Dicle310 Tıp Dergisi / D. Ünal et al. 2012; 39 (2): 310-315 Dicle Medical Journal doi: 10.5798/diclemedj.0921.2012.02.0149 REVIEW ARTICLE / DERLEME

Insulin hormone: Mechanism and effects on the body and relationship with central

İnsülin hormonu: Vücuttaki mekanizması ve etkileri ve merkezi sinir sistemi ile ilişkisi

Deniz Ünal1, Adem Kara2, Selina Aksak1, B. Zuhal Altunkaynak3, Serap Yıldırım4

1 Atatürk Üniversitesi, Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı. Erzurum, Türkiye 2 Atatürk Üniversitesi, Veteriner Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı. Erzurum, Türkiye 3 Ondokuz Mayıs Üniversitesi, Tıp Fakültesi, Histoloji ve Embriyoloji Anabilim Dalı. Samsun, Türkiye 4 Atatürk Üniversitesi, Tıp Fakültesi, Fizyoloji Anabilim Dalı, Erzurum, Türkiye Geliş Tarihi / Received: 28.07.2011, Kabul Tarihi / Accepted: 12.01.2012

ABSTRACT ÖZET mellitus (DM) is one of the most common and Diabetes Mellitus (DM) dünyadaki en yaygın kronik has- chronic disease all over the world. It is characterized with talıklardan biridir. Ya yetersiz insülin salınması ya da insü- either insulin deficiency or insulin resistance. Insulin is a line karşı oluşan direnç ile karakterizedir. İnsülin pankre- hormone which is secreted by beta cells in the Langer- asın Langerhans adacıklarındaki beta hücrelerinden salı- hans Islets of and playing a role in carbohydrate nan ve vücuttaki karbonhidrat metabolizmasının düzen- regulation in association with . Re- lenmesinde glukagon ile birlikte rol alan bir hormondur. garding the insulin’s effects on carbohydrates, almost in İnsülinin, karbonhidratlar üzerindeki etkileri bağlamında, all tissues (except ) insulin increases the facilitated insülin hemen hemen tüm dokularda (beyin hariç), gliko- diffusion of into cells and shows and an effect to zun hücrelere kolaylaştırılmış difüzyonunu hızlandırmakta reduce the glucose levels. In other words, it have ve kan glikoz düzeyini azaltmaya yönelik bir etki oluştur- regulator role on ; insulin is maktadır. Bir başka ifadeyle insülin kan şeker düzeyinin known to be associated with an increase in the amount düzenlenmesinde görev alır. İnsülin sekresyonunun enerji of energy. Insulin secretion is related with increasing glu- miktarındaki artışla alakalı olduğu bilinmektedir. Hücre içi cose level. It has been shown that it is closely related enzimlerle yakından ilişkili olup, insülinin, glikolitik özelli- ğe sahip; glukokinaz, pirüvat kinaz, fosfofrukto kinaz ve with intracellular enzymes and has a stimulating effect fruktoz 2,6 bifosfataz üzerinde transkripsiyonu stimüle on of glucokinase, pyruvate kinase, phos- edici etkisi olduğu, glukoneogenik özellikli fosfofenolpü- phofructo kinase and fructose-2,6 biphosphatase that rivat karboksikinaz üzerinde transkripsiyonu inhibe edici are glicolytic and an inhibitory effect on transcription of etkiye sahip olduğu gösterilmiştir. İnsülinin, karbonhidrat phosphophenolpyruvate carboxykinase that is gluconeo- metabolizmasının birincil dengeleyicisi olmasının yanın- genetic. Besides being the primary regulator of carbohy- da, karbonhidrat metabolizması ile ilişki içinde bulunan drate metabolism, insulin also has an important effect on yağ ve metabolizmaları üzerinde de önemli etkileri and protein that are interrelated with vardır. Diyabetin Merkezi Sinir Sistemi (MSS) üzerindeki . For the basis of diabetes ef- etkilerinin temelinde ise iki mekanizmanın önemi üzerin- fects on (CNS) two mechanisms de durulmakta, bunlardan ilkinin metabolik değişiklikler are emphasized; first is the oxidative developed sonucu ortaya çıkan oksidatif stres olduğu, diğerinin ise due to metabolic changes and the second is damages kalsiyum