- Title:
- Unraveling Insulin's Mechanisms: A Comprehensive Analysis
- Author:
Rehan Haider
- Author Affiliation:
Department of Pharmacy, University of Karachi, Karachi, Pakistan
- Received:Jun.28, 2023
- Accepted:Jul.13, 2023
- Published:Aug.1, 2023
Insulin receptors, insulin movement, insulin receptor substrate, pleckstrin homology domain, protein tyrosine phosphatase.
[1] C. M. Taniguchi, B. Emanuelli, and C. R. Kahn, "Vital nodes in signaling pathways: insights into insulin motion," Nat. Rev. Mol. Cell Biol., vol. 7, pp. 85-96, 2006.
[2] S. Jacobs and P. Cuatrecasas, "Insulin receptor shape and function," Endocr. Rev., vol. 2, pp. 251-263, 1981.
[3] B. Cheatham and C. R. Kahn, "Insulin movement and insulin signaling network," Endocr. Rev., vol. 16, pp. 117-142, 1995.
[4] H. Okamoton et al., "Transgenic rescue of insulin receptor-deficient mice," J. Clin. Invest., vol. 114, pp. 214-223, 2004.
[5] J. C. Bruning et al., "Muscle-specific insulin receptor knockout is a well-known feature of the metabolic syndrome of NIDDM that does not alter glucose tolerance," Mol. Cell, vol. 2, pp. 559-569, 1998.
[6] J. F. Wojtaszewski et al., "Exercise modulates post-receptor insulin signaling and glucose shipping in muscle-specific c insulin receptor-knockout mice," J. Clin. Invest., vol. 104, pp. 1257-1264, 1999.
[7] A. Ullrich et al., "Human insulin receptor and its relationship with the tyrosine kinase circle of oncogene relatives," Nature, vol. 313, pp. 756-761, 1985.
[8] B. Leibiger et al., "Selective insulin signaling through A and B insulin receptors regulates the transcription of insulin andglucokinase genes in pancreatic beta cells," Mol. Cell, vol. 7, pp. 559-570, 2001.
[9] A. R. Saltiel and C. R. Kahn, "Insulin signaling and regulation of glucose and lipid metabolism," Nature, vol. 414, pp. 799-806, 2001.
[10] A. Viinamaki et al., "Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance," J. Clin. Invest., vol. 103, pp. 931-943, 1999.
[11] A. H. Khan and J. E. Pessin, "Insulin regulation of glucose uptake: a complicated interplay of intracellular signaling pathways," Diabetologia, vol. 45, pp. 1475-1483, 2002.
[12] Y. Hirashima et al., "Insulin down-regulates insulin receptor substrate-2 expressions through the phosphatidyl inositol threekinase/Akt pathway," J. Endocrinol., vol. 179, pp. 253-266, 2003.
[13] L. Rui et al., "SOCS-1 and SOCS-3 block insulin signaling through ubiquity-mediated degradation of IRS1 and IRS2," J. Biol. Chem., vol. 277, pp. 42394-42398, 2002.
[14] I. Shimomura et al., "Decreased IRS-2 and increased SREBP-1c resulting in mixed insulin resistance and sensitivity in the livers of lipodystrophic and ob/ob mice," Mol. Cell, vol. 6, pp. 77-86, 2000.
[15] A. W. Stoker, "Protein tyrosine phosphatases and signaling," J. Endocrinol., vol. 185, pp. 19-33, 2005.
[16] L. E. Ball, M. N. Berkaw, and M. G. Buse, "Identification of the primary site of O-connected beta-N-acetyl glucosamine modification within the C terminus of insulin receptor substrate-1," Mol. Cell. Proteomics, vol. 5, pp. 313-323, 2006.
[17] M. A. Carvalho-Filho et al., "Targeted disruption of iNOS prevents LPS-caused S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice," Am. J. Physiol. Endocrinol. Metab., vol. 291, pp. E476-E482, 2006.
[18] L. E. Rameh and L. C. Cantley, "The position of phosphoinositide three-kinase lipid products in mobile characteristic," J. Biol. Chem., vol. 274, pp. 8347-8350, 1999.
