Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis. 1. Introduction Insulin is the primary anabolic hormone known and it regulates several processes, including cellular growth, differentiation, apoptosis, and lipid, protein, and glucose synthesis and breakdown [1]. The first step of insulin action involves its binding to the insulin receptor (IR) and the consequent activation of the receptor intrinsic tyrosine kinase activity. Once activated, the IR catalyzes phosphorylation of other proteins, such as the IR substrate proteins (IRS1, IRS2, IRS3, and IRS4), which, in turn, act as docking molecules for SH2-domain containing proteins, including the regulatory subunits of Phosphoinositides 3 kinase (PI3K). PI3K then catalyzes the phosphorylation of the 3′ hydroxyl subunit of phosphoinositides (PIs), notably converting PtdIns(4,5)P2 (PIP2) to PtdIns(3,4,5)P3 (PIP3), thus activating an assorted group of signaling proteins, containing phosphoinositide-binding domains. The activation of these proteins subsequently leads to the phosphorylation and activation of the serine-threonine kinase Akt (also known as protein kinase B) that ultimately transmits the insulin signal to a branching series
References
[1]
J. E. Pessin and A. R. Saltiel, “Signaling pathways in insulin action: molecular targets of insulin resistance,” The Journal of Clinical Investigation, vol. 106, no. 2, pp. 165–169, 2000.
[2]
G. Sesti, “Pathophysiology of insulin resistance,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 20, no. 4, pp. 665–679, 2006.
[3]
I. D. Goldfine, B. A. Maddux, J. F. Youngren et al., “The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities,” Endocrine Reviews, vol. 29, no. 1, pp. 62–75, 2008.
[4]
N. Hashimoto, E. P. Feener, W. R. Zhang, and B. J. Goldstein, “Insulin receptor protein-tyrosine phosphatases. Leukocyte common antigen- related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain,” The Journal of Biological Chemistry, vol. 267, no. 20, pp. 13811–13814, 1992.
[5]
B. L. Seely, P. A. Staubs, D. R. Reichart, et al., “Protein tyrosine phosphatase 1B interacts with the activated insulin receptor,” Diabetes, vol. 45, no. 10, pp. 1379–1385, 1996.
[6]
X. Pesesse, S. Deleu, F. de Smedt, L. Drayer, and C. Erneux, “Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP,” Biochemical and Biophysical Research Communications, vol. 239, no. 3, pp. 697–700, 1997.
[7]
K. Du, S. Herzig, R. N. Kulkarni, and M. Montminy, “TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver,” Science, vol. 300, no. 5625, pp. 1574–1577, 2003.
[8]
H. E. Lebovitz, “Insulin resistance—a common link between type 2 diabetes and cardiovascular disease,” Diabetes, Obesity and Metabolism, vol. 8, no. 3, pp. 237–249, 2006.
[9]
S. Prudente, E. Morini, and V. Trischitta, “Insulin signaling regulating genes: effect on T2DM and cardiovascular risk,” Nature Reviews Endocrinology, vol. 5, no. 12, pp. 682–693, 2009.
[10]
S. H. Kwak and K. S. Park, “Genetics of type 2 diabetes and potential clinical implications,” Archives of Pharmacal Research, vol. 36, no. 2, pp. 167–177, 2013.
[11]
B. A. Maddux, Y. N. Chang, D. Accili, O. P. McGuinness, J. F. Youngren, and I. D. Goldfine, “Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia,” American Journal of Physiology—Endocrinology and Metabolism, vol. 290, no. 4, pp. E746–E749, 2006.
[12]
R. Gijsbers, H. Ceulemans, and M. Bollen, “Functional characterization of the non-catalytic ectodomains of the nucleotide pyrophosphatase/phosphodiesterase NPP1,” The Biochemical Journal, vol. 371, no. 2, pp. 321–330, 2003.
[13]
B. V. Costanzo, V. Trischitta, R. Di Paola et al., “The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121),” Diabetes, vol. 50, no. 4, pp. 831–836, 2001.
