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

Abstract

Diabetes mellitus (DM) is one of the most common and chronic disease all over the world. It is characterized with either insulin deficiency or insulin resistance. Insulin is a hormone which is secreted by beta cells in the Langerhans Islets of pancreas and playing a role in carbohydrate metabolism regulation in association with glucagon. Regarding the insulin\'s effects on carbohydrates, almost in all tissues (except brain) insulin increases the facilitated diffusion of glucose into cells and shows and an effect to reduce the blood glucose levels. In other words, it have regulator role on blood sugar level; insulin secretion is known to be associated with an increase in the amount of energy. Insulin secretion is related with increasing glucose level. It has been shown that it is closely related with intracellular enzymes and has a stimulating effect on transcription of glucokinase, pyruvate kinase, phosphofructo kinase and fructose-2,6 biphosphatase that are glicolytic and an inhibitory effect on transcription of phosphophenolpyruvate carboxykinase that is gluconeogenetic. Besides being the primary regulator of carbohydrate metabolism, insulin also has an important effect on lipid and protein metabolisms that are interrelated with carbohydrate metabolism. For the basis of diabetes effects on Central Nervous system (CNS) two mechanisms are emphasized; first is the oxidative stress developed due to metabolic changes and the second is damages of calcium ion metabolism. In this review, it was intended to reach detailed information by reviewing insulin\'s basic effect mechanism, its reflection on cellular level and its relationship with central nervous system.

Keywords

• Central nervous system, insulin, diabetes mellitus, carbohydrate metabolism

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

Abstract

Diabetes Mellitus (DM) dünyadaki en yaygın kronik hastalıklardan biridir. Ya yetersiz insülin salınması ya da insüline karşı oluşan direnç ile karakterizedir. İnsülin pankreasın Langerhans adacıklarındaki beta hücrelerinden salınan ve vücuttaki karbonhidrat metabolizmasının düzenlenmesinde glukagon ile birlikte rol alan bir hormondur. İnsülinin, karbonhidratlar üzerindeki etkileri bağlamında, insülin hemen hemen tüm dokularda (beyin hariç), glikozun hücrelere kolaylaştırılmış difüzyonunu hızlandırmakta ve kan glikoz düzeyini azaltmaya yönelik bir etki oluşturmaktadır. Bir başka ifadeyle insülin kan şeker düzeyinin düzenlenmesinde görev alır. İnsülin sekresyonunun enerji miktarındaki artışla alakalı olduğu bilinmektedir. Hücre içi enzimlerle yakından ilişkili olup, insülinin, glikolitik özelliğe sahip; glukokinaz, pirüvat kinaz, fosfofrukto kinaz ve fruktoz 2,6 bifosfataz üzerinde transkripsiyonu stimüle edici etkisi olduğu, glukoneogenik özellikli fosfofenolpürivat karboksikinaz üzerinde transkripsiyonu inhibe edici etkiye sahip olduğu gösterilmiştir. İnsülinin, karbonhidrat metabolizmasının birincil dengeleyicisi olmasının yanında, karbonhidrat metabolizması ile ilişki içinde bulunan yağ ve protein metabolizmaları üzerinde de önemli etkileri vardır. Diyabetin Merkezi Sinir Sistemi (MSS) üzerindeki etkilerinin temelinde ise iki mekanizmanın önemi üzerinde durulmakta, bunlardan ilkinin metabolik değişiklikler sonucu ortaya çıkan oksidatif stres olduğu, diğerinin ise kalsiyum iyonu metabolizmasında meydana gelen bozukluklardan kaynaklandığı iddia edilmektedir. Bu derlemede insülinin temel etki mekanizmaları, hücresel düzeydeki yansımaları ve MSS ile olan ilişkisi üzerinde durularak detaylı bilgiye ulaşılması amaçlanmıştır.

Keywords

• Merkezi sinir sistemi, insülin, diabetes mellitus, karbonhidrat metabolizması

References

1. Best CH, Scott DA. The Preparation of Insulin. J BiolChem 1923;57(6):709-23.
2. Mather KJ, Lteif A, Steinberg HO, Baron AD. Interac- tions between endothelin and nitric oxide in the regula- tion of vascular tone in obesity and diabetes. Diabetes 2004;53(8):2060-6.
3. Rodrigues MA, Gomes DA, Andrade VA, Leite MF, Nathan- son MH. Insulin induces calcium signals in the nucleus of rat hepatocytes. Hepatology 2008;48(5):1621-31.
4. Sanderson TH, Kumar R, Sullivan JM, Krause GS. Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding. J Neurochem 2008;106(3):1248-58.
5. Ishiki M, Klip A. Minireview: recent developments in the regulation of glucose transporter-4 traffic: new signals, lo- cations, and partners. Endocrinology 2005;146(12):5071- 78.
6. Grillo CA, Piroli GG, Hendry RM, Reagan LP. Insulin-stim- ulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res 2009;1296(3):35-45.
7. Watson RT, Pessin JE. Intracellular organization of insulin signaling and GLUT4 translocation. Recent ProgHorm Res 2001;56:175-93.
8. Torlińska T, Maćkowiak P, Nogowski L, et al. Age dependent changes of insulin receptors in rat tissues. J PhysiolPharma- col 2000;51(4 Pt 2):871-81.