[19] R. Katso et al., "Cellular function of phosphoinositide tri kinase: implications for growth, homeostasis, and general cancer," Ann. Cell Dev. Biol., vol. 17, pp. 615-675, 2001.
[20] D. A. Antonetti, P. Algenstaedt, and C. R. Kahn, "Insulin receptor substrate 1 bind a new spliced version of the regulatory subunit of phosphatidyl inositol tri kinase in muscle and brain," Mol. Cell. Biol., Chapter 16, pp. 2195-2203, 1996.
[21] R. Roger and L. C. Cantley, "Phosphoinositide 3-kinase signaling is regulated by p85 and its effects on most cancers," Cell Cycle, vol. 4, pp. 1309-1312, 2005.
[22] C. M. Taniguchi et al., "The p85α regulatory subunit of phosphoinositide tri kinase enhances c-Jun N-terminal kinase-mediated insulin resistance," Mol. Cell. Biol., vol. 27, pp. 2830-2840, 2007.
[23] C. M. Taniguchi et al., "Phosphoinositide 3-kinase regulatory subunit p85α inhibits insulin motility via positive regulation of PTEN," Proc. Natl. Acad. Sci. U S A, vol. 103, pp. 12093-12097, 2006.
[24] A. D. Kohn et al., "Expression of constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and quadruple translocation of glucose transporters," Biol. Chem., vol. 271, pp. 31372-31378, 1996.
[25] H. Cho et al., "Akt1/PKBα is essential for normal growth but essential for the primary tenants of glucose homeostasis in mice," Biochem. J., vol. 276, pp. 38349-38352, 2001.
[26] H. Cho et al., "Mice lacking the protein kinase Akt2 (PKBβ) develop insulin resistance and diabetes," Science, vol. 292, pp. 1728-1731, 2001.
[27] E. Gonzalez and T. E. McGraw, "Transformation of insulin signaling into an organized and independent activity by Akt to regulate GLUT4 vesicle recruitment/insertion and fusion of GLUT4 vesicles to the plasma membrane," Mol. Biol. Cell, vol. 17, pp. 4484-4493, 2006.
[28] S. and D. Zheleva, "Target three in glycogen synthase kinase-insulin signaling," Expert Opin. Ther. Targets, vol. 10, pp. 429-444, 2006.
[29] H. Sano et al., "Insulin-stimulated phosphorylation of Rab GTPase activates the protein to regulate GLUT4 translocation," Biochem. J., vol. 278, pp. 14599-14602, 2003.
[30] M. Larance et al., "Characterization of the role of Rab GTPase activating protein AS160 in insulin-regulated GLUT4 trafficking," J. Biochem., vol. 280, pp. 37803-37813, 2005.
[31] R. V. Frazer, "Characterization and dysfunction of the aPKC isoform of the glucose transporter in insulin-sensitive and insulinresistant mice," Am. J. Physiol. Endocrinol. Metab., vol. 283, pp. e1-e11, 2002.
[32] L. Z. Liu et al., "The protein kinase Cζ mediates insulin-induced glucose transport via actin turnover in L6 myocytes," Mol. Biol. Cell, vol. 17, pp. 2322-2330, 2006.
[33] R. V. Farese, M. P. Sajan, and M. L. Standaert, "Extraordinary protein kinase in insulin action and insulin resistance," C. Society for Biochemistry, vol. 33, pp. 350-353.
[34] R. T. Watson and J. E. JE, "Subcellular compartmentalization and TRAF- regulation of the insulin-responsive glucose transporter GLUT4," Exp. Cell Res., vol. 271, pp. 75-83, 2001.
[35] C. A. Baumann et al., "CAP defines a 2D signaling pathway required for insulin-stimulated glucose shipping," Nature, vol. 407, pp. 202-207, 2000.
[36] M. Kanzaki and J. E. Pessin, "Caveolin-associated filamentous actin (Cavactin) Define a novel F-actin shape in adipocytes," J. Biol. Chem., vol. 277, pp. 25867-25869, 2002.
[37] Inoue et al., "The exocytotic is complicated and is needed for the concentration of Glut4 in the plasma membrane by using insulin," Nature, vol. 422, pp. 629-633, 2003.