[14]
R. Di Paola, N. Caporarello, A. Marucci et al., “ENPP1 affects insulin action and secretion: evidences from in vitro studies,” PLoS ONE, vol. 6, no. 5, article e19462, 2011.
[15]
R. Baratta, P. Rossetti, S. Prudente et al., “Role of the ENPP1 K121Q polymorphism in glucose homeostasis,” Diabetes, vol. 57, no. 12, pp. 3360–3364, 2008.
[16]
A. Pizzuti, L. Frittitta, A. Argiolas et al., “A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance,” Diabetes, vol. 48, no. 9, pp. 1881–1884, 1999.
[17]
N. Abate, L. Carulli, A. Cabo-Chan, M. Chandalia, P. G. Snell, and S. M. Grundy, “Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance,” The Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 12, pp. 5927–5934, 2003.
[18]
N. Abate, M. Chandalia, P. Satija et al., “ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes,” Diabetes, vol. 54, no. 4, pp. 1207–1213, 2005.
[19]
R. Baratta, R. Di Paola, D. Spampinato et al., “Evidence for genetic epistasis in human insulin resistance: the combined effect of PC-1 (K121Q) and PPARγ2 (P12A) polymorphisms,” Journal of Molecular Medicine, vol. 81, no. 11, pp. 718–723, 2003.
[20]
L. Frittitta, R. Baratta, D. Spampinato et al., “The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance,” The Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 12, pp. 5888–5891, 2001.
[21]
J. L. González-Sánchez, M. T. Martínez-Larrad, C. Fernández-Pérez, A. Kubaszek, M. Laakso, and M. Serrano-Ríos, “K121Q PC-1 gene polymorphism is not associated with insulin resistance in a Spanish population,” Obesity Research, vol. 11, no. 5, pp. 603–605, 2003.
[22]
H. F. Gu, P. Almgren, E. Lindholm et al., “Association between the human glycoprotein PC-1 gene and elevated glucose and insulin levels in a paired-sibling analysis,” Diabetes, vol. 49, no. 9, pp. 1601–1603, 2000.
[23]
K. Hamaguchi, H. Terao, Y. Kusuda et al., “The PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic and is associated with type 2 diabetes,” The Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 3, pp. 1359–1364, 2004.
[24]
A. Kubaszek, J. Pihlajam？ki, P. Karhap？？, I. Vauhkonen, and M. Laakso, “The K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with dyslipidemia,” Diabetes Care, vol. 26, no. 2, pp. 464–467, 2003.
[25]
A. Kubaszek, A. Markkanen, J. G. Eriksson et al., “The association of the K121Q polymorphism of the plasma cell glycoprotein-1 gene with type 2 diabetes and hypertension depends on size at birth,” The Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 5, pp. 2044–2047, 2004.
[26]
I. Tasic, M. Milojkovic, R. Sunder-Plassmann, G. Lazarevic, N. M. Tasic, and V. Stefanovic, “The association of PC-1 (ENPP1) K121Q polymorphism with metabolic syndrome in patients with coronary heart disease,” Clinica Chimica Acta, vol. 377, no. 1-2, pp. 237–242, 2007.
[27]
S. Bacci, O. Ludovico, S. Prudente et al., “The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction,” Diabetes, vol. 54, no. 10, pp. 3021–3025, 2005.
[28]
J. Bochenski, G. Placha, K. Wanic et al., “New polymorphism of ENPP1 (PC-1) is associated with increased risk of type 2 diabetes among obese individuals,” Diabetes, vol. 55, no. 9, pp. 2626–2630, 2006.
[29]
D. Meyre, N. Bouatia-Naji, A. Tounian et al., “Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes,” Nature Genetics, vol. 37, no. 8, pp. 863–867, 2005.
[30]
N. Matsuoka, A. Patki, H. K. Tiwari et al., “Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults,” International Journal of Obesity, vol. 30, no. 2, pp. 233–237, 2006.
