Proinsulin lacking the A7-B7 disulfide bond, Ins2Akita, tends to aggregate due to the exposed hydrophobic surface

Yoshinaga, Takao; Nakatome, Keisuke; Nozaki, Junichi; Naitoh, Motoko; Hoseki, Jun; Nagata, Kazuhiro

doi:10.1515/bc.2005.124

Cited by 32 publications

(30 citation statements)

References 30 publications

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“…the variant murine proinsulin indicate partial unfolding with increased aggregation (71). Such perturbations are in accord with structural studies of human insulin and proinsulin analogs lacking cystine A7-B7 (28,60).…”

Section: Diabetes-associated Mutationssupporting

confidence: 77%

Proinsulin and the Genetics of Diabetes Mellitus

Weiss

2009

Journal of Biological Chemistry

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Section: Diabetes-associated Mutationssupporting

confidence: 77%

Proinsulin and the Genetics of Diabetes Mellitus

Weiss

2009

Journal of Biological Chemistry

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“…Most importantly, we directly show that the intermolecular protein complexes containing C(A7)Y mutant also include wild-type endogenous PI, involving covalent (Fig. 4C) as well as possible hydrophobic interactions (25).…”

Section: Discussionmentioning

confidence: 74%

Proinsulin maturation, misfolding, and proteotoxicity

Liu

Hodish

Rhodes

et al. 2007

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

161

241

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As a tool to explore proinsulin (PI) trafficking, a human PI cDNA has been constructed with GFP fused within the C peptide. In regulated secretory cells containing appropriate prohormone convertases, the hProCpepGFP construct undergoes endoproteolytic processing to CpepGFP and native human insulin, which are specifically detected and cosecreted in parallel with endogenous insulin. Expression of C(A7)Y mutant PI results in autosomal dominant diabetes in Akita mice. We directly identify the misfolded PI in Akita islets and also show that C(A7)Y mutant PI, either in the context of the hProCpepGFP chimera or not, engages directly in protein complexes with nonmutant PI, impairing the trafficking and recovery of nonmutant PI. This trapping mechanism decreases insulin production in ␤ cells. Thereafter we observe a loss of ␤ cell viability. The data imply that PI misfolding leading to impaired endoplasmic reticulum exit of nonmutant PI may be a key early step in a chain reaction of ␤ cell dysfunction and demise leading to onset and progression of diabetes.diabetes mellitus ͉ endoplasmic reticulum storage disease ͉ insulin secretion ͉ proinsulin disulfide isomers

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“…This mutation disrupts intramolecular disulfi de bond formation causing improper folding of proinsulin. Proinsulin accumulates intracellularly and, by engorging the endoplasmic reticulum (ER) and triggering the ER stress response, leads to apoptosis of pancreatic ␤ -cells ( 13 ). Despite the co-expression of a normal insulin gene allele, by 3 to 4 weeks of age, Ins2…”

Section: Rna Isolation and Quantitative Real-time Pcr Analysismentioning

confidence: 99%

Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease

Zhou

Pridgen

King

et al. 2011

Journal of Lipid Research

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Accelerated atherosclerosis is the critical manifestation of macrovascular disease in both type 1 and 2 diabetics and the major etiology of morbidity and mortality in these individuals ( 1, 2 ). In 2000, the global excess mortality attributable to diabetes mellitus was estimated at 2.9 million deaths ( 3 ), with 80% the result of major cardiovascular events ( 4 ). Clinical studies of diabetic cardiovascular disease have mainly focused on type 2 diabetes. However, despite its younger age of onset, type 1 diabetes is also associated with a signifi cantly increased risk of cardiovascular diseases, with an age-adjusted risk greater than 10 times the general population, which even exceeds that of type 2 diabetes ( 2, 5-8 ). The mechanism of type 1 diabetesaccelerated atherosclerosis is not well studied, and a major reason has been the lack of a good animal model ( 9 ). The most commonly used animal model of type 1 diabetes is the streptozotocin (STZ)-treated mouse. In this model, injection of STZ ablates pancreatic ␤ -cells. Deficiencies of this model include considerable mouse-tomouse variation; age dependency of pancreatic ␤ -cell destruction; toxicity to other cells and tissues, including DNA damage and induction of carcinogenesis; instability of the diabetes phenotype due to pancreatic islet ␤ -cell regeneration; and the diffi culty of inducing diabetes in females ( 10-12 ). The variability and instability of STZ-treated mouse model make it especially diffi cult to perform the long-term experiments required for atherosclerosis studies.Abstract Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the longterm studies required. In an attempt to create a model for studying diabetic macrovascular disease, we have generated type 1 diabetic Akita mice lacking the low density lipoprotein receptor (

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Proinsulin lacking the A7-B7 disulfide bond, Ins2Akita, tends to aggregate due to the exposed hydrophobic surface

Cited by 32 publications

References 30 publications

Proinsulin and the Genetics of Diabetes Mellitus

Proinsulin and the Genetics of Diabetes Mellitus

Proinsulin maturation, misfolding, and proteotoxicity

Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease

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