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Type 2 diabetes mellitus (T2DM) a metabolic disorder characterized by chronic hyperglycemia,developing as a result of violations of the interaction of insulin with tissue cells. Diabetes one of the most common endocrine disease. The frequency of diabetes mellitus in average ranges from 1.5 -3%, increasing in the developed world (5-6%). In the world there are about 200 million. Diabetes, with almost 90% of them suffer from type 2 diabetes . The problem of type 2 diabetes continues to be the most urgent task of modern endocrinology. The review is devoted to new data from the literature regarding the molecular and genetic mechanisms of type 2 diabetes . Based on the literary analysis conducted, it should be noted that the molecular basis of etiopathogenesis type 2 diabetes are complex and significant role in the formation of insulin resistance and type 2 diabetes play a violation of the b-cells. Of great importance in the development of insulin resistance have tumor necrosis factors having a plurality of biomedical effects.
. . 2015. 16 (213). 31
2
MOLECULAR AND GENETIC MECHANISMS OF THE PATHOGENESIS
OF TYPE 2 DIABETES
.. , .. , .. , .. O.N. Belousova, S.S. Sirotina, T.I. Jakunchenko, N.I. Zhernakova
308015, . , . , . 85
Belgorod National Research University 308015, Belgorod, Pobedy St., 85
: 2 , , .
Key words: type 2 diabetes, the mechanisms of pathogenesis, tumor necrosis factors.
. 2 (2) - ,
, . - . 1.5-3%, ( 5-6%). 200 . , 90% 2- . 2 . , 2 .
Summary. Type 2 diabetes mellitus (T2DM) - a metabolic disorder characterized by chronic hyperglycemia, developing as a result of violations of the interaction of insulin with tissue cells. Diabetes - one of the most common endocrine disease. The frequency of diabetes mellitus in average ranges from 1.5-3%, increasing in the developed world (5-6%). In the world there are about 200 million. Diabetes, with almost 90% of them suffer from type 2 diabetes. The problem of type 2 diabetes continues to be the most urgent task of modern endocrinology. The review is devoted to new data from the literature regarding the molecular and genetic mechanisms of type 2 diabetes. Based on the literary analysis conducted, it should be noted that the molecular basis of etiopathogenesis type 2 diabetes are complex and significant role in the formation of insulin resistance and type 2 diabetes play a violation of the b-cells. Of great importance in the development of insulin resistance have tumor necrosis factors having a plurality of biomedical effects.
2- ( ) , , (, 1999 .). 2 (2) , . 2 60-80%. [, 2010.].
, . , 2- , , , , , - , , , . , , , ^: et.al, 2007]. , ,[Heine et.al., 2005].
. . 2015. 16 (213). 31
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, b-. b- [Monnier et al., 2006]. -, , .. , b- . , , . -, , b-. . ( ), , , ( 5-10% ).
, 2 [Pittas et al., 2004]. , , , , , ,
. . 2015. 16 (213). 31
. , , . , : , , (), , . , , , , , . , , , , . , . 70% [Looker et al., 2012].
2 - , , , [Araki et al., 2003]. , [Boright et al.,
10 60-70% [Davies et al., 2006]. , 2 . , , , . , , , b- , [Argoff et al., 2006].
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. . 2015. 16 (213). 31
(TNF). TNFa TNFP ( a - Lta).
TNFa - 17 , /, , , , - - [, , 2007.]. TNFa (621.) , (HLA-A, , ) (HLA-DP, DQ, DR), Lta Ltp.
30 (SNP-, ), TNFa in vivo. HLA-. , , -308G/A TNFa: 308 -308 TNFa HLA-A1, B8, DR3 . , . 6-7- TNFa. , TNFa (-238G/A), A TNFa [Namkung. et al., 2007]. -308G/A a , [, , 2007.], , , [ ., 2011]. -308G/A TNFa [, , 2007.], [ ., 2012]. -308G/A TNFa , , .