[31]
Y. El Achhab, D. Meyre, N. Bouatia-Naji et al., “Association of the ENPP1 K121Q polymorphism with type 2 diabetes and obesity in the Moroccan population,” Diabetes & Metabolism, vol. 35, no. 1, pp. 37–42, 2009.
[32]
J. B. McAteer, S. Prudente, S. Bacci et al., “The ENPP1 K121Q polymorphism is associated with type 2 diabetes in european populations evidence from an updated meta-analysis in 42,042 subjects,” Diabetes, vol. 57, no. 4, pp. 1125–1130, 2008.
[33]
E. Zeggini, L. J. Scott, R. Saxena, and B. F. Voight, “Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes,” Nature Genetics, vol. 40, no. 5, pp. 638–645, 2008.
[34]
T. M. Frayling, S. Wiltshire, G. A. Hitman et al., “Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11,” Diabetes, vol. 52, no. 7, pp. 1857–1863, 2003.
[35]
A. F. Moore, K. A. Jablonski, C. C. Mason et al., “The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention program,” The Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 2, pp. 449–455, 2009.
[36]
K. Müssig, M. Heni, C. Thamer et al., “The ENPP1 K121Q polymorphism determines individual susceptibility to the insulin-sensitising effect of lifestyle intervention,” Diabetologia, vol. 53, no. 3, pp. 504–509, 2010.
[37]
M. Maranghi, S. Prudente, L. D’Erasmo, et al., “The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K121Q polymorphism modulates the beneficial effect of weight loss on fasting glucose in non-diabetic individuals,” Nutrition, Metabolism, and Cardiovascular Diseases, 2012.
[38]
S. Prudente, M. Chandalia, E. Morini et al., “The Q121/Q121 genotype of ENPP1/PC-1 is associated with lower BMI in non-diabetic whites,” Obesity, vol. 15, no. 1, pp. 1–4, 2007.
[39]
C. Wan, T. Zhang, B. Wang, et al., “Obesity risk associated with the K121Q polymorphism of the glycoprotein PC-1 gene,” Diabetes, Obesity & Metabolism, vol. 8, no. 6, pp. 703–708, 2006.
[40]
Y. B？ttcher, A. K？rner, T. Reinehr, et al., “ENPP1 variants and haplotypes predispose to early onset obesity and impaired glucose and insulin metabolism in German obese children,” The Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 12, pp. 4948–4952, 2006.
[41]
S. Bacci, R. Di Paola, C. Menzaghi et al., “ENPP1 Q121 variant, increased pulse pressure and reduced insulin signaling, and nitric oxide synthase activity in endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 10, pp. 1678–1683, 2009.
[42]
G. Endler, C. Mannhalter, H. Sunder-Plassmann et al., “The K121Q polymorphism in the plasma cell membrane glycoprotein 1 gene predisposes to early myocardial infarction,” Journal of Molecular Medicine, vol. 80, no. 12, pp. 791–795, 2002.
[43]
S. Bacci, S. Rizza, S. Prudente et al., “The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients,” Diabetes, vol. 60, no. 3, pp. 1000–1007, 2011.
[44]
H. N. Lyon, J. C. Florez, T. Bersaglieri et al., “Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity,” Diabetes, vol. 55, no. 11, pp. 3180–3184, 2006.
[45]
L. Frittitta, T. Ercolino, M. Bozzali et al., “A cluster of three single nucleotide polymorphisms in the 3’-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities,” Diabetes, vol. 50, no. 8, pp. 1952–1955, 2001.
[46]
M. J. Chagnon, N. Uetani, and M. L. Tremblay, “Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases,” Biochemistry and Cell Biology, vol. 82, no. 6, pp. 664–675, 2004.
[47]
J. M. Zabolotny, Y. B. Kim, O. D. Peroni et al., “Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 9, pp. 5187–5192, 2001.
