Examination of the phosphoenolpyruvate carboxykinase gene promoter in patients with noninsulin-dependent diabetes mellitus.

Ludwig, David S.; Vidal-Puig, António; O’Brien, Richard M.; Printz, Richard L.; Granner, Daryl K.; Flier, Jeffrey S.

doi:10.1210/jcem.81.2.8636258

Cited by 12 publications

(8 citation statements)

References 35 publications

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“…We have previously postulated that a similar mutation in the PEPCK IRS could contribute to increased HGP (1,6). However, a recent study failed to detect such mutations in a population of human subjects with NIDDM (42). Moreover, a defect in insulin-regulated PEPCK gene transcription, while it could explain the increase in HGP could not, by itself, explain hepatic insulin resistance.…”

Section: The G6pase Promoter Sequence Between ϫ197 and ϫ159 Can Confementioning

confidence: 99%

A Multicomponent Insulin Response Sequence Mediates a Strong Repression of Mouse Glucose-6-phosphatase Gene Transcription by Insulin

Streeper

Svitek

Chapman

et al. 1997

Journal of Biological Chemistry

139

157

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Glucose-6-phosphatase (G6Pase) catalyzes the final step in the gluconeogenic and glycogenolytic pathways. The transcription of the gene encoding the catalytic subunit of G6Pase is stimulated by glucocorticoids, whereas insulin strongly inhibits both basal G6Pase gene transcription and the stimulatory effect of glucocorticoids. To identify the insulin response sequence (IRS) in the G6Pase promoter through which insulin mediates its action, we have analyzed the effect of insulin on the basal expression of mouse G6Pase-chloramphenicol acetyltransferase (CAT) fusion genes transiently expressed in hepatoma cells. Deletion of the G6Pase promoter sequence between ؊271 and ؊199 partially reduces the inhibitory effect of insulin, whereas deletion of additional sequence between ؊198 and ؊159 completely abolishes the insulin response. The presence of this multicomponent IRS may explain why insulin potently inhibits basal G6Pase-CAT expression. The G6Pase promoter region between ؊198 and ؊159 contains an IRS, since it can confer an inhibitory effect of insulin on the expression of a heterologous fusion gene. This region contains three copies of the T(G/A)TTTTG sequence, which is the core motif of the phosphoenolpyruvate carboxykinase (PEPCK) gene IRS. This suggests that a coordinate increase in both G6Pase and PEPCK gene transcription is likely to contribute to the increased hepatic glucose production characteristic of patients with non-insulin-dependent diabetes mellitus.While insulin has long been known to modulate intracellular metabolism by altering the activity or intracellular location of various enzymes, it is only more recently that the regulation of gene transcription by insulin has been recognized as a major action of this hormone (1). cis-Acting elements that mediate the action of insulin on gene transcription, referred to as an insulin response sequences or elements (IRSs/IREs), 1 have been identified in a number of genes but, unlike cAMP (2, 3), which regulates gene transcription predominantly through one cisacting element, it is already apparent that a single consensus IRS does not exist (1). Instead, most of the sequences identified to date appear unique, a situation that resembles that for phorbol esters that regulate gene transcription through at least eight distinct consensus sequences (4).Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by defects in insulin secretion, peripheral glucose utilization, and hepatic glucose production (HGP) (5). The ability of insulin to stimulate peripheral glucose utilization and repress HGP in patients with NIDDM is reduced, a phenomenon known as insulin resistance (5). Various investigators have speculated that an alteration in the insulin-regulated expression of specific genes, a consequence of insulin resistance, may contribute to the pathophysiology of this disease (1, 5, 6). The gene encoding the glucose-6-phosphatase (G6Pase) catalytic subunit (7) is one such candidate, since it catalyzes the final step in the gluconeogenic pathway, the conversion of ...

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Section: The G6pase Promoter Sequence Between ϫ197 and ϫ159 Can Confementioning

confidence: 99%

A Multicomponent Insulin Response Sequence Mediates a Strong Repression of Mouse Glucose-6-phosphatase Gene Transcription by Insulin

Streeper

Svitek

Chapman

et al. 1997

Journal of Biological Chemistry

139

157

View full text Add to dashboard Cite

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“…Despite strong evidence from animal studies (11,12,13), we could not find any evidence for the association of PCK1 variants with obesity‐related phenotypes in children and adolescents. Previous studies have shown association between genetic variation in PCK1 and the risk of type 2 diabetes and related traits (4,17,18,19,20), of which we genotyped four (rs6070157, rs2179706, rs1042531, and rs707555) but found no evidence for association in the EYHS. As this is the first study examining the association of genetic variants in PCK1 gene with obesity in young individuals, more studies are needed to explore the association of PCK1 gene variants with obesity‐related phenotypes in other populations.…”