iyonu metabolizmasında meydana gelen bozuk- of calcium ion metabolism. In this review, it was intended luklardan kaynaklandığı iddia edilmektedir. Bu derlemede to reach detailed information by reviewing insulin’s basic insülinin temel etki mekanizmaları, hücresel düzeydeki effect mechanism, its reflection on cellular level and its yansımaları ve MSS ile olan ilişkisi üzerinde durularak relationship with central nervous system. detaylı bilgiye ulaşılması amaçlanmıştır. Key words: Central nervous system, insulin, diabetes Anahtar kelimeler: Merkezi sinir sistemi, insülin, diabe- mellitus, carbohydrate metabolism tes mellitus, karbonhidrat metabolizması

Yazışma Adresi /Correspondence: Dr. Deniz Ünal Atatürk Üniversitesi, Tıp Fakültesi, Histoloji ve Embriyoloji AD, Erzurum, Türkiye Email: [email protected] Dicle Tıp Derg / Dicle MedCopyright J © Dicle Tıp Dergisi www.diclemedj.org 2012, Her hakkı saklıdır / All rights reserved Cilt / Vol 39, No 2, 310-315 D. Ünal et al. Insulin hormone 311

INTRODUCTION like other grown factors.25 When internalization of insulin- complex in the by endocytosis The basic mechanism of insulin is realized, there are lysosome enzymes which sepa- The discovery of insulin; Medical researcher Fred- rate the insulin-receptor complex from each other, erick Banting and research assistant Charles Best then receptors are transferred the surface of cell by studied the islets of Langerhans in the pancreas of to be used again and also the rest of in- dogs. In 1921, they isolated insulin and successfully sulin in the cell, to provide activation of tyrosine tested in on diabetic dogs, lowering the dogs’ blood kinase in the . The phosphatidylinositol sugar level.1 Insulin has polypeptide structure, 3,4,5 triphosphate effectors phosphatidylinositol which is synthesized in pancreatic B-cells, have 3,4,5 triphosphate receptors were existed in the in- many important function in the mammalian body.2-4 sulin pathway. The insulin pathway shows differ- It can bind to receptors in surface of cells.5-7 The re- ence from classic protein tyrosine kinase receptors ceptors located cell membranes binding each other in that it is always dimerised, nonetheless only ac- with disulphide bond and consist of four subunits. tivated when insulin (its ) is bound. Also, in Two of these subunits, located in the cell surface place of employing phosphatidylinositol 3-kinase membrane, named beta, other two of these subunits directly, the insulin receptor first of all employee located out of cell surface named alpha.8-10 Insulin insulin receptor substrates including src homology binds the first alpha subunits and leads to autophos- 2 domains. IRS-1 in particular is phosphorylated on phorilation of beta subunits which extending cyto- several tyrosine residues by the insulin receptor’s plasm by having bonds of two subunits, and induces intracellular catalytic part and these phosphory- converting active protein kinase.10,11 Therefore, in- lated tyrosine residues in turn employee other pro- sulin triggers many enzymes and teins with src homology 2 domains, one of which is shows its intracellular effects. In brief, insulin is phosphatidylinositol 3-kinase. Phosphatidylinositol necessary for glucose carrying in tissues, so the 3-kinase then catalysis the alteration of phospha- tissues are more permeable to glucose.12,13 Except tidylinositol 4,5 bisphosphate to phosphatidylino- for endocytosis of insulin, the cells are more per- sitol 3,4,5 triphosphate, which activates phospho- meable for K+and PO-4. Intracellular enzymes ac- lipid dependent kinase 1. Activated tyrosine kinase tivation level with phosphorylation changing in ap- leads to increase