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

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.

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“…Additionally, in 1995, Cechowska-Pasko et al [ 62 ], in an in vivo study on diabetic rats, showed that the level of GAGs significantly decreased (by 50% to 70%) in the skin of the rats. In 2021, Dhounchak et al [ 63 ] showed that β-cell failure in T2DM results from HS/HSPGs deficiency; this paper complements previous articles that discussed the importance of preserving HS during inflammatory processes and viral infections [ 5 , 6 ].…”

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“…22,32,93,166 Conversely, it seems that HS and dysfunction of the GL play a role in the etiology of DM in the first place. Recent reviews described that human beta cells have a remarkably high intracellular level of highly sulfated HS, 66,86,162 protecting cells in the pancreatic islet from ROS and cell death. 167 This protective anti-apoptotic effect is neutralized when nearby autoreactive T cells secrete HPSE that subsequently degrade HS, leading to an onset of Type 1 DM (T1D).…”

“…DM is a clinically well‐defined metabolic disease connected with insulin absence or resistance in which obesity, hyperglycemia, dyslipidemia, and chronic low‐grade pancreatic islets inflammation contribute directly or indirectly to beta‐cell failure 162 . Patients with DM display a tendency to develop vascular complications, such as microalbuminuria, retino‐, and nephropathy, elevated the risk of atherothrombotic cardiovascular and cerebrovascular events 14,56 .…”

“…Simeonovic et al demonstrated that beta cell HS is lost before insulin in human T1D and is a sensitive marker of disease progression. More specifically, 3‐O‐sulfation of beta cell HS and sdc4 have been shown to play important roles in the secretion of insulin by beta cell lines 86,162 . Moreover, it has been reported that the loss of Ext3 and consequent dysregulation of HS biosynthesis may be a potential factor in the pathogenesis of DM 85 …”

“…It has been demonstrated in beta cell line studies that undersulfated HS are not protected from hydrogen peroxide‐induced death 162 . Dhounchak et al reported that both beta cell sulfated HS and HSPG core proteins are significantly depleted in prediabetic 3–5 week db/db mice 162 . It was also found that T2D patients present with increased expression of sulfatase (SULF)2, resulting in the removal of 6‐O sulfate groups from HS.…”