Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth

Background: Preproinsulin signal peptide mutations have been linked to human diabetes. Results: Preproinsulin mutants fail to be fully translocated across the endoplasmic reticulum membrane, accumulate in the cytosol, and lead to ␤ cell death. Conclusion: Cytosolic preproinsulin accumulation contributes to ␤ cell failure. Significance: This reveals a novel pathogenesis of diabetes associated with inefficient preproinsulin translocation and cytosolic accumulation.

show abstract

“…5B, lanes 10 -12). Thus, Arg-6 mutants behave very differently from MIDY mutants described previously (9,10).…”

Section: The Positive Charge In the N Region And Charge Gradient Flanmentioning

confidence: 64%

Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes

Guo

Xiong

Witkowski

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pancreatic β cells synthesize large amounts of proinsulin molecules, which represent a major burden on the protein folding machinery in the endoplasmic reticulum (ER) (Liu et al, 2010). Accumulation of unfolded or misfolded proteins in the ER is counteracted by cellular homeostatic responses collectively termed the unfolded protein response (UPR) (Mori, 2000).…”

Section: Introductionmentioning

confidence: 99%

The Antipsychotic Olanzapine Induces Apoptosis in Insulin-secreting Pancreatic β Cells by Blocking PERK-mediated Translational Attenuation

Ozasa

Okada

Nadanaka

et al. 2013

Cell Struct. Funct.

View full text Add to dashboard Cite

ABSTRACT. Patients with schizophrenia receive medication to alleviate various symptoms, but some efficacious second generation antipsychotics, particularly olanzapine, can cause obesity, dyslipidemia, and diabetes mellitus. It has been generally considered that olanzapine contributes to the development of diabetes by inducing obesity and subsequent insulin resistance. In this study, we examined the effect of olanzapine and risperidone, another second generation antipsychotic, on a hamster pancreatic β cell line, and found that both evoked mild endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PERK. Surprisingly, only olanzapine induced marked apoptosis. Phosphorylation of the α subunit of eukaryotic initiation factor 2, an event immediately downstream of PERK activation, was not observed in cells treated with olanzapine, protein synthesis continued despite PERK activation, and ER stress was thereby sustained. Secretion of insulin was markedly inhibited, and both proinsulin and insulin accumulated inside olanzapine-treated cells. Inhibition of protein synthesis and knockdown of insulin mRNA, which result in less unfolded protein burden, both attenuated subsequent olanzapine-induced apoptosis. Given clinical observations that some patients taking olanzapine exhibit hyperlipidemia and hyperglycemia without gaining weight, our observations suggest that damage to pancreatic β cells may contribute to the undesirable metabolic consequences of olanzapine treatment in some cases.

show abstract

“…We are interested in the folding of proinsulin, which is essential for efficient insulin production in pancreatic ␤-cells (8,9). Some in vitro studies have implicated PDI in proinsulin folding (10,11), whereas other studies have implied a direct role for PDI in proinsulin oxidation in the ER of ␤-cells (12).…”

mentioning

confidence: 99%

Action of Protein Disulfide Isomerase on Proinsulin Exit from Endoplasmic Reticulum of Pancreatic β-Cells

Rajpal

Schuiki

Liu

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:We have examined the effect of PDI knockdown in pancreatic ␤-cells. Results: Upon knockdown, proinsulin oxidation to form native disulfide bonds is enhanced and accompanied by improved exit from the ER with increased total insulin secretion. Conclusion:We hypothesize that PDI exhibits unfoldase activity for proinsulin. Significance: Unexpectedly, PDI increases retention of proinsulin within the ER of pancreatic ␤-cells.

show abstract

Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth

Cited by 158 publications

References 85 publications

Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes

Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes

The Antipsychotic Olanzapine Induces Apoptosis in Insulin-secreting Pancreatic β Cells by Blocking PERK-mediated Translational Attenuation

Action of Protein Disulfide Isomerase on Proinsulin Exit from Endoplasmic Reticulum of Pancreatic β-Cells

Contact Info

Product

Resources

About