quantity of c-AMP in the cell, proximately in 10-15 seconds, low effect of insulin then protein named IRS-1, which is responsible for appears in hours (or even days).12-15 These effects function of insulin in the cell, tyrosine, serine, and occur to produce new or arranging DNA threonine residuals are phosphorylated by this IRS- transcription and translation rates decelerating syn- 1 protein.25 At the same time IRS-1 also activates chronously in ribosome.12-15 The effect of insulin the number of proteins. In insulin depended tissues, on carbohydrate metabolism: insulin accelerates glucose transportation from membrane may be per- the facilitated diffusion to cells in almost all tissues formed via IRS-1 and IP-3-kinase with an increase (except for brain) and decreases the blood glucose of phosphatidylinositol 3.4.5- triphosphate. Insulin level.14,15 In other words, insulin helps in decreasing mediates cytoplasmic replacement of GLUT trans- the level of blood glucose.14-17 The effect of insulin location and provides to be functional.25,26 In this re- on : insulin prevents to lipolysis view, it was intended to reach detailed information in the and adipose tissues as well as stimu- by reviewing insulin’s basic effect mechanism, its lates the lipogenesis.18-20 Also the effect of insulin reflection on cellular level and its relationship with on protein and nucleic acid metabolism: it shows central nervous system. effects such as stimulation of the protein synthesis (anabolic effect) or in other word inhibition of the Insulin Deficiency or resistance 21-24 protein destruction. Above we tried to explain Nowadays diabetes mellitus has two broad cat- basic function of the insulin in the body, now we egories designated as type1 (T1DM) and type2 try to explain “which mechanism is contributed or (T2DM). Both types problems are the same, people mediated the insulin action, and when the insulin suffer from diabetes mellitus needing to use exter- functions is performed?” Insulin mediated signal re- nal insulin usage for their life, T1DM divided two leasing mechanism is started by target cell receptors subunits. The first one is immunologic type T1DM, Dicle Tıp Derg / Dicle Med J www.diclemedj.org Cilt / Vol 39, No 2, 310-315 312 D. Ünal et al. Insulin hormone it is characterized pathologically by pancreatic beta surfactant protein-A,35 lipid acid sentetase,36 plas- cells destruction, and the second one is named idio- minogen activator inhibitor-1,37 SHARP2,38 hekzo- pathic T1DM, is characterized with insulin deficien- kinase-2 39 genes by phosphatidyl-inositole-3 kinase cy, and in this type pancreatic destruction signal pathway.40 Also insulin inhibits microsomal does not occurred.27 Both types of diabetes mellitus triglyceride 41 and stimulates Apo A1, c-fos, fos re- complications are classified as acute and chronic lated antigen-1 42 by map kinase signal pathway. In complications. Acute metabolic complications; addition, insulin effects the intracellular enzymes, diabetic ketoacidosis, ketoacidosis coma, hyperos- integral proteins, , secretory proteins, molar non-ketosis coma, lactic acidosis coma and proto-oncogenes and transcription factors.43,44 The hyperglycemia coma as a result of treatment com- effect of insulin on intracellular enzymes are tran- plication. Diabetic effect of different tissues and script stimulation effect on glucokinase, pyruvate organs are classified as chronic diabetic complica- kinase and transcript inhibition effect on fructose tion (neuropathy, nephropathy, and retinopathy) and 2,6 biphosphatase, which has glycolytic effect and macrovascular complications (atherosclerosis, pa- phosphophenolepiruvat-carboxykinase, which