Editors' ChoiceDiabetes

ERAD-icating mutant insulin promotes functional insulin secretion

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Science Translational Medicine  18 Jan 2017:
Vol. 9, Issue 373, eaal4995
DOI: 10.1126/scitranslmed.aal4995

Abstract

Overexpression of a chaperone protein liberates functional insulin from a misfolded mutant partner to improve insulin secretion.

The pancreatic beta cell is an incredible machine producing tens of thousands of insulin molecules every second. When this process works normally, the result is tight regulation of blood glucose and whole body energy stores. However, breakdowns in insulin processing can rapidly overwhelm the beta cell leading to beta cell stress, destruction, and ultimately diabetes. A striking example of this breakdown can be found in the disease MIDY (Mutant INS-gene induced Diabetes of Youth) in which production of a single mutant insulin molecule leads to dominant beta cell failure and diabetes. Now, Cunningham et al. report a potential new pathway that can be exploited to diminish mutant insulin and restore normal insulin secretion.

Misfolded proteins are commonly trapped in the endoplasmic reticulum (ER) where they are triaged by a process known as ER-associated degradation (ERAD) and ultimately destroyed by the cytoplasmic proteasome. Unfortunately, due to insulin’s capacity to form disulfide bonds, mutant insulin often ends up forming large complexes including complexes that trap normal insulin. The investigators determined that the ER chaperone protein GRP170 plays an important role in untangling these deleterious interactions. Knockdown of GRP170 worsened entrapment of the healthy insulin in a beta cell line; conversely, GRP170 overexpression restored insulin secretion to near normal levels. The GRP170 protein directly interacted with mutant insulin while also facilitating interaction with other key ERAD proteins in beta cells.

These findings present GRP170 as an important target that may enable escape of sufficient insulin from islet beta cells undergoing ER stress, which includes cells with mutant insulin but could also extend to other disease states including Type 2 diabetes. Importantly, the authors note that GRP170 is already upregulated in the stressed beta cell, but this level needs to be further increased to see a beneficial effect. These findings support future clinical trials of new pharmaceuticals in diabetes including MIDY to enhance GRP170 or other ERAD components to improve beta cell function.

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