[38] T. G. Boulton et al., "ERKs: a circle of relatives of protein-serine/threonine kinases that might be activated and tyrosine phosphorylated in response to insulin and NGF," Cell, vol. 65, pp. 663-675, 1991.
[39] M. Frodin and S. Gammeltoft, "Position and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction," Mol. Cell. Endocrinol., vol. 151, pp. 65-77, 1999.
[40] D. F. Lazar et al., "Mitogen-activated protein kinase inhibition no longer blocks the stimulation of glucose usage by insulin," J. Biol. Chem., vol. 270, pp. 20801-20807, 1995.
[41] O. Puig and R. Tjian, "Transcriptional feedback control of insulin receptor via dFOXO/FOXO1," Genes Dev., vol. 19, pp. 2435-2446, 2005.
[42] L. Frittitta et al., "Improved computer-1 content in cultured skin fibroblasts correlates with reduced in vivo and in vitro insulin motion in non-diabetic subjects: evidence that pc-1 may be an intrinsic factor in impaired insulin receptor signaling," Diabetes, vol. 47, pp. 1095-1100, 1998.
[43] D. Meyre et al., "Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes," Nat. Genet., vol. 37, pp. 863-867, 2005.
[44] L. J. Holt and K. Siddle, "Grb10 and Grb14: enigmatic regulators of insulin movement - and more?," Biochem. J., vol. 388, pp. 393-406, 2005.
[45] K. R. Wick et al., "Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidyl inositol 3-kinase/Akt signaling pathway via disrupting the association of IRS-1/IRS-2 with the insulin receptor," J. Biol. Chem., vol. 278, pp. 8460-8467, 2003.
[46] M. Elchebly et al., "Increased insulin sensitivity and obesity resistance in mice missing the protein tyrosine phosphatase-1B gene," Science, vol. 283, pp. 1544-1548, 1999.
[47] E. A sante-Appiah and B. P. Kennedy, "Protein tyrosine phosphatases: the quest for negative regulators of insulin action," Am. J. Physiol. Endocrinol. Metab., vol. 284, pp. E663-E670, 2003.
[48] F. Ahmad et al., "Improved sensitivity to insulin in obese subjects following weight reduction is accompanied by reduced protein-tyrosine phosphatases in adipose tissue," Metabolism, vol. 46, pp. 1140-1145, 1997.
[49] F. Ahmad and B. J. Goldstein, "Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus," Metabolism, vol. 44, pp. 1175-1184, 1995.
[50] M. Leitges et al., "Knockout of PKCα enhances insulin signaling through PI3K," Mol. Endocrinol., vol. 16, pp. 847-858, 2002.
[51] Y. F. Liu et al., "Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance," Mol. Cell. Biol., vol. 24, pp. 9668-9681, 2004.
[52] M. Saghizadeh et al., "The expression of TNF alpha by human muscle: relationship to insulin resistance," J. Clin. Invest., vol. 97, pp. 1111-1116, 1996.
[53] H. Kanety et al., "Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1): a possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1," J. Biol. Chem., vol. 270, pp. 23780-23784, 1995.
[54] B. S. Miller et al., "Activation of cJun NH2-terminal kinase/stress-activated protein kinase by insulin," Biochemistry, vol. 35, pp. 8769-8775, 1996.
[55] J. Hirosumi et al., "A central role for JNK in obesity and insulin resistance," Nature, vol. 420, pp. 333-336, 2002.
[56] D. Cai et al., "Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB," Nat. Med., vol. 11, pp. 183-190, 2005.
[57] I. M. Verma et al., "Rel/NF-kappaB/IkappaB family: intimate tales of association and dissociation," Genes Dev., vol. 9, pp. 2723-2735, 1995.
[58] H. Y. Chung et al., "Molecular inflammation: underpinnings of aging and age-related diseases," Aging Res. Rev., vol. 8, pp. 18-30, 2009.
[59] J. K. Kim et al., "Prevention of fat-induced insulin resistance by salicylate," J. Clin. Invest., vol. 108, pp. 437-446, 2001.