has resis, myocardial infarction and gangrene).27 glycogenic effect.43 Other effects of insulin on inte- gral proteins are transcription stimulation factor on The intracellular effects of insulin GLUT-1 stimulation of GLUT-1 gene transcription In this section, we tried to explain that which gene and (Trp), and transcription inhibition 44 expression is effected in case of releasing and syn- factor on of GLUT-4 gene transcription. The ef- thesis of insulin, which proteins are produced as fects of insulin on secretory proteins are transcript a result of this expression, what is the function of stimulation factor of amylase, , and glu- these proteins in the cells. The first stage of insu- cagon, and transcript inhibition factor of Apo Clir, 44 lin synthesis, the mRNA transcription was realized IGFBP-1 and NPY. Also insulin shows transcript from coding insulin gens in the cell’s nucleus, then stimulation effect on c-src, c-jun, c-fos, p21, Ras, 43,44 occurred mRNA was translated in the rough endo- and SREBP1c. plasmic reticulum (REG) and polypeptide synthesis is started with occurring signal polypeptide. This Insulin effects and selected samples polypeptide penetrates into endoplasmic reticulum We try to explain the relationship between glucose membrane and preproinsulin were produced in its metabolism and insulin for better understanding lumen, which the storage form of insulin is called the effect of the insulin hormone on metabolism. . Preproinsulin is converted into proinsu- Glycogen is the principal carbohydrate reserve; lin with leaving N-terminal signal polypeptide.28-31 it is a branched polymer of -D-glucose. Partial or Proinsulin is then moved into a golgi body, here c- complete failure of insulin secretion leading to gly- synthesis is stopped by the effect of prote- cogen production by of amino acids ases and converted into insulin. Producing insulin is and .45,46 In this case (i.e. the lack of insulin), secreted by partial exocytosis.28-31 Insulin secretion glucose uptake reduces in the insulin-dependent tis- mediates the glucose, amino acids (especially argi- sues, such as and muscle .45,46 When fatty nine), glucagon, gastrointestinal hormones (secre- acid concentration is increased, this results in a raise tin, , vasoactive intestinal peptide, and cho- of the intra-mitochondrial acetyl CoA/CoA and lecystokinin), growth hormones, , NADH/NAD+ ratios, with following inactivation prolactin, , sex hormones, and of pyruvate dehydrogenase. This causes increase of parasympathomimetic agents. Except for above, citrate concentrations, which leading to inhibition also hyperthyroid makes B cells sensitive to glu- of phosphofructokinase. These subsequent events cose, stimulates B cells at low catalysis increases in intracellular glucose-6-phos- levels, and high-levels parathyroid hormone inhibits phate concentration, which may inhibits hexokinase the B cells. In previous studies showed that soma- II activity and result in an increase in intracellular tostatin and inhibits the insulin secre- glucose concentration and a decrease in tissue glu- tion.28-31 Which gens are arranged by insulin effect? cose uptake.47 In this way, hyperglycemia occurs in Insulin stimulates glucose-6-phospahte,32 insulin the intercellular area due to failure in the cellular like binding protein,33 CYP2E1,34 glucose uptake.45,46 An increase in osmolality by in- Dicle Tıp Derg / Dicle Med J www.diclemedj.org Cilt / Vol 39, No 2, 310-315 D. Ünal et al. Insulin hormone 313 duced more dense solution (i.e. the excess of glu- ous studies prove above results, increasing of lipid cose) in the intercellular area causes dehydration peroxidation in