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Genetic variants of modulators of insulin action
International Congress Series 1253 (2003) 45 – 53
Genetic variants of modulators of insulin action Vittorio Tassi a, Rosa Di Paola a, Antonio Pizzuti b, Lucia Frittitta c, Vincenzo Trischitta a,d,* a
Unit of Endocrinology, Scientific Institute CSS, San Giovanni Rotondo (FG), Italy b Scientific Institute CSS-Mendel, Rome, Italy c Institute of Internal Medicine, Endocrine and Metabolic Diseases, University of Catania, Garibaldi Hospital, Catania, Italy d Department of Clinical Sciences, University ‘‘La Sapienza’’, Rome, Italy Received 7 February 2003; accepted 7 February 2003
Abstract The insulin resistance syndrome (IRS) is a common clinical condition whose aetiology is poorly understood and which is known to recognize a genetic background. Impairment in insulin receptor (IR) tyrosine-kinase activity has been demonstrated in tissues from insulin-resistant subjects. Several inhibitors of the insulin receptor tyrosine-kinase activity have been recently described and associated with human insulin resistance. Genes encoding for two of these inhibitors, namely PC-1 and PTP1B, have been deeply studied. The obtained results are here reported. PC-1, a class II transmembrane ectoenzyme, modulates insulin sensitivity by different mechanisms, unravelled by the discovery of two genetic variants. A polymorphism in exon 4, namely K121Q, has been described to be strongly associated with insulin resistance. As compared to the more common K variant, the Q variant has a greater inhibitory activity on insulin receptor function and action, by interacting more strongly with the insulin receptor and significantly reducing receptor autophosphorylation, PC-1 Q variant also identifies type 1 diabetic patients with a faster progression of diabetic nephropathy (DN), a condition that may share some common genetic determinants with insulin resistance. Furthermore, a haplotype in the 3V-untranslated region modulates PC-1 expression in skeletal muscle and confers, therefore, an increased risk for insulin resistance. The mechanism of PC-1 overexpression was explained by an observed significant increase in haplotype-specific mRNA half life. PTP1-B, a nonreceptor-type protein-tyrosine phosphatase (PTPase) that physically interacts with and dephosphorylates the activated insulin receptor, is a major regulator of insulin sensitivity and body fat, as shown from experimental evidences in animal models. A number of polymorphic variants, identified in different populations, have been associated to insulin resistance and its
* Corresponding author. Tel.: +39-0882-410627/629; fax: +39-0882-451637. E-mail addresses: [email protected], [email protected] (V. Trischitta). 0531-5131/03 D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00138-9
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associated clinical conditions. A 1484insG variation in the 3V-UTR region was associated with several features of insulin resistance. Subjects carrying the 1484insG variant showed PTP1-B mRNA overexpression in skeletal muscle, supposedly due to an mRNA stabilization, as demonstrated by transfection experiments. A rare missense variation, namely P387L, was found significantly associated with the risk of type 2 diabetes (T2D). Also, a silent third base polymorphism, namely 981CT, was found to be associated with higher risk of either impaired glucose tolerance (IGT) or type 2 diabetes. Altogether, these data clearly indicate that subtle mutations affecting genes encoding for proteins able to inhibit insulin receptor tyrosine-kinase activity may play a role in modulating susceptibility for insulin resistance and/or type 2 diabetes mellitus. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Insulin resistance syndrome; PC-1; PTP1-B; Diabetic nephropathy
1. Introduction The insulin resistance syndrome (IRS) is a common clinical condition which consists in the clustering in the same individual of several cardiovascular risk factors, including abdominal obesity, hypertension, dyslipidaemia, hyperinsulinemia and glucose intolerance. Its etiology is poorly understood. Clustering of the syndrome in families suggests a genetic background. Common variants in a number of candidate genes affecting fat and glucose metabolism, in combination with environmental triggers, are likely to increase susceptibility to the syndrome. Defects in insulin receptor tyrosine-kinase activity have been demonstrated in tissues from insulin-resistant subjects. However, mutations in the insulin receptor gene are rare. Therefore, other molecules capable of modulating insulin receptor function are very likely to play a major role in the IRS. Several inhibitors of the insulin receptor tyrosine-kinase activity have been recently described and associated with human insulin resistance [1]. The genes encoding for these proteins are, therefore, candidates for the IRS. This article will be focused on two of these inhibitors, namely PC-1 and PTP1-B, which have been deeply studied.