Section: Discussionmentioning

confidence: 63%

“…Regions near the PCK1 locus on human chromosome 20 have been implicated in obesity (16). In addition, several studies in humans have shown associations of specific polymorphsims in the PCK1 gene with type 2 diabetes and related metabolic traits (4,17,18,19,20). However, the present study investigates the association of single‐nucleotide polymorphisms (SNPs) in the PCK1 gene with obesity, PA, and fitness and examines the interaction between the PCK1 SNPs, and PA and fitness on obesity risk in the European Youth Heart Study (EYHS), a large population‐based study of children and adolescents from Denmark and Estonia.…”

Section: Introductionmentioning

confidence: 99%

Lack of Association Between PCK1 Polymorphisms and Obesity, Physical Activity, and Fitness in European Youth Heart Study (EYHS)

Vimaleswaran

Franks

Brage

et al. 2010

Obesity

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Phosphoenolpyruvate carboxykinase‐1 (PCK1) is the rate‐limiting enzyme in the hepatic gluconeogenic pathway. Studies have shown that overexpression of Pck1 in mice results in obesity‐related traits and higher levels of physical activity (PA). Therefore, our aims were to investigate whether common genetic variation in the PCK1 gene influences obesity‐related traits, PA, and fitness, and to examine whether PA and fitness attenuate the influence of the PCK1 polymorphisms on obesity in children. Analyses were undertaken on data from Danish and Estonian children (958 boys and 1,104 girls) from the European Youth Heart Study (EYHS), a school‐based, cross‐sectional study of children (mean ± s.d. age: 9.6 ± 0.4 years) and adolescents (15.5 ± 0.5 years). We genotyped eight polymorphisms that captured the common genetic variations in the PCK1 gene. The association between the PCK1 polymorphisms and BMI, waist circumference (WC), sum of four skinfolds, PA, and fitness was tested using an additive model adjusted for age, age‐group, gender, maturity, and country. Interactions were tested by including interaction terms in the model. None of the polymorphisms were significantly associated with BMI, WC, sum of four skinfolds, PA, and fitness, and also with the risk of being overweight or obese (P > 0.05). The interactions between the polymorphisms and age‐group, gender, PA, and fitness were not statistically significant. This is the first study to comprehensively examine the association of PCK1 polymorphisms with obesity, PA, and fitness. Despite strong evidence from animal studies, our study in the EYHS cohort failed to identify an association of PCK1 polymorphisms with obesity, PA, and fitness.

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“…The liver-type and the ␤-cell-type glucokinase promoter variations are associated with insulin resistance and impaired insulin secretion, respectively (23,24). In contrast, mutations were clinically silent in the promoters of insulin, GLUT4, and PEPCK genes (4,25,26). The sensitivity of identifying point mutations with SSCP varies according to the gel conditions and DNA length and sequence (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…Hepatic glucose production is increased in NIDDM patients and correlates positively with fasting glucose levels, which can be attributed to increased gluconeogenesis (2,3). However, no polymorphism was found (4). Recently, a key enzyme, phosphoenolpyruvate carboxykinase (PEPCK) gene promoter, has been examined in diabetic patients.…”

Section: N Oninsulin-dependent Diabetes Mellitus (Niddm)mentioning

confidence: 99%

Mutation/Polymorphism Scanning of Glucose-6-Phosphatase Gene Promoter in Noninsulin-Dependent Diabetes Mellitus Patients1

Yoshiuchi

Shingu

Nakajima

et al. 1998

The Journal of Clinical Endocrinology &Amp; Metabolism

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Glucose-6-phosphatase (G6Pase) catalyzes the rate-limiting step of gluconeogenesis, and hepatic G6Pase activity is increased in diabetes. We have cloned and analyzed the human G6Pase gene promoter region and identified putative regulatory sequences for insulin, cAMP, glucocorticoid, and hepatocyte nuclear factors. The promoter region of the G6Pase gene was analyzed in 154 noninsulin-dependent diabetes mellitus patients and 90 control subjects by PCR-single strand conformation polymorphism and direct sequencing methods. Polymorphisms were not found in any subjects. The results suggested that in noninsulin-dependent diabetic patients, the major cause of the hepatic glucose overproduction was not attributed to dysregulation of the G6Pase gene due to mutation/polymorphism of its promoter region.

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Examination of the phosphoenolpyruvate carboxykinase gene promoter in patients with noninsulin-dependent diabetes mellitus.

Cited by 12 publications

References 35 publications

A Multicomponent Insulin Response Sequence Mediates a Strong Repression of Mouse Glucose-6-phosphatase Gene Transcription by Insulin

A Multicomponent Insulin Response Sequence Mediates a Strong Repression of Mouse Glucose-6-phosphatase Gene Transcription by Insulin

Lack of Association Between PCK1 Polymorphisms and Obesity, Physical Activity, and Fitness in European Youth Heart Study (EYHS)

Mutation/Polymorphism Scanning of Glucose-6-Phosphatase Gene Promoter in Noninsulin-Dependent Diabetes Mellitus Patients1

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