induced-diabetic rat brain,52 anti- within the cell.45,46 As a result, because the absence oxidant protection system members decreased ac- or lack of insulin prevents the use of glucose in the tivity of super oxide dismutase and Catalase prove peripheral tissues, alternative ways occur to provide the above results.52,54 Although, in the brain glucose the energy needs in the tissues. At this point, the transportation is realized without insulin, this glu- produced amino acids from protein demolition are cose intake stage is controlled by insulin.52,54 Insulin used in the gluconeogenesis. are directly bro- receptors are expressed by astrocytes and ken down in order to supply requirement of energy. in the brain, like growing factors. Insulin enhances If fatty acid is not completely broken down, ketone glucose uptake into astrocytes 55 but not in neurons. bodies accumulate in the blood. An increase in free Neuronal insulin receptors are intensive at synaps- fatty acids simulates the lipolysine in near tissues es. In addition, peripheral sensory and autonomic via heavy insulin deficiency. The free fatty acids ganglia have insulin receptors.55,56 In anaerobic are resource of ketogenesis, which is producing condition, the metabolizes the glucose or are ketone bodies as a result of fatty acid breakdown forced to metabolize glucose as glycogen, it leads to (beta-hydroxybutyrate, acetoacetate, and acetone) lactate formation. Hence, increased level of lactate in liver and. It is accelerated by insulin deficiency is indicative of tissue hypoxia and possible dam- and glucagon excess. The excess ketone bodies age. Lactic acidosis is related with lactate levels >5 cause acidosis and loss in body.46,48 An mmol/L and pH <7.35.57 Lactic acidosis in- increase in free fatty acids, glycerol and ketogenic hibits the glycolytic enzymes, especially phospho- amino acids in the blood break down of running ca- fructokinase; anaerobic glycolysis rate needs meta- tabolism toward Krebs cycle in the liver and it cause bolic increases to provide the cell energy consump- accumulation of the hydrogen-ion donor acid bod- tion by ATP production. Nevertheless, glycogen ies (ketone bodies) in the blood. So, bicarbonate and level is not enough, so glycogen is exhausted soon, pH decreases in the blood and tissue. Carbon diox- intracellular pH decrease and causes brain cell dam- ide result of from bicarbonate consumption moves age.58,59 In brief, in cases of insulin deficiency and out of body by respiratory expiration. Because, the resistance some structural and functional damages ketones are excreted by the urine, excess carbonate may lead to central nervous system abnormalities. and liquid-electrolyte loss occurs. The progressive In conclusion, this review emphasized the rela- dehydration, asides, hyperosmolirate and deceased tively novel concept that effects of insulin on the cerebral oxygen consumption can cause patient to body and especially brain function. Insulin receptors 46,47,49 go into coma. are expressed in many body regions. Recent studies show that the influence of insulin on the molecu- The effect of insulin on the central nervous lar and cellular mechanisms of neurodegeneration system is important in contemporary Insulin resistance and deficiency are a serious meta- the body. Many diseases with dysfunction of insulin bolic and functional problem on central nervous are progressively growing day by day such as se- system.50 These problems can lead to cerebral atro- nile dementia, diabetes. Therefore, this conceptual phy, subcortical, brain stem damages, and cognitive review will hopefully lead to scientists designing dysfunctions.50,51 Related studies