[60] M. Yuan et al., "Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta," Science, vol. 293, pp. 1673-1677, 2001.
[61] M. Rohl et al., "Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance," J. Clin. Invest., vol. 113, pp. 474-481, 2004.
[62] S. E. Shoelson, J. Lee, and M. Yuan, "Inflammation and the IKKbeta/IkappaB/NF-kappaB axis in obesity- and diet-induced insulin resistance," Int. J. Obes. Relat. Metab. Disord., vol. 27, Suppl 3, pp. S49-S52, 2003.
[63] N. Nakashima et al., "The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes," J. Biol. Chem., vol. 275, pp. 12889-12895, 2000.
[64] R. A. Mooney et al., "Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor: a potential mechanism for cytokine-mediated insulin resistance," J. Biol. Chem., vol. 276, pp. 25889-25893, 2001.
[65] A. Du et al., "TRB3: a Tribbles homolog that inhibits Akt/PKB activation by insulin in the liver," Science, vol. 300, pp. 1574-1577, 2003.
[66] S. H. Koo et al., "PARK1 promotes insulin resistance in the liver through PPAR-alpha-dependent induction of TRB-3," Nat. Med., vol. 10, pp. 530-534, 2004.
[67] V. Blot and T. E. McGraw, "GLUT4 is internalized via a cholesterol-dependent nystatin-sensitive mechanism inhibited by insulin," EMBO J., vol. 25, pp. 5648-5658, 2006.
[68] A. Ros-Baro et al., "Lipid rafts are required for GLUT4 internalization in adipose cells," Proc. Natl. Acad. Sci. USA, vol. 98, pp. 12050-12055, 2001.
[69] F. S. Thong et al., "Rab GTPase-activating protein AS160 integrates Akt, protein kinase C, and AMP-activated protein kinase signaling to regulate GLUT4 traffic," Diabetes, vol. 56, pp. 414-423, 2007.
[70] L. Jiang et al., "Direct quantification of fusion rate for the distal function of AS160 in the insulin-stimulated fusion of GLUT4 storage vesicles," J. Biochem., vol. 283, pp. 8508-8516, 2008.
[71] J. M. Santos et al., "Skeletal muscle contraction increases glucose uptake," Int. J. Sports Med., vol. 29, pp. 785-794, 2008.
[72] L. J. Goodyear, "Exercise Science Revised Edition," 2000, pp. 113-116.
[73] J. Mu et al., "Effect of insulin on sterol regulatory element binding protein-1c (SREBP-1c) activity in rat hepatocytes," Mol. Cell, vol. 7, pp. 1085-1094, 2001.
[74] "Effect of insulin on sterol regulatory element binding protein-1c (SREBP-1c) activity in rat hepatocytes," J. Biochem., vol. 350, pp. 389-393, 2000.
[75] H. Shimano et al., "Sterol regulatory element binding protein-1 as a key transcription factor for the lipogenic enzyme noob," Biochemistry, vol. 274, pp. 35832-35839, 1999.
[76] C. Londos et al., "Lipolysis damages adipocytes," Ann. N. Y. Acad. Sci., vol. 892, pp. 155-168, 1999.
[77] "Regulation of hormone-sensitive lipase and the molecular mechanism of lipolysis," Biochem. Soc. Trans., vol. 31, pp. 1120-1124, 2003.
[78] S. J. Faith, "Hormone-sensitive lipase: a new role for an old enzyme," J. Biochem., vol. 379, pp. 11-22, 2004.
[79] E. J. Blanchette-Mackie et al., "Perilipin is on the surface of lipid droplets in adipocytes," J. Lipid Res., vol. 36, pp. 1211-1226, 1995.
[80] K. Frick et al., "Protein kinase A and protein kinase C pathways coactivate lipolysis in 3T3-L1 adipocytes," Endocrinol., vol. 145, pp. 4940-4947, 2004.
[81] J. T. Tansey et al., "Perilipin depletion leads to abnormal lipolysis, increases leptin production, and prevents diet-induced obesity in lean mice," Proc. Natl. Acad. Sci., vol. 98, pp. 6494-6499, 2001.