2. PC-1 PC-1 is a class II transmembrane ectoenzyme located both on plasma membrane and in the endoplasmic reticulum as a homodimer of 230 –260 kDa, depending on the cell type, oriented with a short cytoplasmic N-terminal tail, a transmembrane and a large C-terminal extracellular domain [2]. PC-1 is expressed in several human tissues and cells, including skeletal muscle, fat, liver, pancreas, testis, osteoblasts, hepatocytes, skin fibroblast and several continuous cell lines. The ectoenzyme has phosphodiesterase I/pyrophosphatase activities and belongs to a multigene family. Its gene in human is organised in 24 exons [3] on chromosome 6q22 – q23 [4]. Several evidences have proven a negative modulation of PC-1 on insulin signalling and a significant role in insulin resistance and its related abnormalities [5– 7].
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Skin fibroblasts from insulin-resistant and/or T2D patients overexpress an inhibitor of insulin-receptor tyrosine kinase which has been proven to be PC-1 [6]. In addition, overexpression of PC-1 in transfected cultured cells [6,7] reduced insulin signalling and action. PC-1 inhibition of insulin receptor kinase activity is exerted by a direct, physical, interaction with the receptor alpha-subunit [8,9]. A polymorphism in exon 4 of the PC-1 gene [3] (K121Q) has been described to be strongly associated with insulin resistance in 121 healthy nonobese, nondiabetic Caucasians individuals from Sicily. As compared with 80 KK allele subjects, 41 Q allele carriers showed higher glucose and insulin levels during oral glucose tolerance tests ( P < 0.001) and insulin resistance by euglycemic clamp ( P = 0.005). Q carriers had a higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28 –7.0], P < 0.001). Insulin receptor autophosphorylation was significantly reduced in cultured skin fibroblasts from KQ versus KK subjects ( P < 0.01). The results suggested that a Q-containing genotype may identify individuals who are at risk of developing insulin resistance. Although these data were not replicated in a very powerful study performed in Denmark [10], they were confirmed among unrelated individuals from Finland and Sweden [11] where the association data were also ascertained and validated in a familybased study, namely the discordant for genotype sib pairs approach, thus making unlikely the possibility of a false positive result due to a population stratification [11]. In fact, nondiabetic siblings with the QK genotype had significantly higher fasting plasma glucose and insulin concentrations than siblings with the KK genotype. T2D siblings with the QK genotype also had higher glucose concentrations, fasting and after glucose load, and systolic blood pressure, as compared to diabetic siblings with the KK genotype. The mechanism by which the PC-1 Q variant may modulate insulin receptor and sensitivity was investigated in cellular models. In MCF-7 and HEK-293 transfected cells, the Q allele has stronger inhibitory activity on insulin receptor function and action than the more common K allele, and this was considered to be a likely consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the insulin receptor [9]. Moreover, a different mechanism by which PC-1 modulate insulin sensitivity has also been described [12]. A haplotype in the 3V-untranslated region of the PC-1 gene (i.e. a cluster of three single-nucleotide polymorphisms: G2897A, G2906C and C2948T) that modulates PC-1 expression and confers an increased risk for insulin resistance has been shown. In fact, individuals from Sicily, Italy carrying this haplotype were at higher risk ( P < 0.01) for insulin resistance and had higher ( P < 0.05) plasma glucose and insulin levels during an oral glucose tolerance test. These individuals also had higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. Data were replicated and confirmed in a case control study with T2D patients, performed in a different population (Gargano, East Coast Italy). PC-1 protein content in both skeletal muscle and cultured skin fibroblasts from the haplotype carrier individuals was also higher ( P < 0.05– 0.01). The mechanism of this PC-1 overexpression was explained by an observed significant increase in haplotype-specific mRNA half life, as assessed by transfection experiment in CHO cells. Importantly, the K121Q in exon 4 and the haplotype in the 3V-untranslated region were not in linkage disequilibrium.
