Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes.

Sarita Dhounchak,Christopher R Parish,Charmaine J Simeonovic,Trevor J Biden,D Ross Laybutt,Stefan R Bornstein,Debra J Brown,Sarah K Popp,Herve Le Stunff

doi:10.1371/journal.pone.0252607

Abstract

Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.

Highlights

Type 2 diabetes (T2D) is a metabolic syndrome disease in which obesity, insulin resistance, hyperglycemia, dyslipidemia and chronic low-grade inflammation of pancreatic islets contribute directly or indirectly to beta cell failure [1, 2]
Strong immunohistochemical staining for Heparan sulfate proteoglycans (HSPGs) core proteins (COL18, SDC1 and CD44) and heparan sulfate (HS) was observed in the islets of lean control males at 6 weeks of age; in contrast, the islet area stained for HSPGs and HS was significantly decreased in male db/db islets by as early as 3–4 weeks (Fig 1A–1E and S1 File)
Thereafter, the area of COL18, SDC1 and CD44 staining in db/db islets declined to 38.8–62.4% of controls by 5 weeks and 18.7–47.2% at 6–9 weeks (Fig 1B–1D and S1 File)

Summary

Introduction

Type 2 diabetes (T2D) is a metabolic syndrome disease in which obesity, insulin resistance, hyperglycemia, dyslipidemia and chronic low-grade inflammation of pancreatic islets contribute directly or indirectly to beta cell failure [1, 2]. Pancreatic beta cells are highly metabolically active, due to their specialized role in synthesizing proinsulin/ insulin. The ER is a subcellular compartment that functions to chemically modify and fold newly synthesized proteins, including proinsulin, into their mature state. Metabolic dysfunction in T2D and insulin (INS) gene mutations disrupt ER homeostasis, resulting in the accumulation of misfolded proteins in the ER lumen and ER stress [3,4,5]. The unfolded protein response (UPR) is an adaptive response for relieving ER stress by decreasing “global” protein synthesis (at the level of translation) and increasing the transcription of protective genes e.g., ER chaperones [6, 7]. The capacity for the UPR to prolong beta function is determined by a delicate balance between these two processes

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