[48]
D. T. Kulas, W. R. Zhang, B. J. Goldstein, R. W. Furlanetto, and R. A. Mooney, “Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR,” The Journal of Biological Chemistry, vol. 270, no. 6, pp. 2435–2438, 1995.
[49]
F. Ahmad, R. V. Considine, and B. J. Goldstein, “Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects,” The Journal of Clinical Investigation, vol. 95, no. 6, pp. 2806–2812, 1995.
[50]
F. Ahmad, J. L. Azevedo, R. Cortright, G. L. Dohm, and B. J. Goldstein, “Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes,” The Journal of Clinical Investigation, vol. 100, no. 2, pp. 449–458, 1997.
[51]
G. Miscio, V. Tassi, A. Coco et al., “The allelic variant of LAR gene promoter -127 bp T→A is associated with reduced risk of obesity and other features related to insulin resistance,” Journal of Molecular Medicine, vol. 82, no. 7, pp. 459–466, 2004.
[52]
C. Menzaghi, G. Paroni, C. de Bonis et al., “The protein tyrosine phosphatase receptor type f (PTPRF) locus is associated with coronary artery disease in type 2 diabetes,” Journal of Internal Medicine, vol. 263, no. 6, pp. 653–654, 2008.
[53]
K. Norris, F. Norris, D. H. Kono et al., “Expression of protein-tyrosine phosphatases in the major insulin target tissues,” The FEBS Letters, vol. 415, no. 3, pp. 243–248, 1997.
[54]
M. J. Chagnon, M. Elchebly, N. Uetani et al., “Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma,” Canadian Journal of Physiology and Pharmacology, vol. 84, no. 7, pp. 755–763, 2006.
[55]
E. C. L？ngberg, H. F. Gu, S. Nordman, S. Efendic, and C. G. Ostenson, “Genetic variation in receptor protein tyrosine phosphatase sigma is associated with type 2 diabetes in Swedish Caucasians,” European Journal of Endocrinology/European Federation of Endocrine Societies, vol. 157, no. 4, pp. 459–464, 2007.
[56]
F. J. Tsai, C. F. Yang, C. C. Chen et al., “A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese,” PLoS Genetics, vol. 6, no. 2, Article ID e1000847, 2010.
[57]
Y. C. Chang, Y. F. Chiu, P. H. Liu, et al., “Replication of genome-wide association signals of type 2 diabetes in Han Chinese in a prospective cohort,” Clinical Endocrinology, vol. 76, no. 3, pp. 365–372, 2012.
[58]
Q. Pei, Q. Huang, G. P. Yang, et al., “PPAR-γ2 and PTPRD gene polymorphisms influence type 2 diabetes patients’response to pioglitazone in China,” Acta Pharmacologica Sinica, vol. 34, no. 2, pp. 255–261, 2013.
[59]
F. Bauer, N. C. Onland-Moret, O. M. N. Charlotte, et al., “PTPN1 polymorphisms are associated with total and low-density lipoprotein cholesterol,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 17, no. 1, pp. 28–34, 2010.
[60]
F. Bauer, N. C. Onland-Moret, A. G. Niehoff et al., “No association of PTPN1 polymorphisms with macronutrient intake and measures of adiposity,” Obesity, vol. 16, no. 12, pp. 2767–2771, 2008.
[61]
J. L. Bento, N. D. Palmer, J. C. Mychaleckyj, et al., “Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes,” Diabetes, vol. 53, no. 11, pp. 3007–3012, 2004.
[62]
N. D. Palmer, J. L. Bento, J. C. Mychaleckyj et al., “Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: The Insulin Resistance Atherosclerosis Study (IRAS) family study,” Diabetes, vol. 53, no. 11, pp. 3013–3019, 2004.
[63]
N. J. Spencer-Jones, X. Wang, H. Snieder, T. D. Spector, N. D. Carter, and S. D. O'Dell, “Protein tyrosine phosphatase-1B gene PTPN1: selection of tagging single nucleotide polymorphisms and association with body fat, insulin sensitivity, and the metabolic syndrome in a normal female population,” Diabetes, vol. 54, no. 11, pp. 3296–3304, 2005.