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Insulin resistance is likely to precede and play a role in the vascular damage of diabetic nephropathy (DN). In fact, insulin resistance characterizes type 1 diabetic patients who develop albuminuria and their nondiabetic first-degree relatives [13,14] and underlies many of the alterations associated to DN, including high blood pressure, lipid abnormalities, increased left ventricular mass and a family history of hypertension and cardiovascular disease [15]. As for insulin resistance, DN also recognizes genetic background. Insulin resistance and DN may share, therefore, some common genetic determinants. PC-1 is likely to contribute to this common genetic background. In fact, in a study performed on 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years, we have shown that 22 patients carrying the Q allele of PC-1 have a faster ( P < 0.001) decline of the glomerular filtration rate than 55 KK genotype carrier patients [15]. Therefore, PC-1 Q allele identifies type 1 diabetic patients with a faster progression of DN. Furthermore, the K121Q PC-1 polymorphism can interact with the ACE I/D polymorphism in predicting the rate of decline of glomerular filtration rate and identifying patients who are likely to be ‘‘fast progressors’’ toward end-stage renal failure. However, also in the case of DN, the data on the role of PC-1 K121Q polymorphism seem to be conflicting. In a large case – control study [16] from the USA, the role of Q allele of PC-1 in increasing the risk of ND progression was confirmed. The latter study was performed on 659 patients: 307 with normal urinary albumin excretion despite diabetes duration of >15 years (control subjects) and 352 with advanced diabetic nephropathy, of whom 200 had persistent proteinuria and 152 had end-stage renal disease (ESRD). Here, the frequency of Q variant carriers was 21.5% in control subjects, 31.5% in patients with proteinuria, and 32.2% in those with ESRD ( P = 0.012). In a stratified analysis according to duration of diabetes, the risk of early-onset ESRD for Q carrier subjects was estimated to be 2.3 times that for noncarriers (95% CI, 1.2 – 4.6), suggesting that carriers of the Q variant of PC-1 are at increased risk for developing ESRD early in the course of type 1 diabetes. Interestingly, the association data were confirmed by a familybased approach using transmission disequilibrium test, thus making very unlikely the possibility of a false positive result due to a population stratification bias [16]. In contrast, a Danish group [17] found no effect of the K121Q PC-1 polymorphism on the same parameters in a clinically similar and much larger sample of type 1 diabetic patients (295 patients followed up for at least 3 years). In fact, patients carrying the Q allele had a mean rate of decline in glomerular filtration rate, during follow-up, similar to that observed in patients with the KK genotype. It is noteworthy that the same group was unable to demonstrate the association of the Q allele with IRS [17] in the same population. Overall, we believe it to be possible that the observed lack of association of the Q allele of PC-1 with IRS and/or ND may be characteristic of Danish population.
3. Protein tyrosin phosphatases One of the major advances in our understanding of insulin action has been the characterization of the central role of reversible tyrosine phosphorylation of the insulin receptor (IR) and its cellular substrate proteins in the mechanism of insulin action [18]. Over the past several years, evidence has supported the hypothesis that specific cellular
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protein-tyrosine phosphatases (PTPases) are expressed in insulin-sensitive tissues and have a physiological role in the regulation of insulin action in vivo by catalyzing the rapid dephosphorylation and deactivation of the receptor kinase in a manner that determines the steady-state insulin receptor kinase activity. PTPases have been divided into two broad categories: receptor-type, which have a general structure like a membrane receptor with an extracellular domain, a single transmembrane segment and one or two tandemly conserved PTPase catalytic domains; and nonreceptor-type, which have a single PTPase domain and additional functional protein domains. Many of the receptor-type PTPases also have conserved Immunoglobulin- and fibronectin III-like structural repeats in the extracellular segments, as well as other functional domains. Conversely, ‘‘nonreceptor’’ are intracellular PTPases frequently found in cytoplasm as protein complexes or in the endoplasmic reticulum, due to functional segments that target the PTPase to specific intracellular sites [19]. Functionally, all PTPases have in common a conserved f 230 amino acid domain that contains the PTPases signature sequence motif—(I/V)HCXAGXGR(S/T)G—which includes the cysteine residue that catalyzes the hydrolysis of protein-phosphotyrosine residues by the formation of a cysteinyl-phosphate intermediate [20]. In cellular, human and animal studies, the transmembrane, receptor-type PTPase LAR and the intracellular, nonreceptor enzyme PTP1-B have been shown to have a direct impact on insulin action and sensitivity. PTP1-B has also been tested as a possible candidate gene. 3.1. PTP1-B PTP1-B is a widely expressed enzyme that was first identified as a prominent PTPase in the cytosol fraction of placenta. The full-length enzyme is f 50 kDa, with a cleavable Cterminal