The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3368-3371
Copyright © 2003 by The Endocrine Society
The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated with an Atherogenic Profile in Offspring of Type 2 Diabetic Patients
Maria Adelaide Marini,
Simona Frontoni,
Davide Mineo,
Daniela Bracaglia,
Marina Cardellini,
Pierluigi de Nicolais,
Alessandra Baroni,
Rossella D’Alfonso,
Michela Perna,
Davide Lauro,
Massimo Federici,
Sergio Gambardella,
Renato Lauro and
Giorgio Sesti
Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome-Tor Vergata (M.A.M., D.M., M.C., R.D., D.L., M.F., R.L.), 00133 Rome, Italy; Department of Internal Medicine, University of Rome-Tor Vergata (S.F., D.B., A.B., M.P., S.G.), 00133 Rome, Italy; and Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia (P.D.N., G.S.), 88100 Catanzaro, Italy
Address all correspondence and requests for reprints to: Giorgio Sesti, M.D., Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia, Via Tommaso Campanella 115, 88100 Catanzaro, Italy. E-mail: sesti{at}unicz.it.
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Abstract
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The insulin receptor substrate-1 (IRS-1) gene has been considered a candidate for insulin resistance, type 2 diabetes, and coronary artery disease. To investigate the relationship between the common Gly972Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. There were no differences between Arg972 IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg972 IRS-1 (P < 0.03). Carriers of Arg972 IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). These results suggest that the Arg972 IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.
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Introduction
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THE INSULIN RESISTANCE syndrome plays a major role in the pathogenesis of type 2 diabetes mellitus and atherosclerotic cardiovascular diseases (1). Although there is strong evidence that this syndrome is genetically determined, the genetic determinants that link the development of insulin resistance with type 2 diabetes and cardiovascular diseases remain largely unsettled (2). Insulin receptor substrate-1 (IRS-1) is a major substrate for the insulin receptor in target tissues of insulin action, including muscle, fat, and vasculature (3). Once phosphorylated on tyrosine residues, IRS-1 acts as a multisite docking protein for various effector molecules possessing Src homology 2 domains, including the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) (3). The activation of these Src homology 2 domain proteins initiates signaling cascades, leading to the activation of multiple downstream effectors that mediate metabolic responses, cell survival, growth, and differentiation. The IRS-1 gene has been considered a candidate for insulin resistance and type 2 diabetes (4). A recent genomewide linkage analysis of the acute coronary syndrome has mapped a susceptibility locus on chromosome 2q33-q37.3, which harbors the gene encoding IRS-1 (5). Molecular scanning of the IRS-1 gene in normal subjects and patients with type 2 diabetes has revealed several amino acid polymorphisms, the most common of which is a Gly972Arg change (6, 7, 8, 9, 10, 11). This amino acid substitution has functional consequences, causing impairment of IRS-1-associated PI 3-kinase activity due to their defective interaction (12, 13, 14). A 2.8-fold higher frequency of the Arg972 IRS-1 variant has been reported in patients with angiographic evidence of coronary artery disease (CAD) compared with control individuals (15). However, these results have not been confirmed in two different studies of overweight/obese patients with type 2 diabetes and patients with CAD (16, 17). This discrepancy may be due to a biased collection of clinical and biochemical data. The measurement of cardiovascular risk factors in type 2 diabetic patients and patients with CAD is difficult, because such postmorbid data are not reliable indexes of the premorbid situation because they are prone to bias as a result of the metabolic abnormalities secondary to the onset of the disease as well as the lifestyle changes and pharmacological interventions after diagnosis of the disease. To overcome this problem, we studied the effects of the Arg972 IRS-1 variant in individuals at high risk of developing type 2 diabetes, i.e. offspring of type 2 diabetic patients.
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Subjects and Methods
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Experimental subjects
The study group consisted of 153 unrelated offspring of type 2 diabetic patients. Inclusion criteria were: the eldest offspring in each family with only one parent affected by type 2 diabetes, absence of diabetes or impaired glucose tolerance (fasting plasma glucose, <110 mg/dl; 2-h plasma glucose, <140 mg/dl), body mass index (BMI) less than 40 kg/m2, and absence of diseases able to modify glucose metabolism. The protocol was approved by the ethical committee, and informed written consent was obtained from all participants. All investigations were performed in accordance with the principles of the Declaration of Helsinki.