[64]
C. Cheyssac, C. Lecoeur, A. Dechaume et al., “Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population,” BMC Medical Genetics, vol. 7, article 44, 2006.
[65]
K. P. Burdon, J. L. Bento, C. D. Langefeld et al., “Association of protein tyrosine phosphatase-N1 polymorphisms with coronary calcified plaque in the diabetes heart study,” Diabetes, vol. 55, no. 3, pp. 651–658, 2006.
[66]
J. C. Florez, C. M. Agapakis, N. P. Burtt et al., “Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people,” Diabetes, vol. 54, no. 6, pp. 1884–1891, 2005.
[67]
M. Traurig, R. L. Hanson, S. Kobes, C. Bogardus, and L. J. Baier, “Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians,” Diabetologia, vol. 50, no. 5, pp. 985–989, 2007.
[68]
K. Wanic, M. T. Malecki, T. Klupa, J. H. Warram, J. Sieradzki, and A. S. Krolewski, “Lack of association between polymorphisms in the gene encoding protein tyrosine phosphatase 1B (PTPN1) and risk of Type 2 diabetes,” Diabetic Medicine, vol. 24, no. 6, pp. 650–655, 2007.
[69]
R. Di Paola, L. Frittitta, G. Miscio, et al., “A variation in 3'UTR of hPTP1B increases specific gene expression and associates with insulin resistance,” American Journal of Human Genetics, vol. 70, no. 3, pp. 806–812, 2002.
[70]
R. Meshkani, M. Taghikhani, A. Mosapour et al., “1484insG polymorphism of the PTPN1 gene is associated with insulin resistance in an Iranian population,” Archives of Medical Research, vol. 38, no. 5, pp. 556–562, 2007.
[71]
D. Bodhini, V. Radha, S. Ghosh, P. P. Majumder, and V. Mohan, “Lack of association of PTPN1 gene polymorphisms with type 2 diabetes in south Indians,” Journal of Genetics, vol. 90, no. 2, pp. 323–326, 2011.
[72]
I. Dahlman, H. Wahrenberg, L. Persson, and P. Arner, “No association of reported functional protein tyrosine phosphatase 1B 3′ UTR gene polymorphism with features of the metabolic syndrome in a Swedish population,” Journal of Internal Medicine, vol. 255, no. 6, pp. 694–695, 2004.
[73]
S. M. Echwald, H. Bach, H. Vestergaard et al., “A P387L variant in protein tyrosine phosphatase-1B (PTP-1B) is associated with type 2 diabetes and impaired serine phosphorylation of PTP-1B in vitro,” Diabetes, vol. 51, no. 1, pp. 1–6, 2002.
[74]
M. Malodobra, A. Pilecka, B. Gworys, and R. Adamiec, “Single nucleotide polymorphisms within functional regions of genes implicated in insulin action and association with the insulin resistant phenotype,” Molecular and Cellular Biochemistry, vol. 349, no. 1-2, pp. 187–193, 2011.
[75]
H. J. L. Speirs, K. Katyk, N. N. Kumar, A. V. Benjafield, W. Y. S. Wang, and B. J. Morris, “Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension,” Journal of Hypertension, vol. 22, no. 5, pp. 931–936, 2004.
[76]
J. Weng, J. Yan, Z. Huang, Y. Sui, and L. Xiu, “Missense mutation of Pro387Leu in protein tyrosine phosphatase-1B (PTP-1B) is not associated with type 2 diabetes in a Chinese Han population,” Diabetes Care, vol. 26, no. 10, article 2957, 2003.
[77]
M. Santaniemi, O. Ukkola, and Y. A. Kes？niemi, “Tyrosine phosphatase 1B and leptin receptor genes and their interaction in type 2 diabetes,” Journal of Internal Medicine, vol. 256, no. 1, pp. 48–55, 2004.