segment downstream from the PTPase domain that directs its association with the endoplasmic reticulum either through a hydrophobic interaction or by attachment to a noncatalytic subunit [21]. Its gene, in human, spans more than 74 kb and has a large first intron of more than 54 kb [22]. PTP1-B is a major regulator of insulin sensitivity and body fat [23 – 28]. In fact, it physically interacts with and dephosphorylates the activated insulin receptor [29,30]. Furthermore, PTP1-B is greatly increased, as assessed by immunoblot, in the particulate fraction from obese, nondiabetic subjects [31]. These data suggest its role as a negative regulator of insulin action in the pathogenesis of insulin resistance and in human obesity. Additional evidence favoring the potential importance of PTP1-B in type 2 diabetes (T2D) comes from multiple linkage studies on chromosome 20q13.1 –q13.2 [32 –35] which harbors the PTP1-B gene [36]. A major role for PTP1-B in modulating insulin sensitivity has come from animal models. PTP1-B-deficient mice were generated [26] by targeted disruption of the mouse homologue of the PTP1-B gene. Mice were phenotypically and pathologically normal and had normal life span. In the fed state, homozygous mutant mice had slightly lower blood glucose concentrations, and half the circulating insulin concentrations, of wild type littermates. The enhanced insulin sensitivity of PTP1-B-deficient mice was also evident in glucose- and insulin-tolerance tests. After insulin injection, deficient mice showed
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increased phosphorylation of the insulin receptor in liver and muscle tissue compared to wild type mice. On a high-fat diet, PTP1-B-deficient mice were resistant to weight gain and remained insulin sensitive, while wild type mice rapidly gained weight and became insulin resistant. Very similar data were confirmed by subsequent studies [28]. With the availability of genomic structure and DNA sequence for PTP1-B, it has become possible to look for sequence variations which might associate to insulin resistance. In the 3V-UTR region of the PTP1-B gene, a 1484insG variation was identified [37]. This variation was associated in two different populations with several features of insulin resistance. Data were validated through a family-based approach by use of sib pairs discordant for genotype. Subjects carrying the 1484insG variant showed PTP1-B mRNA overexpression in skeletal muscle. PTP1-B mRNA stability was significantly higher in human embryonic kidney cells transfected with 1484insG PTP1-B as compared with those transfected with wild type PTP1-B. The data indicated that the 1484insG allele causes PTP1-B overexpression and plays a role in insulin resistance. Other PTP1-B gene variations were found associated with impaired glucose tolerance (IGT) and T2D. A rare missense variation, namely P387L, was found [38] significantly associated ( P = 0.036) with the risk of T2D. In an association study performed in a Danish Caucasian population, the P387L variant was found in 14 out of 527 T2D subjects (allelic frequency = 0.014) and in 5 out of 542 glucose-tolerant normal controls (allelic frequency = 0.005). Since the proline at position 387 is located next to a serine residue (position 386) which is known to be phosphorylated in vitro by the p34cdc2 kinase, the authors have shown that the 387L allele has a significant reduction in p34cdc2 kinase directed in vitro phosphorylation, as compared to the 387P, wild type, allele. Another single-nucleotide polymorphism (SNP), namely 981CT, was found [39] to be significantly associated with the risk of either impaired glucose tolerance (IGT) or T2D in the Oji-Cree of Sandy Lake, Ontario, Canada. Out of 653 subjects genotyped, 68 were heterozygous, and none was a homozygous. Thus, the overall frequencies of the C allele and the T allele were 0.948 and 0.052, respectively. Subjects with the PTP1-B 981T/981C genotype were approximately 40% less likely to have IGT or diabetes as compared to subjects with the 981C/981C genotype ( P = 0.040). There was no difference in quantitative traits among subjects grouped according to the PTP1-B 981CT genotype, suggesting that some genomic variation in PTP1-B could be associated with a reduced risk of diabetes.
4. Conclusions The IRS plays a major role in the pathogenesis of type 2 diabetes and cardiovascular diseases [1]. Both environmental and genetic determinants contribute to its pathogenesis with the latter being not completely understood [1]. Among others, genes encoding for inhibitors of insulin receptor function certainly play a role in the susceptibility of the IRS. However, their exact contribution and the contest in which takes place their modulation of insulin sensitivity, have to be better understood. In fact, insulin resistance is believed to be caused by a variety of genes able to interact each other (i.e. genetic epistasis) and with several environmental factors. This scenario strongly suggests geneticists to be aware about the risk of underestimating the effect of ‘‘insulin
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resistance’’ genes when individually studied. At variance, allowing for interaction between genes and between genes and environment may help a deeper understanding of the molecular causes of insulin resistance and related metabolic and cardiovascular derangement which, in turn, is a prerequisite for setting up individualized prevention and/or treatment strategies.