On the first day, after 12-h fasting, all subjects underwent anthropometric evaluation, including BMI, waist/hip ratio, and body composition evaluated by bioelectrical impedance. Readings of clinical blood pressure were obtained in the left arm of the supine patients after 5 min of quiet rest using a mercury sphygmomanometer. A 75-g oral glucose tolerance test was performed with 0, 30, 60, 90, and 120 min sampling for plasma glucose and insulin. High resolution B-mode ultrasound was used to measure intima-media thickness of the carotid artery by using an HDI 3000 ultrasound system (Advanced Technology Laboratories, Bothell, WA). The anterior, lateral, and posterolateral projections were used to image longitudinally the right and left common carotid arteries. At each longitudinal projection, three determinations of intima-media thickness were made at 2 cm proximal to the bulb and at the site of greatest thickness. The values at each site were averaged, and the greatest value of the averaged intima-media thickness was used as the representative value of each individual. On the second day at 0800 h, after a 12-h overnight fast, subjects underwent a euglycemic hyperinsulinemic clamp study. Insulin (Humulin, Eli Lilly \|[amp ]\| Co., Indianapolis, IN) was given as a prime continuous infusion targeted to produce plasma insulin levels of about 420 pmol/liter. Thereafter, the insulin infusion rate was fixed at 40 mU/m2·min. The blood glucose level was maintained constant throughout the study by infusing 20% glucose at varying rates according to blood glucose measurements performed at 5-min intervals.
DNA analysis
Genomic DNA was isolated from peripheral blood according to standard procedures. The Gly972Arg of the human IRS-1 sequence was detected by digestion of PCR products with the restriction enzyme BstNI as previously described (6, 7).
Analytical determinations
Plasma glucose was measured in duplicate by the glucose oxidation method (Glucose Analyzer II, Beckman, Milan, Italy). The plasma insulin concentration was determined by RIA. Urinary albumin excretion was measured as the urinary albumin concentration in a morning urine sample. All other biochemical parameters were measured by standard laboratory procedures.
Statistical analysis
Categorical variables were compared by 
2 test. Continuous data are expressed as the mean ± SD. Because only one subject was found to be homozygous for the Arg972 IRS-1 variant, he was combined with the heterozygous group for statistical analysis. Differences between means were compared using unpaired t or Mann-Whitney U test as appropriate. All differences were also tested after adjusting for gender or age by analysis of covariance. The Hardy-Weinberg equilibrium between the two genotypes was evaluated by 2 test. For all analyses P 
0.05 was considered statistically significant. All analyses were performed using the SPSS software program (version 10.0 for Windows, SPSS, Inc., Chicago, IL).
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Results
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One hundred fifty-three nondiabetic offspring with only 1 parent affected by type 2 diabetes were studied. Of these subjects, 25 (16.3%) were heterozygous for the Arg972 IRS-1 variant, 1 was homozygous (0.7%), and the remainder (83%) were homozygous for the wild type. The genotype frequency was in Hardy-Weinberg equilibrium. These frequencies were comparable to those observed by other groups in Caucasian populations at risk for the development of diabetes (18). The clinical characteristics of the offspring stratified according to genotype are shown in Table 1
. Both groups of subjects were well matched with respect to age, gender, BMI, waist/hip ratio, and body composition. Subjects carrying the Arg972 IRS-1 variant, including the homozygous subject, showed glucose and insulin levels comparable to those of the wild-type individuals both in the fasting state and during the oral glucose tolerance test. Insulin secretion estimated by the ß-cell HOMA index (19) or the insulinogenic index (insulin30 - insulin0/glucose30 - glucose0) (20) did not differ between the two groups. Insulin sensitivity, assessed as whole body glucose disposal by the gold standard hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of the Arg972 IRS-1 variant compared with wild-type subjects (P < 0.03). These differences remained significant (P < 0.02) after adjusting for gender, age, and BMI. Steady state glucose concentrations during the clamp were similar between the wild-type subjects (91 ± 11 mg/dl) and subjects carrying the Arg972 IRS-1 variant (93 ± 9 mg/dl). Steady state insulin concentrations during the clamp were not different between the two groups of subjects, thus indicating that insulin clearance was not affected by the Arg972 IRS-1 variant. Carriers of the Arg972 IRS-1 variant showed multiple abnormalities in lipid metabolism, including higher values for serum total/high density lipoprotein cholesterol ratio (P < 0.01), triglycerides (P < 0.01), and free fatty acid levels (P < 0.04). In addition, subjects carrying the Arg972 IRS-1 variant displayed other features of the insulin resistance syndrome, including increased systolic blood pressure (P < 0.04), higher microalbuminuria (P < 0.003), and increased intima-media thickness (P < 0.02).