TNFa: , ; , , , ; . - -, , , IL-1, IL-6, IL-2, , (ICAM-1, VCAM-1 .), , , . TNFa , , , , .
TNFa . TNFa, . TNFa . TNFa , -4 (GLUT-4) . in vivo , TNFa , - -1 6. TNFa .
Lta ( a, TNFP) 33 , - , , , , - .
Lta (621.3), 4 TNFa. Lta , (-). Lta TNFa , . . TNF, Lta , , , , [, 2010]. , Lta , , , Plasmodium falciparum, Haemophilus influenzae, Mycobacterium
. . 2015. 16 (213). 31
tuberculosis [ ., 2010]. Lta , , , , , , , [, , 2007.; , 2011, ., 2011].
, , , Lta , (RANTES, IP-10, -1, BLC, SLC, ELC) (VCAM, ICAM, E-selectin, MAdCAM-1) . Lta , TNFa, Lta , . Lta , -, , , , -, [ ., 2012].
. TNF 20 , TNF- , , . TNF TNF (TNFR1 TNFR2), , p75 ( NGF), CD40 , CD30 CD27. TNF , , 25%. .
1- (TNFR1), CD120a, 55-60 kDa (p55) , , . TNFR1 12p13 [Brian, 2009.]. . . TNFR1 TNF . , , , TNFR1 . TNFR1: -308G/T ,
, TNFR1 (+36A/G), [, 2011.], [, , 2010.], , .
2- (TNFR2) 16.2 10 , 26 . TNFR2 , , TNF- . , [Brian, 2009.].
TNFR2. , . , , . -196R TNFR2 ( ) , . Hohjoh H. et al. (2008) c , -196R TNFR2 -857T TNFa [Hohjoh et al., 2008].
, , 30 , TNFR1.
. . 2015. 16 (213). 31
, TNFR2 - TNF TNFR1, [Brian, 2009.].
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- - , . (TNFa, Lta) , , , . , TNFR1 , , TNFR2 . 2 , . TNFa, Lta, TNFR1 TNFR2 , .
, , 2- 2 b-. , .
.
. ., . . 2010. - . . . . , 16(11): 33-37.
. . . . 2010. - 2- . , 18(23):141-1418.
. . 2010. . , 4: 3-8.
. ., . . 2003. . ., 2:47-51.
. ., . . 2007. , . , 6(4):17-29.
. . . . 2011. . , 3(5):72
. . 2010. : , . , 3: 6-13.
.., . ., . . 2011. - . . . . , 10(14):30-36.
. . 2011. . , 10(14^247-253.
. ., . ., . . 2012. (VEGF) (ILlB, IL4, IL6, IL10, TNFA) 2 . , 3: 4-10.
. . . . 2007. . , 9(3):340-340.
., ., . 2010. . , 4: 45-46.
. . 2009. 1 : . , 55(4):44-49.
Aaki S., Ng D. P., Krolewski B. 2003. Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus. J. Am. Soc. Nephrol., 14(8): 2015-2024.
. . 2015. 16 (213). 31
Argoff C. E., Backonja M. M., Belgrade M. J. 2006. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin. Proc., 81(4):12-S25.
Boright A. P., Paterson A. D., Mirea L. 2005. Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes, 54(4^1238-1244.
Bradley J. R. 2008. TNF-mediated inflammatory disease. J. Pathol., 214(2): 149-160.
Bradley J. R. 2008. TNF-mediated inflammatory disease. J. Pathol., 214(2): 149-160.
Brian E. C. 2009. Peripheral receptor targets for analgesia: novel approaches to pain treatment. Hoboken, New Jersey : Wiley & Sons, 553 p.
Davies M., Brophy S., Williams R. 2006. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care, (7^1518-1522.
Dinarello C. A. 2010. Role of IL-1beta in type 2 diabetes. Curr. Opin. Endocrinol. Diabetes Obes., 17(4):314-321.
Heine R. J., Van Gaal L. F., Johns D. 2005. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann. Intern. Med., 143(8^559-569.
