Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance

Sc, Elbein; Chu, Wei; Ren, Qian; Wang, H; C, Hemphill; Sj, Hasstedt

doi:10.1007/s00125-002-0850-5

Cited by 23 publications

(15 citation statements)

References 46 publications

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“…No excess transmission was detected for either haplotype using a transmission disequilibrium test ( ϭ 0.53, P ϭ 0.5). Furthermore, we found no evidence that either haplotype was associated with fasting or postchallenge glucose, lipid measures, or several indexes of insulin secretion based on the oral glucose tolerance test, as previously described (23). We also found no evidence that PKLR haplotypes were associated with altered insulin secretion (acute insulin response to glucose or disposition index) or insulin sensitivity in 126 members of the families who had undergone intravenous glucose tolerance tests (24) (data not shown).…”

Section: Resultssupporting

confidence: 63%

Liver Pyruvate Kinase Polymorphisms Are Associated With Type 2 Diabetes in Northern European Caucasians

et al. 2002

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Pyruvate kinase is a key glycolytic enzyme. Isoforms that are expressed in the red cell, liver, pancreatic ␤-cells, small intestine, and proximal renal tubule are encoded by the 12 exons of the PKLR gene, which maps to chromosome 1q23. We hypothesized that common variants of the PKLR gene could account for the linkage of diabetes to this region. We screened the promoter regions, exons and surrounding introns, and the 3 untranslated region for mutations. We identified five single-nucleotide polymorphisms (SNPs), and only one (V506I, exon 11) altered the coding sequence. We tested the five SNPs, a poly-T insertion-deletion polymorphism, and an ATT triplet repeat in 131 unrelated diabetic patients and 118 nondiabetic control subjects. The V506I variant was rare and not associated with type 2 diabetes. The four SNPs and the insertion-deletion polymorphism were associated with diabetes, with a 10% difference between individuals with diabetes and nondiabetic individuals (P ‫؍‬ 0.001-0.011, relative risk for minor allele 1.85). The same trend was found for the ATT repeat (P ‫؍‬ 0.029). Common variants in the PKLR are associated with increased risk of type 2 diabetes, but because of strong linkage disequilibrium between variants, the actual susceptibility allele may be in a different gene. Diabetes 51:2861-2865, 2002

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Section: Resultssupporting

confidence: 63%

Liver Pyruvate Kinase Polymorphisms Are Associated With Type 2 Diabetes in Northern European Caucasians

et al. 2002

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“…Among nondiabetic family members, individuals heterozygous for D76N were slightly younger and less obese by both BMI and waist-to-hip ratio (a measure of central adiposity), but only waist-to-hip ratio was borderline significant (P ϭ 0.05). No measure of insulin or insulin secretion (insulinogenic index) differed between the two genotypes, including an index derived in our laboratory based on the fasting insulin and change in insulin to 60 min that correlates well with the FSIGT-based disposition index (21). Restricting our comparison of carriers and noncarriers to members of families in which the mutation segregated showed the same results; neither insulin levels nor measures of insulin secretion differed be- , P ϭ 0.02).…”

Section: Discussionmentioning

confidence: 69%

Does the Aspartic Acid to Asparagine Substitution at Position 76 in the Pancreas Duodenum Homeobox Gene (PDX1) Cause Late-Onset Type 2 Diabetes?

