PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicity-mediated impairment of insulin secretion in pancreatic beta cells.

Abdullah Yalçin,Gülçin Şarkici,Umut Kerem Kolaç

doi:10.3906/biy-1909-20

Abdullah Yalçin, Gülçin Şarkici + Show 1 more

Open Access

https://doi.org/10.3906/biy-1909-20

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Abstract

Type 2 diabetes mellitus is characterized by insulin resistance and hypersecretion of insulin from the pancreas to compensate for decreased insulin sensitivity in the peripheral tissues. In later stages of the disease insulin-secreting beta cell degeneration commences and patients require insulin replacement therapy in order to accomplish proper regulation of their blood glucose. Endoplasmic reticulum (ER) stress in the beta cells is one of the factors contributing to this detrimental effect. Protein kinase R (PKR) is a cellular stress kinase activated by ER stress and contributing to degeneration of pancreatic islets. In order to determine whether inhibition of PKR activation by specific small molecule inhibitors of PKR ameliorates pancreatic insulin secretion capacity, we treated beta cells with two imidazole/oxindole-derived inhibitors of PKR kinase, imoxin (C16) and 2-aminopurine (2-AP), in the presence of ER stress. Our results demonstrate that PKR inhibition suppresses tunicamycin-mediated ER stress without altering the insulin production capacity of the cells. Palmitic acid-mediated suppression of insulin secretion, however, was subdued significantly by PKR inhibitor treatment through an ER stress-related mechanism. We suggest that PKR inhibitor treatment may be used to increase the insulin secretion capacity of the pancreas in later stages of diabetes.

Highlights

Type 2 diabetes (T2D) is a chronic disease that affects millions of people around the world negatively and causes various micro- and macrovascular complications in the body (Drong et al, 2012)
Endoplasmic reticulum stress is suppressed by Protein kinase R (PKR) inhibitors in pancreatic beta cell line Tunicamycin increased phosphorylation of the serine residue of elF2α (Ser-51) compared to the controls, as expected, which is an indicator of ER stress (Figure 1a)
It has been shown that inflammatory pathways are triggered and that insulin signaling is altered by PKR (Nakamura et al, 2010; Carvalho-Filho et al, 2012), so the suppression of the PKR pathway may be a novel target of treatment

Summary

Introduction

Type 2 diabetes (T2D) is a chronic disease that affects millions of people around the world negatively and causes various micro- and macrovascular complications in the body (Drong et al, 2012). Insulin-sensitizing drugs that relieve insulin resistance and reduce its detrimental effects are frequently used in early stages of the disease (Peters, 2013). These conventional drugs exhibit well-documented blood glucose-lowering actions and are preferred for their effectiveness in controlling micro- and macrovascular complications of diabetes. Given the progressive nature of the disease, conventional insulin-sensitizing drugs remain effective in controlling blood glucose levels for a while. In the later stages of the disease, gradual cellular degeneration of insulin-producing cells of the pancreas

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