SMPDB

Pathway Description

Insulin (New)

Homo sapiens

Physiological Pathway

Created: 2023-09-14

Last Updated: 2023-11-27

Insulin is a peptide hormone secreted in the body by beta cells of islets of Langerhans of the pancreas and regulates blood glucose levels. Medical treatment with insulin is indicated when there is inadequate production or increased insulin demands in the body. Insulin is responsible for the regulation of glucose levels in the body. It stimulates the storage of energy and inhibits the breakdown of high energy metabolites. Insulin acts by directly binding to its receptors on the plasma membranes of the cells. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density being on the hepatic cells and adipocytes. The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and the beta subunits. The extracellular alpha subunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity. When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit, which causes the translocation of glucose transporters from the cytoplasm to the cell's surface. Insulin promotes glycogen synthesis, lipid synthesis, protein synthesis, DNA synthesis, and cellular growth and differentiation. Once glucose gets absorbed from a meal, it enters the blood, and then the pancreas releases insulin. Insulin synthesis occurs in the beta cells of the pancreas initially as preproinsulin. Preproinsulin then converts to proinsulin, which then transforms into a single peptide with A, B, and C peptide units. The A and B peptides are joined by disulfide bonds to make insulin and are secreted into the bloodstream. Insulin binds to its cellular receptor. The insulin receptor is composed of alpha subunits, beta subunits, and a tyrosine kinase enzyme. When insulin binds to the alpha subunit, this triggers phosphorylation and activation of the target proteins intracellularly by the tyrosine kinase leading to many effects on cellular metabolism. Activation of the insulin receptor also leads to increased expression of GLUT (a glucose transporter) to the membrane surface and promotes the entry of glucose to the intracellular compartment and then undergoes cellular metabolism. Insulin signals glucose conversion to glycogen for storage and the formation of acetyl coenzyme A and triacylglycerol, which get stored in adipose tissue. Also, insulin directs amino acids for protein synthesis. Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion.

References

Insulin (New) References

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Pubmed: 16545079

Cheng Z, Tseng Y, White MF: Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab. 2010 Oct;21(10):589-98. doi: 10.1016/j.tem.2010.06.005. Epub 2010 Jul 16.

Pubmed: 20638297

Fu Z, Gilbert ER, Liu D: Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013 Jan 1;9(1):25-53.

Pubmed: 22974359

Thota S, Akbar A: Insulin.

Pubmed: 32809523

Dave HD, Preuss CV: Human Insulin.

Pubmed: 31424774

Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nurnberg B, et al.: Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science. 1995 Aug 4;269(5224):690-3. doi: 10.1126/science.7624799.

Pubmed: 7624799

Hillier LW, Fulton RS, Fulton LA, Graves TA, Pepin KH, Wagner-McPherson C, Layman D, Maas J, Jaeger S, Walker R, Wylie K, Sekhon M, Becker MC, O'Laughlin MD, Schaller ME, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Cordes M, Du H, Sun H, Edwards J, Bradshaw-Cordum H, Ali J, Andrews S, Isak A, Vanbrunt A, Nguyen C, Du F, Lamar B, Courtney L, Kalicki J, Ozersky P, Bielicki L, Scott K, Holmes A, Harkins R, Harris A, Strong CM, Hou S, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Leonard S, Rohlfing T, Rock SM, Tin-Wollam AM, Abbott A, Minx P, Maupin R, Strowmatt C, Latreille P, Miller N, Johnson D, Murray J, Woessner JP, Wendl MC, Yang SP, Schultz BR, Wallis JW, Spieth J, Bieri TA, Nelson JO, Berkowicz N, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Bedell JA, Mardis ER, Clifton SW, Chissoe SL, Marra MA, Raymond C, Haugen E, Gillett W, Zhou Y, James R, Phelps K, Iadanoto S, Bubb K, Simms E, Levy R, Clendenning J, Kaul R, Kent WJ, Furey TS, Baertsch RA, Brent MR, Keibler E, Flicek P, Bork P, Suyama M, Bailey JA, Portnoy ME, Torrents D, Chinwalla AT, Gish WR, Eddy SR, McPherson JD, Olson MV, Eichler EE, Green ED, Waterston RH, Wilson RK: The DNA sequence of human chromosome 7. Nature. 2003 Jul 10;424(6945):157-64. doi: 10.1038/nature01782.