showed that there their experiments aimed at a full understanding of are two possible effects of diabetic mechanism; the the neural mechanisms involved in neuroendocrine first one is characterized the dynamics of metabolic system insulin mechanism in the body. change during oxidative stress, the second one is 52 abnormalities in calcium mechanism. The hyper- REFERENCES glycemic effect of circulation system; in brain tis- sue rest of glucose convert into sorbitol and fructose 1. Best CH, Scott DA. The Preparation of Insulin. J BiolChem 1923;57(6):709-23. via polyol, increasing level of sorbitol and fructose 2. Mather KJ, Lteif A, Steinberg HO, Baron AD. Interac- upset the relationship between the reactive oxygen tions between endothelin and nitric oxide in the regula- species production and elimination. Therefore, it tion of vascular tone in obesity and diabetes. Diabetes leads to toxic effect on related tissues.53 The previ- 2004;53(8):2060-6. Dicle Tıp Derg / Dicle Med J www.diclemedj.org Cilt / Vol 39, No 2, 310-315 314 D. Ünal et al. Insulin hormone

3. Rodrigues MA, Gomes DA, Andrade VA, Leite MF, Nathan- 18. Wang Z, Iwasaki Y, Zhao LF, Nishiyama M, Taguchi T, Tsu- son MH. Insulin induces calcium signals in the nucleus of gita M, Kambayashi M, Hashimoto K, Terada Y. Hormonal rat hepatocytes. Hepatology 2008;48(5):1621-31. regulation of glycolytic enzyme gene and pyruvate dehy- 4. Sanderson TH, Kumar R, Sullivan JM, Krause GS. Insulin drogenase kinase/phosphatase gene transcription. Endocr J blocks cytochrome c release in the reperfused brain through 2009;56(8):1019-30. PI3-K signaling and by promoting Bax/Bcl-XL binding. J 19. Liu LF, Purushotham A, Wendel AA, Belury MA. Com- Neurochem 2008;106(3):1248-58. bined effects of rosiglitazone and conjugated linoleic acid 5. Ishiki M, Klip A. Minireview: recent developments in the on adiposity, insulin sensitivity, and hepatic steatosis in regulation of glucose transporter-4 traffic: new signals, lo- high-fat-fed mice. Am J Physiol Gastrointest Liver Physiol cations, and partners. 2005;146(12):5071- 2007;292(6):1671-82. 78. 20. Rossi AS, Lombardo YB, Chicco AG. Lipogenic en- 6. Grillo CA, Piroli GG, Hendry RM, Reagan LP. Insulin-stim- zyme activities and glucose uptake in fat tissue of dysli- ulated translocation of GLUT4 to the plasma membrane pemic, insulin-resistant rats: Effects of oil. Nutrition in rat hippocampus is PI3-kinase dependent. Brain Res 2010;26(2):209-17. 2009;1296(3):35-45. 21. Dulloo AG. A role for suppressed thermo- 7. Watson RT, Pessin JE. Intracellular organization of insulin genesis in pathways from weight fluctuations to the- in signaling and GLUT4 translocation. Recent ProgHorm Res sulin resistance syndrome: A Review. ActaPhysiolScand 2001;56:175-93. 2005;184(4):295-307. 8. Torlińska T, Maćkowiak P, Nogowski L, et al. Age dependent 22. Meshkani R, Adeli K. Hepatic insulin resistance, meta- changes of insulin receptors in rat tissues. J PhysiolPharma- bolic syndrome and cardiovascular disease. ClinBiochem col 2000;51(4 Pt 2):871-81. 2009;42(13-14):1331-46. 9. Thulasi R, Dias P, Houghton PJ, Houghton JA. Alpha 2a- 23. Griffin MJ, Sul HS. Insulin regulation of fatty acidsyn- interferon-induced differentiation of human alveolar rhab- thase gene transcription: Roles of USF and SREBP-1c: A domyosarcoma cells: correlation with down-regulation of Review. IUBMB Life 2004;56(10):595-600. the insulin-like growth factor type I receptor. Cell Growth 24. Després JP. The endocannabinoid system: a new target for Differ 1996;7(4):531-41. the regulation of energy balance and metabolism: A review. 