[78]
I. Gouni-Berthold, E. Giannakidou, D. Müller-Wieland et al., “The Pro387Leu variant of protein tyrosine phosphatase-1B is not associated with diabetes mellitus type 2 in a German population,” Journal of Internal Medicine, vol. 257, no. 3, pp. 272–280, 2005.
[79]
O. Ukkola, T. Rankinen, T. Lakka et al., “Protein tyrosine phosphatase 1B variant associated with fat distribution and insulin metabolism,” Obesity Research, vol. 13, no. 5, pp. 829–834, 2005.
[80]
S. Kipfer-Coudreau, D. Eberlé, M. Sahbatou et al., “Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects,” Diabetologia, vol. 47, no. 7, pp. 1278–1284, 2004.
[81]
J. Mo, J. Wu, Z. Sun, H. Yang, M. Lei, and W. Liu, “Association of PTP1B gene polymorphism with obesity in Chinese children,” Journal of Central South University. Medical Sciences, vol. 35, no. 9, pp. 915–920, 2010.
[82]
A. Mok, H. Cao, B. Zinman et al., “A single nucleotide polymorphism in protein tyrosine phosphatase PTP-1B is associated with protection from diabetes or impaired glucose tolerance in oji-cree,” The Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 2, pp. 724–727, 2002.
[83]
P. Gu, W. Jiang, H. Du, et al., “Protein tyrosine phosphatase 1B gene polymorphisms and essential hypertension: a case-control study in Chinese population,” Journal of Endocrinological Investigation, vol. 33, no. 7, pp. 483–488, 2010.
[84]
R. Meshkani, M. Taghikhani, H. Al-Kateb et al., “Polymorphisms within the protein tyrosine phosphatase IB (PTPN1) gene promoter: functional characterization and association with type 2 diabetes and related metabolic traits,” Clinical Chemistry, vol. 53, no. 9, pp. 1585–1592, 2007.
[85]
T. Wada, T. Sasaoka, M. Funaki et al., “Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity,” Molecular and Cellular Biology, vol. 21, no. 5, pp. 1633–1646, 2001.
[86]
T. Sasaoka, H. Hori, T. Wada et al., “SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes,” Diabetologia, vol. 44, no. 10, pp. 1258–1267, 2001.
[87]
P. Vollenweider, M. Clodi, S. S. Martin, T. Imamura, W. M. Kavanaugh, and J. M. Olefsky, “An SH2 domain-containing 5' inositolphosphatase inhibits insulin- induced GLUT4 translocation and growth factor-induced actin filament rearrangement,” Molecular and Cellular Biology, vol. 19, no. 2, pp. 1081–1091, 1999.
[88]
S. Clément, U. Krause, F. Desmedt, et al., “The lipid phosphatase SHIP2 controls insulin sensitivity,” Nature, vol. 409, no. 6816, pp. 92–97, 2001.
[89]
S. Clément, U. Krause, F. Desmedt, et al., “Corrigendum: the lipid phosphatase SHIP2 controls insulin sensitivity,” Nature, vol. 431, no. 7010, pp. 878–878, 2004.
[90]
M. W. Sleeman, K. E. Wortley, K. M. V. Lai, et al., “Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity,” Nature Medicine, vol. 11, no. 2, pp. 199–205, 2005.
[91]
X. Xu, J. J. Rogus, H. A. Terwedow et al., “An extreme-sib-pair genome scan for genes regulating blood pressure,” American Journal of Human Genetics, vol. 64, no. 6, pp. 1694–1701, 1999.
[92]
C. I. M. Panhuysen, L. A. Cupples, P. W. F. Wilson, A. G. Herbert, R. H. Myers, and J. B. Meigs, “A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study,” Diabetologia, vol. 46, no. 4, pp. 579–587, 2003.