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Discussion
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In the present study, we show evidence that the Arg972 variant of IRS-1 confers an atherogenic profile in Italian offspring of type 2 diabetic patients. These subjects have become a valuable model to study the pathogenic mechanism(s) responsible for the susceptibility of the disease without the confounding effect of hyperglycemia. In fact, they have a 30–40% lifetime risk of developing diabetes, and insulin resistance seems to be the best predictor. Offspring of type 2 diabetic patients carrying the Arg972 IRS-1 variant displayed many features of the insulin resistance syndrome, including reduced insulin sensitivity, assessed by gold standard euglycemic hyperinsulinemic clamp; higher values for free fatty acid levels, serum triglycerides, and total/high density lipoprotein cholesterol ratio; increased systolic blood pressure; higher microalbuminuria; and increased intima-media thickness. The present data are consistent with previous observations in other populations at risk to develop atherosclerotic cardiovascular disease. Thus, in a group of patients selected from the UK Prospective Diabetes Study, the prevalence of the Arg972 IRS-1 variant was increased in type 2 diabetic patients who have insulin resistance associated, or not associated, with dyslipidemia (9). Furthermore, it has been shown that obese nondiabetic carriers of the Arg972 IRS-1 variant exhibit a clustering of metabolic cardiovascular risk factors with elevated fasting plasma glucose and reduced insulin sensitivity, serum triglycerides, plasma tissue plasminogen activator, and its inhibitor compared with wild-type obese mice (21). Interestingly, homozygous IRS-1 knockout mice exhibit insulin resistance associated with hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation (22). These data may also help explain the conflicting results of case-control studies that failed to find a positive association between the Arg972 IRS-1 variant and risk for cardiovascular atherosclerotic cardiovascular diseases associated with type 2 diabetes. In fact, one could speculate that patients carrying the Arg972 IRS-1 variant are more likely to have been removed from the cohort of type 2 diabetic patients with CAD because of an early mortality for cardiovascular disease as the result of prolonged exposure to the cluster of insulin resistance-related metabolic abnormalities. On the other hand, the finding that a positive association of the Arg972 IRS-1 variant with components of the insulin resistance syndrome was almost exclusively seen in populations at risk to develop atherosclerotic cardiovascular disease may be explained by the relatively small effect of the Arg972 IRS-1 variant, which may impede detection in subjects without predisposition to the insulin resistance syndrome. Two previous studies that have attempted to correlate the Arg972 IRS-1 variant with insulin sensitivity in offspring of type 2 diabetic patients failed to find positive results (18, 23). Apart from the obvious ethnic differences in the genetic background, possible explanations for these apparent discrepancies may lie in differences in clinical characteristics of the populations studied or differences in sample size. In one study (23), insulin sensitivity was estimated by insulin tolerance test in only nine subjects carrying the Arg972 IRS-1 variant, of whom six were from three families, and the impact of the Arg972 IRS-1 variant on features of the insulin resistance syndrome, including lipid profile, blood pressure, and microalbuminuria, was not explored, thus making it difficult to determine the atherogenic potential of the Arg972 IRS-1 variant. The other study was carried out on subjects younger and with lower BMI than those in the present study (18). Because the Arg972 IRS-1 variant has been shown to interact with BMI (21), and its prevalence is related to aging in individuals at risk for development of type 2 diabetes (24), it is possible that the effects of the Arg972 IRS-1 variant might have been diluted.