Elbein

Karim

2004

Diabetes Care

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OBJECTIVE -Considerable data support an inherited defect in insulin secretion as one component of type 2 diabetes. Coding variants of the pancreas duodenum homeobox gene (PDX1) were proposed to predispose late-onset type 2 diabetes and to decrease transactivation in vitro. We tested the hypothesis that the Asp76Asn (D76N) variant that was identified in several populations predisposed type 2 diabetes and reduced insulin secretion.RESEARCH DESIGN AND METHODS -We performed a case-control study in 191 control subjects and 190 individuals with type 2 diabetes, all of European descent, then characterized the D76N variant in 704 members of 68 families. We compared the phenotypic characteristics of those with and without the variant by diagnostic status and determined the insulin secretory response to intravenous glucose and tolbutamide among nondiabetic family members.RESULTS -D76N was not associated with type 2 diabetes, either in our population or when all reported studies in Caucasians were combined. D76N did not segregate with diabetes among the families examined. Among D76N carriers, nondiabetic individuals had a lower waist-to-hip ratio and a trend to lower BMI than their diabetic counterparts. Diabetic carriers of D76N were significantly leaner by BMI (P ϭ 0.012) and tended to be younger than diabetic individuals with the D/D genotype. However, insulin secretion in response to oral and intravenous glucose challenge and to intravenous tolbutamide was not reduced in D76N carriers.CONCLUSIONS -The D76N variant of PDX1 does not significantly alter insulin secretion or act as a high-risk susceptibility allele for late-onset type 2 diabetes as proposed previously, although we cannot exclude a minor role in increasing risk of diabetes. Diabetes Care 27:1968 -1973, 2004T ype 2 diabetes results from combined defects of insulin action (insulin resistance) and impaired insulin secretion (1). In work from our laboratory (2) and others (3,4), indexes of pancreatic ␤-cell function were strongly heritable, suggesting that genetic factors play an important role in the response of the pancreas to reduced insulin sensitivity (5). Although some common variants may impact this ability among Caucasian families (6,7), most of the genetic propensity to impaired ␤-cell compensation and to genetically programmed ␤-cell failure remains undefined.The failure of the pancreatic ␤-cell to increase insulin secretion in response to increased demands might result from functional defects (failure of increased insulin biosynthesis and secretion) or defects in ␤-cell mass (inherited differences in ␤-cell number or an impaired increase in ␤-cell mass in response to insulin resistance). Both processes may be controlled by ␤-cell transcription factors. Defects in hepatocyte nuclear factors 1␣ (TCF1), 4␣, and 1␤, and in the pancreas duodenum homeobox gene 1 (PDX1) all cause autosomal-dominant, insulin-deficient diabetes in humans (5,8,9). Our laboratory previously showed that genetic variants in TCF1 were present in up to 10% of our cohort of Caucasia...

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“…This phenotype resembles the dyslipidemia observed in diabetes, suggesting that stimulation of the hepatic synthesis of apoA-II may contribute to the dyslipidemia syndrome that occurs in patients with type 2 diabetes. Several studies in humans have linked the apoA-II gene to type 2 diabetes (41)(42)(43)(44). In our transgenic mice, there is a positive correlation between blood glucose and the plasma human apoA-II.…”

Section: Discussionmentioning

confidence: 61%

In Vitro Transcriptional Induction of the Human Apolipoprotein A-II Gene by Glucose

Sauvaget

Chauffeton²,

Dugué-Pujol³

et al. 2004

Diabetes

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Type 2 diabetic patients present high triglyceride and low HDL levels, significant determinants for the risk of atherosclerosis. Transgenic mice overproducing human apolipoprotein (apo)A-II, one of the two major apos of HDLs, display the same lipid disorders. Here, we investigated the possible regulation of apoA-II gene expression by glucose. In primary rat hepatocytes and in HepG2 cells, the transcription of the human apoA-II gene was upregulated by glucose. This response was mediated by a hormone-responsive element within the enhancer of the apoA-II promoter and was dependent on hepatocyte nuclear factor-4␣. Accordingly, in transgenic mice, the human apoA-II gene is stimulated by a high-carbohydrate diet after fasting and at weaning. By contrast, the apoA-II mRNA level is not modified in streptozotocin-induced diabetic rats. In transgenic mice overexpressing the human apoA-II gene, plasma human apoA-II concentration was positively correlated with blood glucose levels. These mice displayed a marked delay in plasma glucose tolerance as compared with control mice. We hypothesize that the following pathogenic pathway might occur in the course of type 2 diabetes: increased apoA-II level causes a rise in plasma triglyceride level and glucose intolerance, resulting in hyperglycemia, which in turn might further increase apoA-II gene transcription. Diabetes 53: [672][673][674][675][676][677][678] 2004

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Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance

Cited by 23 publications

References 46 publications

Liver Pyruvate Kinase Polymorphisms Are Associated With Type 2 Diabetes in Northern European Caucasians

Liver Pyruvate Kinase Polymorphisms Are Associated With Type 2 Diabetes in Northern European Caucasians

Does the Aspartic Acid to Asparagine Substitution at Position 76 in the Pancreas Duodenum Homeobox Gene (PDX1) Cause Late-Onset Type 2 Diabetes?

In Vitro Transcriptional Induction of the Human Apolipoprotein A-II Gene by Glucose

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