDDM, or CHD in this Taiwanese population.

Age of Onset↗
PubMed1997

Effects of the insect growth regulator (S)-methoprene on survival and reproduction of the freshwater cladoceran Moina macrocopa.

This study examines the acute and chronic effects of the insecticide (S)-methoprene on the survival and reproduction of the freshwater cladoceran Moina macrocopa. In laboratory toxicity tests, the 24- and 48-h LC50 values for (S)-methoprene were 0.51 and 0.34 mg litre(-1), respectively. Survival, longevity and fecundity were reduced at 0.05 mg litre(-1) and higher concentrations. At 0.005 and 0.01 mg litre(-1), longevity and fecundity increased slightly as compared to control animals. If environmental concentrations of methoprene do not exceed 0.05 mg litre(-1), as is generally the case, application of this insecticide is unlikely to induce detrimental effects on natural cladoceran populations. The stimulatory effect of very low levels of methoprene on reproductive performance is consistent with the hypothesis of a regulatory role of juvenile hormone-like compounds in crustacean reproduction.

Journal Article↗
PubMed1997

Nucleotide(-258) G-to-A transition variant of the liver glucokinase gene is associated with essential hypertension.

Hypertension is a complex disease with strong genetic influences. Essential hypertension has been shown to be associated with insulin resistance. A molecular variant with G-to-A transition at the nucleotide -258 of the liver glucokinase (GCK) promoter was found in diabetic patients. The variant A allele is associated with insulin resistance. We examine the role of this genetic variant in the pathogenesis of hypertension using a population association study. We recruited 205 Taiwanese subjects and they were divided into two groups based on either presence (65 subjects) or absence (140 subjects) of essential hypertension. Genomic DNA was extracted from peripheral leukocytes. Genotypes at this locus were determined by using a polymerase chain reaction restriction fragment length polymorphism. The distribution of genotypic frequency was different between the hypertensive and control groups (P = .009). The frequency of variant A allele was greater in hypertensive subjects than in control (23% v 10%, P = .001). Subjects with at least an A allele had a risk for hypertension by 2.52 times (95% confidence interval 1.29 to 4.91) as compared with those without an A allele. Thus, we first demonstrate the association between the G-to-A variants at the nucleotide -258 of the liver GCK gene and essential hypertension. This may explain the insulin resistance in essential hypertension and the variant A allele as a risk factor for essential hypertension in the Taiwanese population.

Alleles↗
PubMed1997

Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs.

As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.

Age Factors↗
PubMed1996

Promoter variation in the liver glucokinase is a risk factor for non-insulin-dependent diabetes mellitus.

We have previously reported a common variation in the liver promoter of the human glucokinase, which is regulated by insulin, in the patients with non-insulin-dependent diabetes mellitus (NIDDM). The variation occurred within a 10-bp region completely conserved between human and rat. Its basic motif was almost identical to the insulin regulatory element of the phosphoenolpyruvate carboxykinase gene. In vitro transfection experiment showed that the G-to-A variation causes a 58% reduction in the promoter activity. After oral glucose challenge, the homozygous A/A subjects had the highest stimulated insulin levels at 60 and 90 minutes and the highest insulin area under the curve as compared to the subjects with other genotypes, which suggested the homozygous A/A subjects were more insulin resistant. As insulin resistance is a risk factor of NIDDM, we concluded that this promoter variation is a risk factor for NIDDM.

Adult↗
PubMed1996

Identification of trinucleotide repeat-containing genes in human pancreatic islets.