[82] N. Arimura et al., "Peroxisome proliferator-activated receptor gamma regulates the expression of perilipin genes in adipocytes," J. Biochem., vol. 279, pp. 10070-10076, 2004.
[83] J. M. Fernandez-Nowell et al., "Glucose induces the translocation of glycogen synthase to the cell cortex in rat hepatocytes," J. Biochem., vol. 321, pp. 227-231, 1997.
[84] S. A. Summers et al., "Role of glycogen synthase kinase 3β in insulin-stimulated glucose metabolism," J. Biochem., vol. 274, pp. 17934-17940, 1999.
[85] E. Slago et al., "Metabolic and hormonal regulation of phosphoenolpyruvate carboxykinase and malic enzymes in rat liver," J. Biochem., vol. 238, pp. 3188-3192, 1963.
[86] S. L. Samson and N. C. Huang, "The role of Sp1 in the regulation of insulin gene expression," J. Mol. Endocrinol., vol. 29, pp. 265-279, 2002.
[87] G. Rena et al., "Two novel phosphorylation sites on FKHR are critical for its nuclear exclusion," Embo J., vol. 21, pp. 2263-2271, 2002.
[88] T. Obsil et al., "Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding," Biochemistry, vol. 42, pp. 15264-15272, 2003.
[89] E. D. Don et al., "Negative regulation of the forkhead transcription factor FKHR by Akt," J. Biochem., vol. 274, pp. 16741-16746, 1999.
[90] R. K. Saloon et al., "Insulin regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor binding protein 1 gene expression: role of poultry helix/forkhead proteins," Biochem. J., vol. 275, pp. 30169-30175, 2000.
[91] H. Daitoku et al., "Sirtuin 2 enhances Foxo1-mediated transcription through its deacetylase activity," Proc. Natl. Acad. Sci. A, vol. 101, pp. 10042-10047, 2004.
[92] J. Nakae et al., "Forkhead transcription factor Foxo1 regulates adipocyte differentiation," Giant Cell, vol. 4, pp. 119-129, 2003.
[93] Insulin regulates hepatic gluconeogenesis through the FOXO1-PGC-1alpha interaction," Nature, vol. 423, pp. 550-555, 2003.
[94] SREBP: Junction of Physiological and Pathological Lipid Homeostasis," Trends Endocrinol. Metab., vol. 19, pp. 65-73, 2008.
[95] Role of insulin receptor substrate 1 and phosphatidyl inositol 3-kinase signaling in insulin-induced gene expression of sterol regulatory element-binding protein 1c and glucokinase in rat hepatocytes," Diabetes, vol. 51, pp. 1672-1680, 2002.
[96] The antidiabetic effects of hepatic X receptor agonists are mediated by inhibition of hepatic gluconeogenesis," Biochem. J., vol. 278, pp. 1131-1136, 2003.
[97] H. Zitzer et al., "Sterol regulatory element-binding protein 1 mediates hepatic X receptor-β-mediated insulin secretion, attenuating diabetes in obese mice," Endocrinology, vol. 147, no. 12, pp. 3898-3905, 2006.
[98] Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, et al. Tshooj , TshoojNature 2001; 413:131-138.
[99] Eagle D, Guo S, Onterman T, Quinn PG. Article: Journal of Biochemistry 2001; 276: 33705 – -33710.
[100] Effect of Insulin Therapy on Insulin Secretion and Insulin Effect (Item ) Diabetes 1985; 34: 222-234.
[101] Glucose toxicity. Diabetes Care, 1990; 13:610–630.
[102] Marshall S. The role of insulin, adipocyte hormones, and food sensing pathways in regulating fat metabolism and energy homeostasis: A nutritional perspective on diabetes, obesity, and cancer. Scientific STKE, 2006; 2006: re7.
[103] Kadowaki T., Yamauchi T. Adiponectin and adiponectin receptor. Endocrine Reviews, 2005; 26:439-451.
[104] Cooksey R.S., Hebert L.F. Jr., Zhu J.H., Wofford P., Garvey W.T., McClain D.A. Mechanism of hexosamine-induced insulin resistance in transgenic mice overexpressing glutamine: fructose-6-phosphate aminotransferase: decrease in translocation of the glucose transporter GLUT4 and reversal by thiazolidinedione treatment. Endocrinology, 1999; 140: 1151 – 1157.