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Genetic variants of modulators of insulin action Vittorio Tassi a, Rosa Di Paola a, Antonio Pizzuti b, Lucia Frittitta c, Vincenzo Trischitta a,d,* a
Unit of Endocrinology, Scientific Institute CSS, San Giovanni Rotondo (FG), Italy b Scientific Institute CSS-Mendel, Rome, Italy c Institute of Internal Medicine, Endocrine and Metabolic Diseases, University of Catania, Garibaldi Hospital, Catania, Italy d Department of Clinical Sciences, University ‘‘La Sapienza’’, Rome, Italy Received 7 February 2003; accepted 7 February 2003
Abstract The insulin resistance syndrome (IRS) is a common clinical condition whose aetiology is poorly understood and which is known to recognize a genetic background. Impairment in insulin receptor (IR) tyrosine-kinase activity has been demonstrated in tissues from insulin-resistant subjects. Several inhibitors of the insulin receptor tyrosine-kinase activity have been recently described and associated with human insulin resistance. Genes encoding for two of these inhibitors, namely PC-1 and PTP1B, have been deeply studied. The obtained results are here reported. PC-1, a class II transmembrane ectoenzyme, modulates insulin sensitivity by different mechanisms, unravelled by the discovery of two genetic variants. A polymorphism in exon 4, namely K121Q, has been described to be strongly associated with insulin resistance. As compared to the more common K variant, the Q variant has a greater inhibitory activity on insulin receptor function and action, by interacting more strongly with the insulin receptor and significantly reducing receptor autophosphorylation, PC-1 Q variant also identifies type 1 diabetic patients with a faster progression of diabetic nephropathy (DN), a condition that may share some common genetic determinants with insulin resistance. Furthermore, a haplotype in the 3V-untranslated region modulates PC-1 expression in skeletal muscle and confers, therefore, an increased risk for insulin resistance. The mechanism of PC-1 overexpression was explained by an observed significant increase in haplotype-specific mRNA half life. PTP1-B, a nonreceptor-type protein-tyrosine phosphatase (PTPase) that physically interacts with and dephosphorylates the activated insulin receptor, is a major regulator of insulin sensitivity and body fat, as shown from experimental evidences in animal models. A number of polymorphic variants, identified in different populations, have been associated to insulin resistance and its
* Corresponding author. Tel.: +39-0882-410627/629; fax: +39-0882-451637. E-mail addresses: [email protected], [email protected] (V. Trischitta). 0531-5131/03 D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00138-9
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associated clinical conditions. A 1484insG variation in the 3V-UTR region was associated with several features of insulin resistance. Subjects carrying the 1484insG variant showed PTP1-B mRNA overexpression in skeletal muscle, supposedly due to an mRNA stabilization, as demonstrated by transfection experiments. A rare missense variation, namely P387L, was found significantly associated with the risk of type 2 diabetes (T2D). Also, a silent third base polymorphism, namely 981CT, was found to be associated with higher risk of either impaired glucose tolerance (IGT) or type 2 diabetes. Altogether, these data clearly indicate that subtle mutations affecting genes encoding for proteins able to inhibit insulin receptor tyrosine-kinase activity may play a role in modulating susceptibility for insulin resistance and/or type 2 diabetes mellitus. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Insulin resistance syndrome; PC-1; PTP1-B; Diabetic nephropathy
1. Introduction The insulin resistance syndrome (IRS) is a common clinical condition which consists in the clustering in the same individual of several cardiovascular risk factors, including abdominal obesity, hypertension, dyslipidaemia, hyperinsulinemia and glucose intolerance. Its etiology is poorly understood. Clustering of the syndrome in families suggests a genetic background. Common variants in a number of candidate genes affecting fat and glucose metabolism, in combination with environmental triggers, are likely to increase susceptibility to the syndrome. Defects in insulin receptor tyrosine-kinase activity have been demonstrated in tissues from insulin-resistant subjects. However, mutations in the insulin receptor gene are rare. Therefore, other molecules capable of modulating insulin receptor function are very likely to play a major role in the IRS. Several inhibitors of the insulin receptor tyrosine-kinase activity have been recently described and associated with human insulin resistance [1]. The genes encoding for these proteins are, therefore, candidates for the IRS. This article will be focused on two of these inhibitors, namely PC-1 and PTP1-B, which have been deeply studied.