9. Thulasi R, Dias P, Houghton PJ, Houghton JA. Alpha 2a- interferon-induced differentiation of human alveolar rhab- domyosarcoma cells: correlation with down-regulation of the insulin-like growth factor type I receptor. Cell Growth Differ 1996;7(4):531-41.
10. Zhao M, Wan ZL, Whittaker L, et al. Design of an insulin analog with enhanced receptor-binding selectivity. Ratio- nale, structure, and therapeutic implications. J BiolChem 2010;285:11755-59.
11. Park S, Hong SM, Ahn IS. Exendin-4 and exercise improve hepatic glucose homeostasis by promoting insulin signaling in diabetic rats. Metabolism 2010;59(1):123-33.
12. Varea O, Arevalo MA, Garrido JJ, Garcia-Segura LM, Wan- dosell F, Mendez P. Interaction of estrogen receptors with insulin-like growth factor-I and Wnt signaling in the ner- vous system. Steroids 2010;75(8-9):565-9.
13. Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hor- mones: lessons from single and double incretin receptor knockout mice: A review. Regul Pept 2005;128(2):125-34.
14. Havel PJ. Peripheral signals conveying metabolic informa- tion to the brain: short-term and long-term regulation of food intake and energy homeostasis: A review. Exp Biol Med (Maywood) 2001;226(11):963-77.
15. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus: A review. Coron Ar- tery Dis 2005;16(8):465-472.
16. Krupanidhi S, Sedimbi SK, Vaishnav G, Madhukar SS, Sanjeevi CB. Diabetes-Role of epigenetics, genetics, and physiological factors. Zhong Nan Da XueBao Yi Xue Ban 2009;34(9):837-45.
17. Seneviratne HR, Lankeshwara D, Wijeratne S, Somasun- deram N, Athukorale D. Serum insulin patterns and the relationship between insulin sensitivity and glycaemic profile in women with polycystic ovary syndrome. BJOG 2009;116(13):1722-8.
18. Wang Z, Iwasaki Y, Zhao LF, Nishiyama M, Taguchi T, Tsu- gita M, Kambayashi M, Hashimoto K, Terada Y. Hormonal regulation of glycolytic enzyme gene and pyruvate dehy- drogenase kinase/phosphatase gene transcription. Endocr J 2009;56(8):1019-30.
19. Liu LF, Purushotham A, Wendel AA, Belury MA. Com- bined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice. Am J Physiol Gastrointest Liver Physiol 2007;292(6):1671-82.
20. Rossi AS, Lombardo YB, Chicco AG. Lipogenic en- zyme activities and glucose uptake in fat tissue of dysli- pemic, insulin-resistant rats: Effects of fish oil. Nutrition 2010;26(2):209-17.
21. Dulloo AG. A role for suppressed skeletal muscle thermo- genesis in pathways from weight fluctuations to the in- sulin resistance syndrome: A Review. ActaPhysiolScand 2005;184(4):295-307.
22. Meshkani R, Adeli K. Hepatic insulin resistance, meta- bolic syndrome and cardiovascular disease. ClinBiochem 2009;42(13-14):1331-46.
23. Griffin MJ, Sul HS. Insulin regulation of fatty acid syn- thase gene transcription: Roles of USF and SREBP-1c: A Review. IUBMB Life 2004;56(10):595-600.
24. Després JP. The endocannabinoid system: a new target for the regulation of energy balance and metabolism: A review. Crit Pathw Cardiol 2007;6(2):46-50.
25. Goldstein BJ, Müller-Wieland D. Type 2 Diabetes (Patho- genesis of Type 2 Diabetes) 2nd edition, 2008, Informa Healthcare USA, 2008;13-26.
26. Leibowitz MD, Biswas e. Brady EJ et aL. A novel insu- lin secretogogue is a phosphodiesterase inhibitor. Diabetes 1995;44:67-70.
27. Taylor SI. Lilly Lecture: Molecular mechanisms of insulin resistance: lessons from patients with mutations in the insu- lin receptor gene. Diabetes 1992;41:1473-90.
28. Pedersen O, Bak JF, Andersen PH. Evidence against altered expression of GLUT 1 or GLUT 4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 1990;39:865-70.
29. Nelson DL, Michael M. Cox MM. Lehninger Principles of Biochemistry. W. H. Freeman (Fourth Edition) 2004.
30. Fox SI. Human Physiology. McGraw-Hill Science / Engi- neering (Eighth Edition) 2003.
31. Das UN. GLUT-4, tumor necrosis factor, essential fatty ac- ids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus: A review. Prosta- glandins LeukotEssent Fatty Acids 1999;60(1):13-20.
32. Mues C, Zhou J, Manolopoulos KN, et al. Regulation of glucose-6-phosphatase gene expression by insulin and met- formin. HormMetab Res 2009;41(10):730-35.
33. Rajpathak SN, Gunter MJ, Wylie-Rosett J, et al. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes Metab Res Rev 2009;25(1):3-12.