Hohjoh H., Terada N., Kawashima M. 2008. Significant association of the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy. Tissue Antigens, 56(5^446-448.
Lamb, R. E. Goldstein B. J. 2008. Modulating an oxidative-inflammatory cascade: potential new treatment strategy for improving glucose metabolism, insulin resistance, and vascular function. Int. J. Clin. Pract., 62(7):1087-1095.
Looker H.C., Livingstone S.J., Hothersall E.J. 2012. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med, 9(10):e1001321.
Mayorov A., Urbanova K., Galstyan G. 2009. Insulin sensitivity and adipocytokines in patients with diabetes and prediabetes. Journal of Diabetes, 1(1):A173.
Monnier L., Mas E., Ginet C. 2006. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA, 295(14):1681-1687.
Namkung J. H., Lee J. E., Kim E. 2007. IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in Koreans. Allergy, 62(8^934-942.
Pittas A. G., Joseph N. A., Greenberg A. S. 2004. Adipocytocines and insulin resistance. J. Clin. Endocrinol. Metab. 89(2^447-452.
Rung J., Cauchi S., Albrechtsen A. 2010. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nature genetics, 41(10):1110-1115.
Schwarz P. E., Towers G. W., Fischer S. 2006. Hypoadiponectinemia is associated with progression toward type 2 diabetes and genetic variation in the ADIPOQ gene promoter. Diabetes Care, 29(7^1645-1650.
Scott L. J., Mohlke K. L., Bonnycastle L. L. 2007. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science, 316(5829):1341-1345.
Swardfager W., Lanctot K., Rothenburg L. 2010. A meta-analysis of cytokines in Alzheimer's disease. Biol. Psychiatry, 68(10):930-941.
Verstrepen L., Bekaert T., Chau T. L. 2008. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell. Mol. Life Sci, 65(19)^964-2978.
Wisse B. E. 2004. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J. Am. Soc. Nephrol, 15(11):2792-2800.
Altuhova O. B., Churnosov M. I. 2010. Raspredelenie molekuljarno-geneticheskih markerov pri miome matki. Nauchnye vedomosti BelGU. Ser. Medicina. Farmacija, 16(11): 33-37. (in Russian).
Ametov A. S. Bogdanova L. N. 2010. Giperglikemija i gljukozotoksichnost' - kljuchevye faktory progressirovanija saharnogo diabeta 2-go tipa. Russkij medicinskij zhurnal, 18(23):1416-1418 (in Russian).
Beloborodov V. B. 2010. Immunopatologija tjazhelogo sepsisa i vozmozhnosti ee korrekcii. Vestnik intensivnoj terapii, 4: 3-8. (in Russian).
Bojcov S. A., Goloshhapov A. V. 2003. Svjaz' osnovnyh parametrov metabolicheskogo serdechno-sosudistogo sindroma so stepen'ju narushenija uglevodnogo obmena i vyrazhennost'ju abdominal'nogo ozhirenija u muzhchin. Arterial'naja gipertenzija., 2:47-51. (in Russian).
Glotov O. S., Baranov V. S. 2007. Geneticheskij polimorfizm, mul'tifaktorial'nye bolezni i dolgoletie. Medicinskaja genetika, 6(4):17-29. (in Russian).
Dedov I. I. Shestakova M. V. 2011. Algoritmy specializirovannoj medicinskoj pomoshhi bol'nym caharnym diabetom. Saharnyj diabet, 3(5):72(in Russian).
Dedov I. I. 2010. Saharnyj diabet: razvitie tehnologij v diagnostike, lechenii i profilaktike. Saharnyj diabet, 3: 6-13. (in Russian).
Demin S.S., Parfenov I. P., Churnosov M. I. 2011. Sovremennye predstavlenija ob jetiopatogeneze hronicheskogo kal'kuleznogo holecistita i rol' molekuljarno-geneticheskih markerov v ego formirovanii. Nauchnye vedomosti BelGU. Ser. Medicina. Farmacija, 10(14)^0-36. (in Russian).