2. PC-1 PC-1 is a class II transmembrane ectoenzyme located both on plasma membrane and in the endoplasmic reticulum as a homodimer of 230 –260 kDa, depending on the cell type, oriented with a short cytoplasmic N-terminal tail, a transmembrane and a large C-terminal extracellular domain [2]. PC-1 is expressed in several human tissues and cells, including skeletal muscle, fat, liver, pancreas, testis, osteoblasts, hepatocytes, skin fibroblast and several continuous cell lines. The ectoenzyme has phosphodiesterase I/pyrophosphatase activities and belongs to a multigene family. Its gene in human is organised in 24 exons [3] on chromosome 6q22 – q23 [4]. Several evidences have proven a negative modulation of PC-1 on insulin signalling and a significant role in insulin resistance and its related abnormalities [5– 7].
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Skin fibroblasts from insulin-resistant and/or T2D patients overexpress an inhibitor of insulin-receptor tyrosine kinase which has been proven to be PC-1 [6]. In addition, overexpression of PC-1 in transfected cultured cells [6,7] reduced insulin signalling and action. PC-1 inhibition of insulin receptor kinase activity is exerted by a direct, physical, interaction with the receptor alpha-subunit [8,9]. A polymorphism in exon 4 of the PC-1 gene [3] (K121Q) has been described to be strongly associated with insulin resistance in 121 healthy nonobese, nondiabetic Caucasians individuals from Sicily. As compared with 80 KK allele subjects, 41 Q allele carriers showed higher glucose and insulin levels during oral glucose tolerance tests ( P < 0.001) and insulin resistance by euglycemic clamp ( P = 0.005). Q carriers had a higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28 –7.0], P < 0.001). Insulin receptor autophosphorylation was significantly reduced in cultured skin fibroblasts from KQ versus KK subjects ( P < 0.01). The results suggested that a Q-containing genotype may identify individuals who are at risk of developing insulin resistance. Although these data were not replicated in a very powerful study performed in Denmark [10], they were confirmed among unrelated individuals from Finland and Sweden [11] where the association data were also ascertained and validated in a familybased study, namely the discordant for genotype sib pairs approach, thus making unlikely the possibility of a false positive result due to a population stratification [11]. In fact, nondiabetic siblings with the QK genotype had significantly higher fasting plasma glucose and insulin concentrations than siblings with the KK genotype. T2D siblings with the QK genotype also had higher glucose concentrations, fasting and after glucose load, and systolic blood pressure, as compared to diabetic siblings with the KK genotype. The mechanism by which the PC-1 Q variant may modulate insulin receptor and sensitivity was investigated in cellular models. In MCF-7 and HEK-293 transfected cells, the Q allele has stronger inhibitory activity on insulin receptor function and action than the more common K allele, and this was considered to be a likely consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the insulin receptor [9]. Moreover, a different mechanism by which PC-1 modulate insulin sensitivity has also been described [12]. A haplotype in the 3V-untranslated region of the PC-1 gene (i.e. a cluster of three single-nucleotide polymorphisms: G2897A, G2906C and C2948T) that modulates PC-1 expression and confers an increased risk for insulin resistance has been shown. In fact, individuals from Sicily, Italy carrying this haplotype were at higher risk ( P < 0.01) for insulin resistance and had higher ( P < 0.05) plasma glucose and insulin levels during an oral glucose tolerance test. These individuals also had higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. Data were replicated and confirmed in a case control study with T2D patients, performed in a different population (Gargano, East Coast Italy). PC-1 protein content in both skeletal muscle and cultured skin fibroblasts from the haplotype carrier individuals was also higher ( P < 0.05– 0.01). The mechanism of this PC-1 overexpression was explained by an observed significant increase in haplotype-specific mRNA half life, as assessed by transfection experiment in CHO cells. Importantly, the K121Q in exon 4 and the haplotype in the 3V-untranslated region were not in linkage disequilibrium.