[93]
K. Silander, L. J. Scott, T. T. Valle, et al., “A large set of Finnish affected sibling pair families with type 2 diabetes suggests susceptibility loci on chromosomes 6, 11, and 14,” Diabetes, vol. 53, no. 3, pp. 821–829, 2004.
[94]
E. Marion, P. J. Kaisaki, V. Pouillon et al., “The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man,” Diabetes, vol. 51, no. 7, pp. 2012–2017, 2002.
[95]
P. J. Kaisaki, M. Delépine, P. Y. Woon et al., “Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome,” Diabetes, vol. 53, no. 7, pp. 1900–1904, 2004.
[96]
A. C. B. Mar？ano, B. Burke, J. Gungadoo et al., “Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension,” Journal of Medical Genetics, vol. 44, no. 9, pp. 603–605, 2007.
[97]
S. Kagawa, T. Sasaoka, S. Yaguchi et al., “Impact of Src homology 2-containing inositol 5′-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling,” The Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 5, pp. 2911–2919, 2005.
[98]
R. Matsushima, N. Harada, N. J. G. Webster, Y. M. Tsutsumi, and Y. Nakaya, “Effect of TRB3 on insulin and nutrient-stimulated hepatic p70 S6 kinase activity,” The Journal of Biological Chemistry, vol. 281, no. 40, pp. 29719–29729, 2006.
[99]
J. Liu, X. Wu, J. L. Franklin et al., “Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance,” American Journal of Physiology—Endocrinology and Metabolism, vol. 298, no. 3, pp. E565–E576, 2010.
[100]
S. Prudente, M. L. Hribal, E. Flex et al., “The functional Q84R polymorphism of mammalian tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from Italy,” Diabetes, vol. 54, no. 9, pp. 2807–2811, 2005.
[101]
C. W. Liew, J. Bochenski, D. Kawamori et al., “The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells,” The Journal of Clinical Investigation, vol. 120, no. 8, pp. 2876–2888, 2010.
[102]
F. Andreozzi, G. Formoso, S. Prudente et al., “TRIB3 R84 variant is associated with impaired insulin-mediated nitric oxide production in human endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 7, pp. 1355–1360, 2008.
[103]
S. Prudente, D. Scarpelli, M. Chandalia et al., “The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes,” The Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 1, pp. 190–196, 2009.
[104]
S. Prudente, R. Baratta, F. Andreozzi et al., “TRIB3 R84 variant affects glucose homeostasis by altering the interplay between insulin sensitivity and secretion,” Diabetologia, vol. 53, no. 7, pp. 1354–1361, 2010.
[105]
C. R. Kahn, “Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes,” Experimental Diabesity Research, vol. 4, no. 3, pp. 169–182, 2003.
[106]
E. Morini, S. Prudente, E. Succurro et al., “IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants,” Diabetologia, vol. 52, no. 9, pp. 1852–1857, 2009.
[107]
S. Bacci, S. Prudente, M. Copetti, et al., “Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance,” Atherosclerosis, vol. 226, no. 1, pp. 140–145, 2013.
[108]
A. Doria, M. E. Patti, and C. R. Kahn, “The emerging genetic architecture of type 2 diabetes,” Cell Metabolism, vol. 8, no. 3, pp. 186–200, 2008.
[109]
N. Grarup and G. Andersen, “Gene-environment interactions in the pathogenesis of type 2 diabetes and metabolism,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 10, no. 4, pp. 420–426, 2007.
[110]
M. C. Cornelis, E. J. T. Tchetgen, L. Liang, et al., “Gene-environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes,” American Journal of Epidemiology, vol. 175, no. 3, pp. 191–202, 2012.
[111]
M. L. Metzker, “Sequencing technologies—the next generation,” Nature Reviews Genetics, vol. 11, no. 1, pp. 31–46, 2010.
[112]
M. I. McCarthy, P. Rorsman, and A. L. Gloyn, “TCF7L2 and diabetes: a tale of two tissues, and of two species,” Cell Metabolism, vol. 17, no. 2, pp. 157–159, 2013.