[105] D'Alessandris C, Andreozzi F, Federici M, Cardellini M, Brunetti A, Ranalli M, et al. Increased O-glycosylation of insulin signaling proteins results in impaired activation and increased susceptibility to apoptosis in pancreatic beta cells. FASEB Journal, 2004; 18:959-961.
[106] Finger DS, Richardson S.J., Tee AR, Cheetham L., Tsou S., Bernice J.. mTOR controls cell cycle progression through the S6K1 and 4E cell growth effectors (BP1/eukaryotic translation initiation factor 4E). Molecular and Cellular Biology, 2004; 24: 200 – 216.
[107] Burnett P.E., Barrow R.C., Cohen N.A., Snyder S.H., Sabatini D.M. RAFT1 phosphorylation of translation regulators p70 S6 kinase and 4E-BP1. Proceedings of the National Academy of Sciences USA, 1998; 95: 1432 – 1437.
[108] Sarbasov D.D., Gertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005; 307: 1098 - 1101.
[109] Shah OJ, Van Z, Hunter T. Aberrant activation of the TSC/Rheb/mTOR/S6K cassette causes IRS1/2 depletion, insulin resistance, and failure of cell viability. Current Biology, 2004; 14: 1650 – 1656.
[110] Kim D.H., Sarbasov D.D., Ali S.M., King J.E., Latek R.R., Erjument-Bromage H., et al. mTOR interacts with raptor to form a nutrient-sensing complex that signals cell growth mechanisms. Cell, 2002; 110: 163 – 175.
[111] Um S.H., Frigerio F., Watanabe M., Picard E., Joaquim M., Sticker M. et al. Insulin. Nature, 2004; 431: 200–205.
[112] Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, et al. Amino acids mediate mTOR/raptor signaling through the activation of class 3 phosphatidyl inositol 3-kinase. Proceedings of the National Academy of Sciences USA, 2005.
[113] Krebs M, Brunmair B, BrehmA, Artwohl M, Szendroedi J, Nowotny P, et al. Mammalian targets of the rapamycin pathway regulate nutrient-sensitive glucose uptake in humans. Diabetes, 2007; 56:1600 - 1607.
[114] Hardy D.G. Role of the AMP/SNF1 activating protein kinase family on cellular stress. Biochemical Society Symposium, 1999; 64: 13 – 27.
[115] Leclerc I, Kahn A, Doiron B. Activated 5'-AMP protein kinase inhibits glucose stimulation of transcription in hepatocytes acting through the glucose response complex. FEBS Letters, 1998; 431: 180 – 184.
[116] Yang J., Craddock L., Hong S., Liu Z.M. AMP-activated protein kinase inhibits LXR-dependent sterol regulatory elementbinding protein 1c transcription in McA-RH7777 murine hepatoma cells. Journal of Cellular Biochemistry, 2009; 106: 414 –426.
[117] Nuruz-Zade J., Rahimi A., Tajaddini-Sarmadi J., Tritchler H., Rosen P., Halliwell B. et al. Relationship between plasma oxidative stress measurements and metabolic regulation in NIDDM. Diabetologia, 1997; 40:647-653.
[118] Nathan S. Type 3 specificity: reactive oxygen and nitrogen intermediates in cell signaling. Journal of Clinical Investigation, 2003; 111:769-778.
[119] Dinarello, CA. Interleukin-1 beta. Critical Care Medicine, 2005; 33: S460-462.
[120] Somm E, Setur-Rose P, Asensio K, Charolle A, Klein M, Teaander-Carrillo K, et al. rodents. Diabetes, 2006; 49:387-393.
[121] Ozjan L, Ergin AS, Lu A, Chang J, Sarkar S, Ni D, et al. Endoplasmic reticulum stress plays a central role in the development of leptin resistance. Cell Metabolism, 2009; 9:35–51.
[122] Scheuner D, Kaufman R.J. The unfolded protein response: a pathway linking insulin requirements to beta cell deficiency and diabetes. Endocrine, 2008; 29:317-333.