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Insulin resistance is likely to precede and play a role in the vascular damage of diabetic nephropathy (DN). In fact, insulin resistance characterizes type 1 diabetic patients who develop albuminuria and their nondiabetic first-degree relatives [13,14] and underlies many of the alterations associated to DN, including high blood pressure, lipid abnormalities, increased left ventricular mass and a family history of hypertension and cardiovascular disease [15]. As for insulin resistance, DN also recognizes genetic background. Insulin resistance and DN may share, therefore, some common genetic determinants. PC-1 is likely to contribute to this common genetic background. In fact, in a study performed on 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years, we have shown that 22 patients carrying the Q allele of PC-1 have a faster ( P < 0.001) decline of the glomerular filtration rate than 55 KK genotype carrier patients [15]. Therefore, PC-1 Q allele identifies type 1 diabetic patients with a faster progression of DN. Furthermore, the K121Q PC-1 polymorphism can interact with the ACE I/D polymorphism in predicting the rate of decline of glomerular filtration rate and identifying patients who are likely to be ‘‘fast progressors’’ toward end-stage renal failure. However, also in the case of DN, the data on the role of PC-1 K121Q polymorphism seem to be conflicting. In a large case – control study [16] from the USA, the role of Q allele of PC-1 in increasing the risk of ND progression was confirmed. The latter study was performed on 659 patients: 307 with normal urinary albumin excretion despite diabetes duration of >15 years (control subjects) and 352 with advanced diabetic nephropathy, of whom 200 had persistent proteinuria and 152 had end-stage renal disease (ESRD). Here, the frequency of Q variant carriers was 21.5% in control subjects, 31.5% in patients with proteinuria, and 32.2% in those with ESRD ( P = 0.012). In a stratified analysis according to duration of diabetes, the risk of early-onset ESRD for Q carrier subjects was estimated to be 2.3 times that for noncarriers (95% CI, 1.2 – 4.6), suggesting that carriers of the Q variant of PC-1 are at increased risk for developing ESRD early in the course of type 1 diabetes. Interestingly, the association data were confirmed by a familybased approach using transmission disequilibrium test, thus making very unlikely the possibility of a false positive result due to a population stratification bias [16]. In contrast, a Danish group [17] found no effect of the K121Q PC-1 polymorphism on the same parameters in a clinically similar and much larger sample of type 1 diabetic patients (295 patients followed up for at least 3 years). In fact, patients carrying the Q allele had a mean rate of decline in glomerular filtration rate, during follow-up, similar to that observed in patients with the KK genotype. It is noteworthy that the same group was unable to demonstrate the association of the Q allele with IRS [17] in the same population. Overall, we believe it to be possible that the observed lack of association of the Q allele of PC-1 with IRS and/or ND may be characteristic of Danish population.
3. Protein tyrosin phosphatases One of the major advances in our understanding of insulin action has been the characterization of the central role of reversible tyrosine phosphorylation of the insulin receptor (IR) and its cellular substrate proteins in the mechanism of insulin action [18]. Over the past several years, evidence has supported the hypothesis that specific cellular
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protein-tyrosine phosphatases (PTPases) are expressed in insulin-sensitive tissues and have a physiological role in the regulation of insulin action in vivo by catalyzing the rapid dephosphorylation and deactivation of the receptor kinase in a manner that determines the steady-state insulin receptor kinase activity. PTPases have been divided into two broad categories: receptor-type, which have a general structure like a membrane receptor with an extracellular domain, a single transmembrane segment and one or two tandemly conserved PTPase catalytic domains; and nonreceptor-type, which have a single PTPase domain and additional functional protein domains. Many of the receptor-type PTPases also have conserved Immunoglobulin- and fibronectin III-like structural repeats in the extracellular segments, as well as other functional domains. Conversely, ‘‘nonreceptor’’ are intracellular PTPases frequently found in cytoplasm as protein complexes or in the endoplasmic reticulum, due to functional segments that target the PTPase to specific intracellular sites [19]. Functionally, all PTPases have in common a conserved f 230 amino acid domain that contains the PTPases signature sequence motif—(I/V)HCXAGXGR(S/T)G—which includes the cysteine residue that catalyzes the hydrolysis of protein-phosphotyrosine residues by the formation of a cysteinyl-phosphate intermediate [20]. In cellular, human and animal studies, the transmembrane, receptor-type PTPase LAR and the intracellular, nonreceptor enzyme PTP1-B have been shown to have a direct impact on insulin action and sensitivity. PTP1-B has also been tested as a possible candidate gene. 3.1. PTP1-B PTP1-B is a widely expressed enzyme that was first identified as a prominent PTPase in the cytosol fraction of placenta. The full-length enzyme is f 50 kDa, with a cleavable Cterminal segment downstream from