The Arg972 variant can confer the observed atherogenic profile by several mechanisms. It has been shown that expression of the Arg972 IRS-1 variant in various cell types caused a specific defect in binding of the p85 regulatory subunit of PI 3-kinase to the IRS-1 variant, resulting in a decrease in IRS-1-associated PI 3-kinase activity and subsequent activation of the Ser/Thr kinase Akt, a key enzyme linking PI 3-kinase activation to multiple biological functions of insulin (12, 13, 14). We have previously demonstrated that expression the Arg972 IRS-1 variant in L6 skeletal muscle cells resulted in a decrease in glycogen synthesis as well as glucose transport due to a reduction in the translocation of GLUT4 glucose transporters to the plasma membrane (13), thus accounting for decreased insulin sensitivity observed in offspring carrying the Arg972 variant. A potential mechanism by which the Arg972 variant could contribute to multiple abnormalities in lipid profile is by affecting activation of phosphodiesterase 3B, a downstream target of Akt that mediates the antilipolytic effect of insulin (25). Thus, impaired activation of phosphodiesterase 3B may lead to increased delivery of free fatty acids to the liver and consequently increased production of triglycerides. Furthermore, as the signaling pathway involving IRS-1/PI-3 kinase has been shown to exert a vasodilatory effect by increasing nitric oxide production (26), it is conceivable that offspring carrying the Arg972 variant might have reduced nitric oxide bioavailability, leading to cardiovascular/renal endothelial dysfunction, vasoconstriction, and vascular smooth muscle cell growth. Indeed, the results of preliminary studies carried out with human umbilical vein endothelial cells obtained from carriers of the Arg972 polymorphism have shown an impaired ability of insulin to increase endothelial nitric oxide synthase expression (27). In addition, in carrying the Arg972 variant, an impaired stimulation of the Na+,K+-adenosine triphosphatase pump, which is known to be stimulated by insulin via the IRS-1/PI-3 kinase pathway, may result in increased intracellular concentration of Ca2+ in vascular smooth muscle cells and, consequently, vasoconstriction.
In conclusion, the present results suggest that the Arg972 IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.
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Footnotes
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This work was supported in part by grants from European Community: EuroDiabetesGene QLG1-CT-1999-00674 (to G.S.), Progetto di Ricerca Finalizzata-Ministero della Sanità (to G.S.), and PRIN-COFIN 2001-Ministero dell’Università e Ricerca Scientifica e Tecnologica (to G.S. and R.L.).
M.A.M. and S.F. contributed equally to this manuscript.
Abbreviations: BMI, Body mass index; CAD, coronary artery disease; IRS-1, insulin receptor substrate-1; PI 3-kinase, phosphatidylinositol 3-kinase.
Received November 4, 2002.
Accepted April 1, 2003.
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References
|
|---|
- Reaven GM 1988 Role of insulin resistance in human disease. Diabetes 37:1595–1607[Abstract]
- Hong Y, Pedersen NL, Brismar K, de Faire U 1997 Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genet 60:143–152[Medline]
- Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF 1991 Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77[CrossRef][Medline]
- Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R 2001 Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 15:2099–2111[Abstract/Free Full Text]
- Harrap SB, Zammit KS, Wong ZY, Williams FM, Bahlo M, Tonkin AM, Anderson ST 2002 Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler Thromb Vasc Biol 22:874–878
- Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald SM, Pedersen O 1993 Amino acid polymorphism in insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342:828–832[CrossRef][Medline]
- Imai Y, Fusco A, Suzuki Y, Lesniak M, D’Alfonso R, Sesti G, Bertoli A, Lauro R, Accili D, Taylor SI 1994 Variant sequences of insulin receptor substrate-1 in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 79:1655–1658[Abstract]