In the search for diabetes genes, the combined approaches of positional cloning with random markers and subsequent evaluation of candidate genes mapping to areas of interest will be increasingly used. For islet candidate genes of unknown function, expressed trinucleotide (triplet) repeats represent a unique subset. It is unlikely that abnormal expansion of expressed islet triplet repeats would be a major cause of diabetes, yet the triplet repeats are frequently polymorphic and can thus be used to map the genes in the human genome. In this study, a human islet cDNA library was screened with (CGG)7 and (CAG)7, and 23 triplet repeats were isolated. Sequencing revealed four known and six novel islet genes containing 4-15 triplet repeats. The four known cDNAs included ferritin, the major iron-binding protein in cells; HSGSA2R, a full-length clone of the alpha-subunit of the G-regulatory protein; HUMSATB1A, a DNA-binding protein expressed predominantly in thymus; and HUMPPA-PRO, a ribosomal protein. The triplet repeats in ferritin and HUMPPAPRO were found to be monomorphic. Characterization of the six unique novel expressed islet triplet cDNAs revealed that they were 0.6-1.5 kb in size, contained 4-15 triplet repeats, and were expressed in islets and all other tissues examined. Four of the novel clones, CGG-isl 10, CGG-isl 11, CAG-isl 6, and CAG-isl 7, were mapped to human chromosomes 19, 16, 12, and 3, respectively, via somatic cell hybrids. One islet cDNA, CAG-isl 7, contained a repeat that was highly polymorphic, with 14 alleles (4-18 triplets) in African-Americans (heterozygosity = 0.86) and 6 alleles (heterozygosity = 0.77) in whites. Northern analysis indicated that the mRNA was abundant in pancreatic islets. A putative full-length clone contained an open reading frame encoding 213 amino acids with a variable number of alanines (4-18) within the COOH-terminal. The gene was uniquely mapped with odds > 1,000:1 on chromosome 3p in Centre d'Etude du Polymorphisme Humain pedigrees. There were no differences in CAG-isl 7 allele frequencies between African-American patients with NIDDM (n = 108) and control subjects (n = 116), nor was expansion above 18 repeats noted. Linkage analysis in 14 nonglucokinase maturity-onset diabetes of the young pedigrees showed a cumulative logarithm of odds score of -33.19 at theta = 0.00. Abnormal expansion was not observed in 20 IDDM patients with one NIDDM parent. While these data suggest no major role for CAG-isl 7 in diabetes, at least four of the six novel islet triplet genes are coexpressed in pancreatic islets and neural tissue, and these genes can now be considered as candidates for diabetes and/or neuropsychiatric diseases.

Amino Acid Sequence↗
PubMed1996

The GENNID Study. A resource for mapping the genes that cause NIDDM.

OBJECTIVE: To develop a resource, consisting of comprehensive data and lymphoblastoid cell lines, of well-characterized NIDDM families that will be available to the scientific community for genetic studies of NIDDM. RESEARCH DESIGN AND METHODS: Non-Hispanic white, Hispanic, African-American, and Japanese-American multiplex NIDDM families, with a minimum of one affected sib-pair, are being collected by the eight Harold Rifkin Family Acquisition Centers. Detailed family and medical histories are obtained from all participants. Family members with diabetes have fasting blood samples drawn, while nondiabetic family members have an oral glucose tolerance test and, when possible, insulin sensitivity and insulin secretion measurements by frequently sampled intravenous glucose tolerance testing or euglycemic insulin clamp. Lymphoblastoid cell lines are established for all participants. RESULTS: Over 1,400 individuals from approximately 220 families have been studied since the start of the GENNID (Genetics of NIDDM) program in July 1993. The goal is that by July 1997, data from 300 non-Hispanic white families, > 100 Hispanic families, > 100 African-American families, and 15 Japanese-American families will have been collected. CONCLUSIONS: The identification of the genes responsible for NIDDM may now be achievable, but only if sound phenotypic data are linked to genetic material from a large number of well-described multiplex families. The GENNID project of the American Diabetes Association is creating a comprehensive resource that will expedite the identification of the genetic basis of NIDDM.

Black or African American↗
PubMed1995

CA-repeated microsatellite polymorphism of the glucokinase gene and its association with non-insulin-dependent diabetes mellitus in Taiwanese.