the PTPase domain that directs its association with the endoplasmic reticulum either through a hydrophobic interaction or by attachment to a noncatalytic subunit [21]. Its gene, in human, spans more than 74 kb and has a large first intron of more than 54 kb [22]. PTP1-B is a major regulator of insulin sensitivity and body fat [23 – 28]. In fact, it physically interacts with and dephosphorylates the activated insulin receptor [29,30]. Furthermore, PTP1-B is greatly increased, as assessed by immunoblot, in the particulate fraction from obese, nondiabetic subjects [31]. These data suggest its role as a negative regulator of insulin action in the pathogenesis of insulin resistance and in human obesity. Additional evidence favoring the potential importance of PTP1-B in type 2 diabetes (T2D) comes from multiple linkage studies on chromosome 20q13.1 –q13.2 [32 –35] which harbors the PTP1-B gene [36]. A major role for PTP1-B in modulating insulin sensitivity has come from animal models. PTP1-B-deficient mice were generated [26] by targeted disruption of the mouse homologue of the PTP1-B gene. Mice were phenotypically and pathologically normal and had normal life span. In the fed state, homozygous mutant mice had slightly lower blood glucose concentrations, and half the circulating insulin concentrations, of wild type littermates. The enhanced insulin sensitivity of PTP1-B-deficient mice was also evident in glucose- and insulin-tolerance tests. After insulin injection, deficient mice showed
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increased phosphorylation of the insulin receptor in liver and muscle tissue compared to wild type mice. On a high-fat diet, PTP1-B-deficient mice were resistant to weight gain and remained insulin sensitive, while wild type mice rapidly gained weight and became insulin resistant. Very similar data were confirmed by subsequent studies [28]. With the availability of genomic structure and DNA sequence for PTP1-B, it has become possible to look for sequence variations which might associate to insulin resistance. In the 3V-UTR region of the PTP1-B gene, a 1484insG variation was identified [37]. This variation was associated in two different populations with several features of insulin resistance. Data were validated through a family-based approach by use of sib pairs discordant for genotype. Subjects carrying the 1484insG variant showed PTP1-B mRNA overexpression in skeletal muscle. PTP1-B mRNA stability was significantly higher in human embryonic kidney cells transfected with 1484insG PTP1-B as compared with those transfected with wild type PTP1-B. The data indicated that the 1484insG allele causes PTP1-B overexpression and plays a role in insulin resistance. Other PTP1-B gene variations were found associated with impaired glucose tolerance (IGT) and T2D. A rare missense variation, namely P387L, was found [38] significantly associated ( P = 0.036) with the risk of T2D. In an association study performed in a Danish Caucasian population, the P387L variant was found in 14 out of 527 T2D subjects (allelic frequency = 0.014) and in 5 out of 542 glucose-tolerant normal controls (allelic frequency = 0.005). Since the proline at position 387 is located next to a serine residue (position 386) which is known to be phosphorylated in vitro by the p34cdc2 kinase, the authors have shown that the 387L allele has a significant reduction in p34cdc2 kinase directed in vitro phosphorylation, as compared to the 387P, wild type, allele. Another single-nucleotide polymorphism (SNP), namely 981CT, was found [39] to be significantly associated with the risk of either impaired glucose tolerance (IGT) or T2D in the Oji-Cree of Sandy Lake, Ontario, Canada. Out of 653 subjects genotyped, 68 were heterozygous, and none was a homozygous. Thus, the overall frequencies of the C allele and the T allele were 0.948 and 0.052, respectively. Subjects with the PTP1-B 981T/981C genotype were approximately 40% less likely to have IGT or diabetes as compared to subjects with the 981C/981C genotype ( P = 0.040). There was no difference in quantitative traits among subjects grouped according to the PTP1-B 981CT genotype, suggesting that some genomic variation in PTP1-B could be associated with a reduced risk of diabetes.
4. Conclusions The IRS plays a major role in the pathogenesis of type 2 diabetes and cardiovascular diseases [1]. Both environmental and genetic determinants contribute to its pathogenesis with the latter being not completely understood [1]. Among others, genes encoding for inhibitors of insulin receptor function certainly play a role in the susceptibility of the IRS. However, their exact contribution and the contest in which takes place their modulation of insulin sensitivity, have to be better understood. In fact, insulin resistance is believed to be caused by a variety of genes able to interact each other (i.e. genetic epistasis) and with several environmental factors. This scenario strongly suggests geneticists to be aware about the risk of underestimating the effect of ‘‘insulin
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resistance’’ genes when individually studied. At variance, allowing for interaction between genes and between genes and environment may help a deeper understanding of the molecular causes of insulin resistance and related metabolic and cardiovascular derangement which, in turn, is a prerequisite for setting up individualized prevention and/or treatment strategies.
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