Koneva O. A. 2011. Geneticheskie markery i vozrast manifestacii genital'nogo jendometrioza. Nauchnye vedomosti BelGU, 10(14)^47-253 (in Russian).
Konenkov V. I., Shevchenko A. V., Prokofev V. F. 2012. Associacii variantov gena faktora rosta sosudistogo jendotelija (VEGF) i genov citokinov (IL1B, IL4, IL6, IL10, TNFA) s saharnym diabetom 2 tipa u zhenshhin. Saharnyj diabet, 3: 4-10. (in Russian).
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Nekipelova E. V. Churnosov M. I. 2007. Vlijanie geneticheskih faktorov na skorost' pro-gressirovanija hronicheskogo glomerulonefrita. Nefrologija i dializ, 9(3):340-340. (in Russian)
Cherevko N., Ogorodova L., Klimov V. 2010. Osobennosti citokinovogo profilja pri razlichnyh tipah klinicheskogo techenija gerpesvirusnoj infekcii. Vrach, 4: 45-46. (in Russian).
Shvarc V. Vospalenie zhirovoj tkani. 2009. Chast' 1 : Morfologicheskie i funkcional'nye projavlenija. Problemy jendokrinologii, 55(4):44-49 (in Russian).
Araki S., Ng D. P., Krolewski B. 2003. Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus. J. Am. Soc. Nephrol., 14(8): 2015-2024.
Argoff C. E., Backonja M. M., Belgrade M. J. 2006. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin. Proc., 81(4):12-S25.
Boright A. P., Paterson A. D., Mirea L. 2005. Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes, 54(4^1238-1244.
Brian E. C. 2009. Peripheral receptor targets for analgesia: novel approaches to pain treatment. Hoboken, New Jersey : Wiley & Sons, 553 p.
Davies M., Brophy S., Williams R. 2006. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care, (7):1518-1522.
Heine R. J., Van Gaal L. F., Johns D. 2005. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann. Intern. Med., 143(8^559-569.
Hohjoh H., Terada N., Kawashima M. 2008. Significant association of the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy. Tissue Antigens, 56(5^446-448.
Lamb, R. E. Goldstein B. J. 2008. Modulating an oxidative-inflammatory cascade: potential new treatment strategy for improving glucose metabolism, insulin resistance, and vascular function. Int. J. Clin. Pract., 62(7):1087-1095.
Looker H.C., Livingstone S.J., Hothersall E.J. 2012. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med, 9(10):e1001321.
Mayorov A., Urbanova K., Galstyan G. 2009. Insulin sensitivity and adipocytokines in patients with diabetes and prediabetes. Journal of Diabetes, 1(1):Al73.
Monnier L., Mas E., Ginet C. 2006. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA, 295(14):1681-1687.
Namkung J. H., Lee J. E., Kim E. 2007. IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in Koreans. Allergy, 62(8^934-942.
Pittas A. G., Joseph N. A., Greenberg A. S. 2004. Adipocytocines and insulin resistance. J. Clin. Endocrinol. Metab. 89(2^447-452.
Rung J., Cauchi S., Albrechtsen A. 2010. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nature genetics, 41(10):1110-1115.
Schwarz P. E., Towers G. W., Fischer S. 2006. Hypoadiponectinemia is associated with progression toward type 2 diabetes and genetic variation in the ADIPOQ gene promoter. Diabetes Care, 29(7^1645-1650.
Scott L. J., Mohlke K. L., Bonnycastle L. L. 2007. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science, 316(5829):1341-1345.
Swardfager W., Lanctot K., Rothenburg L. 2010. A meta-analysis of cytokines in Alzheimer's disease. Biol. Psychiatry, 68(10^930-941.
Verstrepen L., Bekaert T., Chau T. L. 2008. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell. Mol. Life Sci, 65(19^2964-2978.
Wisse B. E. 2004. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J. Am. Soc. Nephrol, 15(11):2792-2800.
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