Pubmed: 12853948

Scherer SW, Cheung J, MacDonald JR, Osborne LR, Nakabayashi K, Herbrick JA, Carson AR, Parker-Katiraee L, Skaug J, Khaja R, Zhang J, Hudek AK, Li M, Haddad M, Duggan GE, Fernandez BA, Kanematsu E, Gentles S, Christopoulos CC, Choufani S, Kwasnicka D, Zheng XH, Lai Z, Nusskern D, Zhang Q, Gu Z, Lu F, Zeesman S, Nowaczyk MJ, Teshima I, Chitayat D, Shuman C, Weksberg R, Zackai EH, Grebe TA, Cox SR, Kirkpatrick SJ, Rahman N, Friedman JM, Heng HH, Pelicci PG, Lo-Coco F, Belloni E, Shaffer LG, Pober B, Morton CC, Gusella JF, Bruns GA, Korf BR, Quade BJ, Ligon AH, Ferguson H, Higgins AW, Leach NT, Herrick SR, Lemyre E, Farra CG, Kim HG, Summers AM, Gripp KW, Roberts W, Szatmari P, Winsor EJ, Grzeschik KH, Teebi A, Minassian BA, Kere J, Armengol L, Pujana MA, Estivill X, Wilson MD, Koop BF, Tosi S, Moore GE, Boright AP, Zlotorynski E, Kerem B, Kroisel PM, Petek E, Oscier DG, Mould SJ, Dohner H, Dohner K, Rommens JM, Vincent JB, Venter JC, Li PW, Mural RJ, Adams MD, Tsui LC: Human chromosome 7: DNA sequence and biology. Science. 2003 May 2;300(5620):767-72. doi: 10.1126/science.1083423. Epub 2003 Apr 10.

Pubmed: 12690205

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Pubmed: 6298635

Reddy EP: Nucleotide sequence analysis of the T24 human bladder carcinoma oncogene. Science. 1983 Jun 3;220(4601):1061-3. doi: 10.1126/science.6844927.

Pubmed: 6844927

Sekiya T, Fushimi M, Hori H, Hirohashi S, Nishimura S, Sugimura T: Molecular cloning and the total nucleotide sequence of the human c-Ha-ras-1 gene activated in a melanoma from a Japanese patient. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4771-5. doi: 10.1073/pnas.81.15.4771.

Pubmed: 6087347

Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID, et al.: The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985 Apr;40(4):747-58. doi: 10.1016/0092-8674(85)90334-4.

Pubmed: 2859121

Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, et al.: Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985 Feb 28-Mar 6;313(6005):756-61. doi: 10.1038/313756a0.

Pubmed: 2983222

Seino S, Seino M, Bell GI: Human insulin-receptor gene. Partial sequence and amplification of exons by polymerase chain reaction. Diabetes. 1990 Jan;39(1):123-8. doi: 10.2337/diacare.39.1.123.

Pubmed: 2210055

Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. doi: 10.1016/0092-8674(92)90167-b.

Pubmed: 1322798

Bochmann H, Gehrisch S, Jaross W: The gene structure of the human growth factor bound protein GRB2. Genomics. 1999 Mar 1;56(2):203-7. doi: 10.1006/geno.1998.5692.

Pubmed: 10051406

Skolnik EY, Lee CH, Batzer A, Vicentini LM, Zhou M, Daly R, Myers MJ Jr, Backer JM, Ullrich A, White MF, et al.: The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J. 1993 May;12(5):1929-36.

Pubmed: 8491186

Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, Ballif BA: RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. Biochem J. 2012 Oct 1;447(1):159-66. doi: 10.1042/BJ20120938.

Pubmed: 22827337

Hart TC, Zhang Y, Gorry MC, Hart PS, Cooper M, Marazita ML, Marks JM, Cortelli JR, Pallos D: A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet. 2002 Apr;70(4):943-54. doi: 10.1086/339689. Epub 2002 Feb 26.

Pubmed: 11868160

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Pubmed: 17143285

	D-Glucose
	Guanosine diphosphate
	Guanosine triphosphate
	Magnesium
	Phosphate
	PIP2(16:0/16:0)
	PIP3(16:0/16:0)
	Zinc

	3-phosphoinositide-dependent protein kinase 1
	Dual specificity mitogen-activated protein kinase kinase 1
	Dual specificity mitogen-activated protein kinase kinase 2
	Forkhead box protein O1
	Growth factor receptor-bound protein 2
	GTPase HRas
	Insulin
	Insulin receptor
	Insulin receptor substrate 1
	Insulin receptor substrate 2
	Mitogen-activated protein kinase 1
	Mitogen-activated protein kinase 8
	Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
	Phosphoinositide 3-kinase regulatory subunit 6
	RAC-alpha serine/threonine-protein kinase
	RAF proto-oncogene serine/threonine-protein kinase
	SHC-transforming protein 1
	Solute carrier family 2, facilitated glucose transporter member 4
	Son of sevenless homolog 1

		D-Glucose
		Guanosine diphosphate
		Guanosine triphosphate
		Magnesium
		Phosphate
		PIP2(16:0/16:0)
		PIP3(16:0/16:0)
		Zinc

		3-phosphoinositide-dependent protein kinase 1
		Dual specificity mitogen-activated protein kinase kinase 1
		Dual specificity mitogen-activated protein kinase kinase 2
		Forkhead box protein O1
		Growth factor receptor-bound protein 2
		GTPase HRas
		Insulin
		Insulin receptor
		Insulin receptor substrate 1
		Insulin receptor substrate 2
		Mitogen-activated protein kinase 1
		Mitogen-activated protein kinase 8
		Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
		Phosphoinositide 3-kinase regulatory subunit 6
		RAC-alpha serine/threonine-protein kinase
		RAF proto-oncogene serine/threonine-protein kinase
		SHC-transforming protein 1
		Solute carrier family 2, facilitated glucose transporter member 4
		Son of sevenless homolog 1

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Insulin (New)

Insulin (New) References