- Hitman GA, Hawrami K, McCarthy MI, Viswanathan M, Snehalatha C, Ramachandran A, Tuomilehto J, Tuomilehto-Wolf E, Nissinen A, Pedersen O 1995 Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease. Diabetologia 38:481–486[Medline]
- Zhang Y, Wat N, Stratton IM, Warren-Perry MG, Orho M, Groop L, Turner RC 1996 UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and ß-3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. Diabetologia 39:1505–1511[CrossRef][Medline]
- Sigal RJ, Doria A, Warram JH, Krolewski AS 1996 Codon 972 polymorphism in the insulin receptor substrate-1 gene, obesity, and risk for noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81:1657–1659[Abstract]
- Laakso M, Malkki M, Kekalainen P, Kuusisto J, Deeb S 1994 Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. J Clin Invest 94:1141–1146
- Almind K, Inoue G, Pedersen O, Kahn CR 1996 A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. J Clin Invest 97:2569–2575[Medline]
- Hribal ML, Federici M, Porzio O, Lauro D, Borboni P, Accili D, Lauro R, Sesti G 2000 The Gly
Arg972 amino acid polymorphism in IRS-1 affects glucose metabolism in skeletal muscle cells. J Clin Endocrinol Metab 85:2004–2013[Abstract/Free Full Text]
- Federici M, Hribal ML, Ranalli M, Marselli L, Porzio O, Lauro D, Borboni P, Lauro R, Marchetti P, Melino G, Sesti G 2001 The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. FASEB J 15:22–24[Free Full Text]
- Baroni MG, D’andrea MP, Montali A, Pannitteri G, Barilla F, Campagna F, Mazzei E, Lovari S, Seccareccia F, Campa PP, Ricci G, Pozzilli P, Urbinati G, Arca M 1999 A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 19:2975–2980[Abstract/Free Full Text]
- Grant PJ, Stickland MH, Mansfield MW 1995 Insulin receptor substrate-1 gene and cardiovascular risk factors in NIDDM. Lancet 346:841–842
- Ossei-Gerning N, Mansfield MW, Stickland MH, Grant PJ 1997 Insulin receptor substrate-1 gene polymorphism and cardiovascular risk in non-insulin dependent diabetes mellitus and patients undergoing coronary angiography. Clin Lab Haematol 19:123–128[CrossRef][Medline]
- Koch M, Rett K, Volk A, Maerker E, Haist K, Deninger M, Renn W, Haring HU 1999 Amino acid polymorphism Gly972Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 107:318–322[Medline]
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
- Hanson RL, Pratley RE, Bogardus C, Narayan KM, Roumain JM, Imperatore G, Fagot-Campagna A, Pettitt DJ, Bennett PH, Knowler WC 2000 Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 151:190–198[Abstract/Free Full Text]
- Clausen JO, Hansen T, Bjorbaek C, Echwald SM, Urhammer SA, Rasmussen S, Andersen CB, Hansen L, Almind K, Winther K, Haraldsdottir J, Borch-Johnsen K, Pedersen O 1995 Insulin resistance: interaction between obesity and a common variant of insulin receptor substrate-1. Lancet 346:397–402[CrossRef][Medline]
- Abe H, Yamada N, Kamata K, Kuwaki T, Shimada M, Osuga J, Shionoiri F, Yahagi N, Kadowaki T, Tamemoto H, Ishibashi S, Yazaki Y, Makuuchi M 1998 Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin-receptor substrate-1. J Clin Invest 101:1784–1788[Medline]
- Armstrong M, Haldane F, Avery PJ, Mitcheson J, Stewart MW, Turnbull DM, Walker M 1996 Relationship between insulin sensitivity and insulin receptor substrate-1 mutations in non-diabetic relatives of NIDDM families. Diabet Med 13:341–345[CrossRef][Medline]
- Yamada K, Yuan X, Ishiyama S, Shoji S, Kohno S, Koyama K, Koyanagi A, Koyama W, Nonaka K 1998 Codon 972 polymorphism of the insulin receptor substrate-1 gene in impaired glucose tolerance and late-onset NIDDM. Diabetes Care 21:753–756[Abstract]
- Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M 1999 Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol Cell Biol 19:6286–6296[Abstract/Free Full Text]
- Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ 2000 Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101:1539–1545[Abstract/Free Full Text]
- Pandolfi A, De Filippis EA, Federici M, Sesti G, Consoli A 2002 G972R IRS-1 variant impairs insulin regulation of eNOS in human endothelial cell in culture. Diabetes 51(Suppl 2):A83
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Abstract
Introduction