Mutation of the glucokinase gene has recently been identified as a cause of maturity-onset diabetes of the young (MODY), a subset of non-insulin-dependent diabetes mellitus (NIDDM). However, its role in the wide variety of NIDDM remains controversial due to conflicting reports of association studies, negative results of linkage studies and low prevalence of glucokinase mutations in the common variety of NIDDM. In this study, two (CA)n-microsatellite polymorphisms flanking both ends of the glucokinase gene, termed GCK1 and GCK2, were used to evaluate the role of glucokinase on NIDDM susceptibility of Taiwanese. For GCK1, three alleles (Z,Z+2 and Z+4 with a polymorphic information content index (PIC) of 0.53) and six genotypes were evident in 119 Taiwanese. When compared with control subjects, the NIDDM group had a much less frequency of the Z+2 allele (14.0% vs. 23.9%). In addition, the Z+2 allele was noted to have a marginal protective effect for NIDDM in Taiwanese with the odds ratio of 0.52 (95% confidence interval (C.I.) 0.26-1.03, P = 0.058). For GCK2, four alleles (0, 2, 4 and 6 with a PIC of 0.48) and seven genotypes were identified. There was no significant difference in allele frequency between NIDDM and control groups in the locus of GCK2. Our data were in agreement with reports from American Blacks, Mauritian Creoles, Asian Indians, Japanese and Finnish--that there is a positive association of GCK1 and a negative association of GCK2 with NIDDM. Furthermore, the Z+2 allele was a protective factor for NIDDM in Taiwanese.

Alleles↗
PubMed1995

Recombinant mapping of the familial hyperinsulinism gene to an 0.8 cM region on chromosome 11p15.1 and demonstration of a founder effect in Ashkenazi Jews.

A gene for autosomal recessive familial hyperinsulinism (HI) (OMIM: 256450), a neonatal metabolic disease characterized by inappropriate insulin secretion in the presence of severe hypoglycemia, was recently mapped to a 6.6 cM interval between the markers D11S926 and D11S928 on chromosome 11p in 15 families (1). In the current study we evaluated six additional families and five new markers, and further localized the gene between D11S419 and D11S1310. Using genotype data from CEPH Version 7 and data generated from this study, this region was estimated to be 0.8 cM in length. Significant linkage disequilibrium between markers and the HI gene was observed over a region of 10.3 cM (11 pter-D11S926-D11S1308-11pcen) for Ashkenazi Jewish chromosomes. Haplotype analysis showed that 12 of 36 HI chromosomes, versus one of 36 non-HI chromosomes, bore a specific haplotype for D11S419-D11S902-D11S921 (p < 0.0007), strongly suggesting a founder effect in this ethnic group.

Alleles↗
PubMed1995

Mitochondrial gene mutations in familial non-insulin-dependent diabetes mellitus in Taiwan.

Mitochondrial gene mutations are found to cause certain forms of diabetes mellitus and related syndromes. To study the prevalence of mitochondrial gene mutations in subjects with non-insulin-dependent diabetes mellitus (NIDDM) in Taiwan, 23 pedigrees with multiple siblings affected with NIDDM were consecutively collected from patients living in northern Taiwan. The A-to-G mutation at position 3243 np in the tRNA Leu gene and the mutation at position 8344 were screened by PCR-RFLP methods and confirmed by direct DNA sequence analysis. Among 23 NIDDM pedigrees, one pedigree was found to carry the 3243 np mutation. There was no 8344 np mutation in this series. Clinical features of this pedigree were consistent with mitochondrial disease in terms of maternal transmission, relatively early onset, non-obesity, insulin-requirement and association with hearing impairment. There was no correlation between the degree of heteroplasmy of mitochondrial gene mutation in leukocyte DNA and clinical severity. We conclude that a mitochondrial gene defect is an important genetic factor in familial cases with NIDDM in Taiwan.

Adult↗
PubMed1995

Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM.

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A mutation in the Glut2 glucose transporter gene of a diabetic patient abolishes transport activity.

Glut2, the facilitative glucose transporter isoform expressed in pancreatic beta cells, is believed to play a role in glucose-stimulated insulin secretion. Two polymorphisms that result in amino acid substitutions have been reported in the human Glut2 gene (Tanizawa, Y., Riggs, A. C., Chiu, K. C., Janssen, R. C., Bell, D. S. H., Go, R. P. C., Roseman, J. M., Acton, R. T., and Permutt, M. A. (1994) Diabetologia 37, 420-427). A threonine 110-->isoleucine substitution was present at equal frequency in diabetic and control populations, and a valine 197-->isoleucine substitution was discovered in a single allele of a patient with non-insulin-dependent diabetes. The effect of these amino acid changes on glucose transport activity was tested by expression of the mutant proteins in Xenopus oocytes. The polymorphism at threonine 110 had no effect on the expression of Glut2 protein or the uptake of 2-deoxyglucose. Remarkably, however, the highly conservative valine 197-->isoleucine amino acid change abolished transport activity of the Glut2 transporter expressed in Xenopus oocytes. This represents the first known dysfunctional mutation in a human facilitative glucose transporter protein. The presence of this mutation in a diabetic patient suggests that defects in Glut2 expression may be causally involved in the pathogenesis of non-insulin-dependent diabetes.