10. Zhao M, Wan ZL, Whittaker L, et al. Design of an insulin Crit Pathw Cardiol 2007;6(2):46-50. analog with enhanced receptor-. Ratio- 25. Goldstein BJ, Müller-Wieland D. Type 2 Diabetes (Patho- nale, structure, and therapeutic implications. J BiolChem genesis of Type 2 Diabetes) 2nd edition, 2008, Informa 2010;285:11755-59. Healthcare USA, 2008;13-26. 11. Park S, Hong SM, Ahn IS. Exendin-4 and exercise improve 26. Leibowitz MD, Biswas e. Brady EJ et aL. A novel insu- hepatic glucose by promoting insulin signaling lin secretogogue is a phosphodiesterase inhibitor. Diabetes in diabetic rats. Metabolism 2010;59(1):123-33. 1995;44:67-70. 12. Varea O, Arevalo MA, Garrido JJ, Garcia-Segura LM, Wan- 27. Taylor SI. Lilly Lecture: Molecular mechanisms of insulin dosell F, Mendez P. Interaction of receptors with resistance: lessons from patients with mutations in the insu- insulin-like growth factor-I and Wnt signaling in the ner- lin receptor gene. Diabetes 1992;41:1473-90. vous system. 2010;75(8-9):565-9. 28. Pedersen O, Bak JF, Andersen PH. Evidence against altered 13. Hansotia T, Drucker DJ. GIP and GLP-1 as hor- expression of GLUT 1 or GLUT 4 in skeletal muscle of mones: lessons from single and double incretin receptor patients with obesity or NIDDM. Diabetes 1990;39:865-70. knockout mice: A review. Regul Pept 2005;128(2):125-34. 29. Nelson DL, Michael M. Cox MM. Lehninger Principles of 14. Havel PJ. Peripheral signals conveying metabolic informa- Biochemistry. W. H. Freeman (Fourth Edition) 2004. tion to the brain: short-term and long-term regulation of 30. Fox SI. Human . McGraw-Hill Science / Engi- intake and energy homeostasis: A review. Exp Biol neering (Eighth Edition) 2003. Med (Maywood) 2001;226(11):963-77. 31. Das UN. GLUT-4, tumor necrosis factor, essential fatty ac- 15. Simonson GD, Kendall DM. Diagnosis of insulin resistance ids and daf-genes and their role in insulin resistance and and associated syndromes: the spectrum from the metabolic non-insulin dependent diabetes mellitus: A review. Prosta- syndrome to type 2 diabetes mellitus: A review. Coron Ar- glandins LeukotEssent Fatty Acids 1999;60(1):13-20. tery Dis 2005;16(8):465-472. 32. Mues C, Zhou J, Manolopoulos KN, et al. Regulation of 16. Krupanidhi S, Sedimbi SK, Vaishnav G, Madhukar SS, glucose-6-phosphatase by insulin and met- Sanjeevi CB. Diabetes-Role of epigenetics, , and formin. HormMetab Res 2009;41(10):730-35. physiological factors. Zhong Nan Da XueBao Yi Xue Ban 33. Rajpathak SN, Gunter MJ, Wylie-Rosett J, et al. The role 2009;34(9):837-45. of insulin-like growth factor-I and its binding proteins in 17. Seneviratne HR, Lankeshwara D, Wijeratne S, Somasun- glucose homeostasis and type 2 diabetes. Diabetes Metab deram N, Athukorale D. Serum insulin patterns and the Res Rev 2009;25(1):3-12. relationship between insulin sensitivity and glycaemic 34. Woodcroft KJ, Hafner MS, Novak RF. Insulin signaling profile in women with polycystic syndrome. BJOG in the transcriptional and posttranscriptional regulation of 2009;116(13):1722-8. CYP2E1 expression. Hepatology 2002;35(2):263-73.

Dicle Tıp Derg / Dicle Med J www.diclemedj.org Cilt / Vol 39, No 2, 310-315 D. Ünal et al. Insulin hormone 315

