A structurally abnormal insulin causing human diabetes

Tager, Howard S.; Given, Bruce D.; Baldwin, David; Mako, Mary E.; Markese, J.; Rubenstein, Arthur H.; Olefsky, Jerrold M.; Kobayashi, Masashi; Kolterman, Orville G.; Poucher, Russel

doi:10.1038/281122a0

Cited by 182 publications

(88 citation statements)

References 24 publications

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“…The earlier described mutations primarily affected the biological activity of the resultant (pro)insulin molecules but did not impair their biosynthesis significantly, leading to impaired clearance accompanied by hyperinsulinemia and hyperproinsulinemia (16,17). They only resulted in diabetes in the presence of insulin resistance and in adults.…”

Section: Discussionmentioning

confidence: 99%

Insulin gene mutations as a cause of permanent neonatal diabetes

Støy

Edghill

Flanagan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

507

478

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We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with ␤ cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially ␤ cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of ␤ cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.endoplasmic reticulum stress ͉ insulin biosynthesis ͉ disulfide bonds ͉ unfolded protein response

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Section: Discussionmentioning

confidence: 99%

Insulin gene mutations as a cause of permanent neonatal diabetes

Støy

Edghill

Flanagan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

507

478

View full text Add to dashboard Cite

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“…In fact, amino-acid substitutions within these regions have been identified in the insulins from © 1997 International Union of Crystallography Printed in Great Britain -all rights reserved three individuals in whom genetic mutations resulted in the secretion of abnormal hormones associated with diabetes (Tager et al, 1979(Tager et al, , 1980Shoelson, Fickova et al, 1983;Haneda, Chan, Kowk, Rubenstein & Steiner, 1983), insulin Chicago (B25-Phe--~B25-Leu), insulin Los Angeles (B24-Phe--->B24-Ser), and insulin Wakayama (A3-Val--->A3-Leu). The structural analysis of a A1-B29 cross-linked insulin, which was completely inactive, indicates that its conformation is nearly same as that of native insulin (Derewenda et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Structure of Monomeric Porcine DesB1–B2 Despentapeptide (B26–B30) Insulin at 1.65 Å Resolution

et al. 1997

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Insulin has a concentration of 10-8-10 -11M in the blood which ensures that it circulates and exerts its physiological functions in vivo as a monomer. The crystal structure of monomeric porcine desB1-B2 despentapeptide (B26-B30) insulin (DesB1-2 DPI) with M r = 4934 Da has been determined at 1.65 A resolution using the molecular replacement method. A structural comparison between DesB1-2 DPI and 2Zn insulin reveals that the conformation of DesB1-2 DPI is more similar to molecule I than molecule II of 2Zn insulin. The remarkable conformational difference between B25-Phe in DesB1-2 DPI and B25-Phe in despentapeptide (B26-B30) insulin (DPI) indicates that the residue B25-Phe possesses great flexibility and mobility.

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“…By the techniques of protein chemistry and recombinant DNA technology, the abnormal insulins from two of these individuals have been identified as human insulin B25 (Phe -Leu) (human [LeuB25]-insulin, insulin Chicago) (1)(2)(3)(4)(5) and human insulin B24 (Phe -Ser) (human [SerB24]_ insulin, insulin Los Angeles) (1,6,7); the structure of the abnormal insulin from the third remains to be determined. Because small amounts of normal insulin (in addition to large amounts of abnormal insulin) were detected in the serum of all three individuals (1), and because restriction endonuclease mapping has shown that two have both normal and abnormal insulin gene alleles (1,(4)(5)(6), it seems that normal and abnormal insulin gene alleles are coexpressed in affected subjects.…”

Section: Introductionmentioning

confidence: 99%

Human insulin B24 (Phe----Ser). Secretion and metabolic clearance of the abnormal insulin in man and in a dog model.

Shoelson¹,

Polonsky²,

Zeidler³

et al. 1984

J. Clin. Invest.

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As bstract. We have already demonstrated that a hyperinsulinemic, diabetic subject secreted an abnormal insulin in which serine replaced phenylalanine B24 (Shoelson S., M. Fickova, M. Haneda, A. Nahum, G. Musso, E. T. Kaiser, A. H. . Proc. NatL. Acad. . High performance liquid chromatography analysis now shows that the circulating insulin in several other family members also consists of a mixture of the abnormal human insulin B24 (Phe -+ Ser) and normal human insulin in a ratio of -9.5:1 during fasting. Although all affected subjects show fasting hyperinsulinemia, only the propositus and her father are overtly diabetic. Analysis of the serum insulin from two nondiabetic siblings revealed that normal insulin increased from -2 to 15% of total serum insulin after the ingestion of glucose and that the proportion ofthe normal hormone plateaued or fell while the level oftotal insulin continued to rise. Animal studies involving the graded intraportal infusion of equimolar amounts of semisynthetic human [SerB24]-insulin and normal human insulin in pancreatectomized dogs (to simulate the secretion of insulin due to oral glucose in man) also showed both a rise in the fraction of normal insulin that reached the periphery and the attainment of a brief steady state in this fraction while total insulin levels continued to rise. Separate experiments documented a decreased hepatic extraction, a decreased metabolic clearance rate, and an increased plasma half-life of human[SerB24]-insulin within the same parameters as those determined for normal human insulin. These results form Please address correspondence to Howard S. Tager, Department of Biochemistry, University of Chicago.Received for publication 27 October 1983 and in revised form 19 January 1984. a basis for considering (a) the differential clearance of low activity abnormal insulins and normal insulin from the circulation in vivo, and (b) the causes of hyperinsulinemia in both diabetic and nondiabetic individuals who secrete abnormal human insulins.

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A structurally abnormal insulin causing human diabetes

Cited by 182 publications

References 24 publications

Insulin gene mutations as a cause of permanent neonatal diabetes

Insulin gene mutations as a cause of permanent neonatal diabetes

Structure of Monomeric Porcine DesB1–B2 Despentapeptide (B26–B30) Insulin at 1.65 Å Resolution

Human insulin B24 (Phe----Ser). Secretion and metabolic clearance of the abnormal insulin in man and in a dog model.

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