Animals↗
PubMed1994

Variability of the pancreatic islet beta cell/liver (GLUT 2) glucose transporter gene in NIDDM patients.

The purpose of these experiments was to test the hypothesis that impaired glucose-stimulated insulin secretion in NIDDM is due to mutations in the islet beta cell/liver glucose transporter (GLUT 2) gene. Using oligonucleotide primers flanking each of the 11 exons, the structural portion of the gene was studied by PCR-SSCP analysis. DNA from African-American females (n = 48), who had gestational diabetes but developed overt NIDDM after delivery, was studied. Each SSCP variant was sequenced directly from genomic DNA. Two amino acid substitutions from the previously reported sequence were found, one in exon 3 and the other in exon 4B. Four additional silent mutations in the coding region, and six intron mutations outside the splice junction consensus sequences, were also identified. The mutation GTC x ATC in exon 4B substituted Val197 to Ile197. This amino acid substitution was found in only one NIDDM patient in a single allele, and was not found in 52 control subjects. This residue exists in the fifth membrane spanning domain, and Val at this position is conserved in mouse and rat GLUT 2, and human GLUT 1 to GLUT 4. The other codon change in exon 3, ACT x ATT, substituted Thr110 to Ile110 in the second membrane spanning domain. To determine the frequency of this non-conservative amino acid substitution, a PCR-LCR assay was developed. This assay was simple and highly specific for detection of this single nucleotide substitution. The allelic frequency of the ATT (Ile110) in NIDDM patients (39.6%, n = 48) and that in controls (47.1%, n = 52) did not differ (p = 0.32, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning.

Mutations of the glucokinase gene result in early-onset familial Type 2 (non-insulin-dependent) diabetes mellitus, and several members of the mutant glucokinase kindreds were originally diagnosed as having gestational diabetes. This study examined the glucokinase gene in 270 American Black women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed Type 2 diabetes after pregnancy (overt diabetes), and 99 normal control subjects who were recruited during the peripartum period. Two simple sequence repeat polymorphisms flanking either end of the glucokinase gene were evaluated. No association was found between glucokinase alleles and gestational diabetes only or overt diabetes, after adjustment for multiple comparisons. To detect single base changes, all 11 exons and proximal islet and liver promoter regions were examined by polymerase chain reaction plus single-stranded conformational polymorphism analysis in 45 gestational diabetes only patients who had not yet developed Type 2 diabetes. Nine coding region variants were identified: Ala11 (GCC) to Thr11 (ACC) in islet exon 1, and 8 variants either in untranslated regions or in the third base of a codon. Four variant sites were found in introns, but none in splicing consensus sequences. Analysis of the promoter regions revealed two common variants, G-->A at islet -30 (24%), and G-->A at liver -258 (42%). The frequencies of the promoter variants, determined by allele specific polymerase chain reaction analysis, but did not differ among the three groups. Thus, no significant coding sequence glucokinase mutations were found in 90 alleles from 45 patients with gestational diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Familial hyperinsulinism maps to chromosome 11p14-15.1, 30 cM centromeric to the insulin gene.

Familial hyperinsulinism (HI) is the most common cause of persistent neonatal hyperinsulinaemic hypoglycemia. Linkage analysis in 15 families (12 Ashkenazi Jewish, 2 consanguineous Arab, 1 non-Jewish Caucasian) mapped HI to chromosome 11p14-15.1 (lod score = 9.5, theta = 0 at D11S921). Recombinants localized the disease locus to the 6.6 cM interval between D11S926 and D11S928. In Jewish families, association (p = 0.003) with specific D11S921/D11S419 haplotypes suggested a founder effect. This locus, which is important for normal glucose-regulated insulin secretion, represents a candidate gene for studies of other diseases of beta-cell dysfunction including non-insulin-dependent diabetes mellitus (NIDDM).

Chromosome Mapping↗