35. Miakotina OL, Goss KL, Snyder JM. Insulin utilizes the PI and pyruvate, and of alloxan, diabetes and starvation, on 3-kinase pathway to inhibit SP-A gene expression in lung the uptake and metabolic fate of glucose in rat and epithelial cells. Respir Res 2002;3(1):27. diaphragm muscles. Biochem J 1964;93:652-65. 36. Murdolo G, Smith U. The dysregulated : a 48. Rosenthal MD. Glewm RH. Medical biochemistry: Human connecting link between insulin resistance, type 2 diabetes metabolism in health and disease. A John Wiley & Sons, mellitus and atherosclerosis: Review. NutrMetabCardio- Inc., Publication, USA, 2009;112-40. vasc Dis 2006;16(1):35-38. 49. Morgensen CE, Christensen CK. changes 37. Morange PE, Aubert J, Peiretti F, et al. Glucocorticoids and and renal function in incipient and overt diabetic nephropa- insulin promote plasminogen activator inhibitor 1 produc- thy. Hypertension 1985; 7: II64-II73. tion by human adipose tissue. Diabetes 1999;48(4):890-5. 50. Delibaş N, Kılınç İ. İnsülin ve gliklazid tedavisinin strep- 38. Yamada K, Kawata H, Shou Z, Mizutani T, Noguchi T, Mi- tozotosin diabetik rat hipokampuslarında lipid peroksidas- yamoto K. Insulin induces the expression of the SHARP-2/ yonuna etkisi. Turk Klinik Biyokimya Derg 2003;1:33-9. Stra13/DEC1 gene via a phosphoinositide 3-kinase path- 51. Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, way. J BiolChem 2003;278(33):30719-24. Gispen WH. Water maze learning and hippocampal synap- 39. Pendergrass M, Koval J, Vogt C, et al. Insulin-induced tic plasticity in -diabetic rats: effects of insu- hexokinase II expression is reduced in obesity and NID- lin treatment. Brain Res 1998;800(1):125-35. DM. Diabetes 1998;47(3):387-94. 52. Gispen WH, Biessels GJ. Cognition and synaptic plas- 40. Kok K, Geering B, Vanhaesebroeck B. Regulation of phos- ticity in diabetes mellitus, A Review. Trends Neurosci phoinositide 3-kinase expression in health and disease: A 2000;23(11):542-9. review. Trends BiochemSci 2009;34(3):115-27. 53. Friedman EA. Renal syndromes in diabetes. Endocrinol 41. Au WS, Kung HF, Lin MC. Regulation of microsomal Metab Clin North Am 1996;25(2):293-324. triglyceride transfer protein gene by insulin in HepG2 54. Makar TK, Rimpel-Lamhaouar K, Abraham DG, Gokhale cells: roles of MAPKerk and MAPKp38. Diabetes VS, Cooper AJ. Antioxidant defense systems in the brains 2003;52(5):1073-80. of type II diabetic mice. J Neurochem 1995;65(1):287-91. 42. Kim SJ, Kahn CR. Insulin stimulates phosphorylation of c- 55. Kum W, Zhu SQ, Ho SK, Young JD, Cockram CS. Effect of Jun, c-Fos, and Fos-related proteins in cultured adipocytes. insulin on glucose and glycogen metabolism and leucine in- J BiolChem 1994;269(16):11887-92. corporation into protein in cultured mouse astrocytes. Glia 43. O’Brien RM, Granner DK. Regulation of gene expression 1992;6:264-8. by insulin: A Review. Biochem J 1991;278(Pt3):609-19. 56. Zhu SQ, Kum W, Ho SK, Young JD, Cockram SS. Struc- 44. Maciel RM, Moses AC, Villone G, Tramontano D, Ingbar ture-function relationships of insulin receptor interactions SH. Demonstration of the production and physiological in cultured mouse astrocytes. Brain Res 1990;529:329-32. role of insulin-like growth factor II in rat follicular 57. Luft FC. Lactic acidosis update for critical care clinicians. J cells in culture. J Clin Invest 1988;82(5):1546-53. Am Soc Nephrol 2001;12(Suppl. 17):15-9. 45. Goldstein BJ, Müller-Wieland D. Type 2 Diabetes (Insulin 58. Knudsen GM, Jakobsen J, Barry DI, Compton AM, Tomlin- in Type 2 Diabetes) 2nd edition, Informa Health- son DR. Myo- normalizes decreased sodium perme- care USA, 2008;181-206. ability of the blood-brain barrier in streptozotocin diabetes. 46. Kahn CR, Weir GC, King GI, Jacobson AM, Moses AC, Neuroscience 1989;29(3):773-7. Smith RJ (ed.). Joslin’s Diabetes mellitus 2005; chapter 59. Altınova A, Aktürk M, Törüner FB, Arslan M. Tip 1 Diabe- 19:336-7. tes mellitus ve insülin direnci (Type 1 diabetes mellitus and 47. Randle PJ, Newsholme EA, Garland PB. Regulation of glu- ınsulin resistance: Review). Turkiye Klinikleri J Med Sci cose uptake by muscle. Effects of fatty acids, ketone bodies 2007;27(1):220-23.

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