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Proinsulin
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== Medical Relevance == Historically, the focus of many insulin related metabolic diseases has focused on mature insulin. However, in recent years the importance of studying the structure and function of proinsulin or proinsulin:insulin ratio<ref>{{cite journal | vauthors = Mezza T, Ferraro PM, Sun VA, Moffa S, Cefalo CM, Quero G, Cinti F, Sorice GP, Pontecorvi A, Folli F, Mari A, Alfieri S, Giaccari A | display-authors = 6 | title = Increased β-Cell Workload Modulates Proinsulin-to-Insulin Ratio in Humans | journal = Diabetes | volume = 67 | issue = 11 | pages = 2389–2396 | date = November 2018 | pmid = 30131390 | doi = 10.2337/db18-0279 | hdl = 2434/587996 | s2cid = 52058695 | hdl-access = free }}</ref> in relation to these diseases has become increasingly clear. === [[Diabetes mellitus|Diabetes Mellitus]] === Increased levels of proinsulin in the [[circulatory system]] relative to mature insulin concentrations can indicate impending [[insulin resistance]] and the development of [[type 2 diabetes]].<ref>{{cite journal | vauthors = Mykkänen L, Haffner SM, Hales CN, Rönnemaa T, Laakso M | title = The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects | journal = Diabetes | volume = 46 | issue = 12 | pages = 1990–5 | date = December 1997 | pmid = 9392485 | doi = 10.2337/diab.46.12.1990 | s2cid = 44874023 }}</ref> Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding.<ref name="Weiss_2009"/> If the mutation causes only a mild change it could simply stress the endoplasmic reticulum’s ability to properly fold the protein.<ref name="Weiss_2009" /> This stress, after a while, would lead to a decrease in the number of [[Beta cell|β-cells]] producing mature insulin, and would then lead to diabetes mellitus.<ref name="Weiss_2009" /> === [[Neonatal diabetes mellitus|Neonatal Diabetes Mellitus]] === Postnatal proinsulin is crucial for metabolic regulation. However, proinsulin in [[neonates]] is important for normal development of the nerves of the eye, development of the heart, and general survival of embryonic cells.<ref name="Hernández-Sánchez_2006">{{cite journal | vauthors = Hernández-Sánchez C, Mansilla A, de la Rosa EJ, de Pablo F | title = Proinsulin in development: New roles for an ancient prohormone | journal = Diabetologia | volume = 49 | issue = 6 | pages = 1142–50 | date = June 2006 | pmid = 16596360 | doi = 10.1007/s00125-006-0232-5 | doi-access = free | hdl = 10261/72608 | hdl-access = free }}</ref> Regulation of the concentration of proinsulin during embryonic development is crucial, as too much or too little of the peptide can cause defects and death of the fetus.<ref name="Hernández-Sánchez_2006" /> Thus far in the study of neonatal diabetes mellitus, only amino acid change mutations found in the B domain lead to the disease.<ref name="Weiss_2009"/>
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