34. Woodcroft KJ, Hafner MS, Novak RF. Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology 2002;35(2):263-73.
35. Miakotina OL, Goss KL, Snyder JM. Insulin utilizes the PI 3-kinase pathway to inhibit SP-A gene expression in lung epithelial cells. Respir Res 2002;3(1):27.
36. Murdolo G, Smith U. The dysregulated adipose tissue: a connecting link between insulin resistance, type 2 diabetes mellitus and atherosclerosis: Review. NutrMetabCardio- vasc Dis 2006;16(1):35-38.
37. Morange PE, Aubert J, Peiretti F, et al. Glucocorticoids and insulin promote plasminogen activator inhibitor 1 produc- tion by human adipose tissue. Diabetes 1999;48(4):890-5.
38. Yamada K, Kawata H, Shou Z, Mizutani T, Noguchi T, Mi- yamoto K. Insulin induces the expression of the SHARP-2/ Stra13/DEC1 gene via a phosphoinositide 3-kinase path- way. J BiolChem 2003;278(33):30719-24.
39. Pendergrass M, Koval J, Vogt C, et al. Insulin-induced hexokinase II expression is reduced in obesity and NID- DM. Diabetes 1998;47(3):387-94.
40. Kok K, Geering B, Vanhaesebroeck B. Regulation of phos- phoinositide 3-kinase expression in health and disease: A review. Trends BiochemSci 2009;34(3):115-27.
41. Au WS, Kung HF, Lin MC. Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes 2003;52(5):1073-80.
42. Kim SJ, Kahn CR. Insulin stimulates phosphorylation of c- Jun, c-Fos, and Fos-related proteins in cultured adipocytes. J BiolChem 1994;269(16):11887-92.
43. O’Brien RM, Granner DK. Regulation of gene expression by insulin: A Review. Biochem J 1991;278(Pt3):609-19.
44. Maciel RM, Moses AC, Villone G, Tramontano D, Ingbar SH. Demonstration of the production and physiological role of insulin-like growth factor II in rat thyroid follicular cells in culture. J Clin Invest 1988;82(5):1546-53.
45. Goldstein BJ, Müller-Wieland D. Type 2 Diabetes (Insulin Therapy in Type 2 Diabetes) 2nd edition, Informa Health- care USA, 2008;181-206.
46. Kahn CR, Weir GC, King GI, Jacobson AM, Moses AC, Smith RJ (ed.). Joslin’s Diabetes mellitus 2005; chapter 19:336-7.
47. Randle PJ, Newsholme EA, Garland PB. Regulation of glu- cose uptake by muscle. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan, diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem J 1964;93:652-65.
48. Rosenthal MD. Glewm RH. Medical biochemistry: Human metabolism in health and disease. A John Wiley & Sons, Inc., Publication, USA, 2009;112-40.
49. Morgensen CE, Christensen CK. Blood pressure changes and renal function in incipient and overt diabetic nephropa- thy. Hypertension 1985; 7: II64-II73.
50. Delibaş N, Kılınç İ. İnsülin ve gliklazid tedavisinin strep- tozotosin diabetik rat hipokampuslarında lipid peroksidas- yonuna etkisi. Turk Klinik Biyokimya Derg 2003;1:33-9.
51. Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Water maze learning and hippocampal synap- tic plasticity in streptozotocin-diabetic rats: effects of insu- lin treatment. Brain Res 1998;800(1):125-35.
52. Gispen WH, Biessels GJ. Cognition and synaptic plas- ticity in diabetes mellitus, A Review. Trends Neurosci 2000;23(11):542-9.
53. Friedman EA. Renal syndromes in diabetes. Endocrinol Metab Clin North Am 1996;25(2):293-324.
54. Makar TK, Rimpel-Lamhaouar K, Abraham DG, Gokhale VS, Cooper AJ. Antioxidant defense systems in the brains of type II diabetic mice. J Neurochem 1995;65(1):287-91.
55. Kum W, Zhu SQ, Ho SK, Young JD, Cockram CS. Effect of insulin on glucose and glycogen metabolism and leucine in- corporation into protein in cultured mouse astrocytes. Glia 1992;6:264-8.
56. Zhu SQ, Kum W, Ho SK, Young JD, Cockram SS. Struc- ture-function relationships of insulin receptor interactions in cultured mouse astrocytes. Brain Res 1990;529:329-32.
57. Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol 2001;12(Suppl. 17):15-9.
58. Knudsen GM, Jakobsen J, Barry DI, Compton AM, Tomlin- son DR. Myo-inositol normalizes decreased sodium perme- ability of the blood-brain barrier in streptozotocin diabetes. Neuroscience 1989;29(3):773-7.
59. Altınova A, Aktürk M, Törüner FB, Arslan M. Tip 1 Diabe- tes mellitus ve insülin direnci (Type 1 diabetes mellitus and ınsulin resistance: Review). Turkiye Klinikleri J Med Sci 2007;27(1):220-23.