Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.

Regulation of Heparanase in Diabetes-Associated Pancreatic Carcinoma

“…On the other hand, emerging involvement of heparanase in diabetes, including its role in the islet/beta cell damage (32,(78)(79)(80), taken together with augmented production of the enzyme by pancreatic carcinoma cells under hyperglycemic conditions (this study), implies that the enzyme may exacerbate PDAC-associated diabetes. Indeed, pioneering studies by C R. Parish and his group identified multiple roles for heparanase in islet damage (originally-in the setting of type 1 diabetes) (32,(78)(79)(80).…”

“…On the other hand, emerging involvement of heparanase in diabetes, including its role in the islet/beta cell damage (32,(78)(79)(80), taken together with augmented production of the enzyme by pancreatic carcinoma cells under hyperglycemic conditions (this study), implies that the enzyme may exacerbate PDAC-associated diabetes. Indeed, pioneering studies by C R. Parish and his group identified multiple roles for heparanase in islet damage (originally-in the setting of type 1 diabetes) (32,(78)(79)(80). The islet-damaging heparanase actions include promotion of the leukocyte migration from pancreatic blood vessels and their passage across the islet basement membrane, as well as depletion of heparan sulfate which is required for beta cell survival (32,(78)(79)(80).…”

“…Indeed, pioneering studies by C R. Parish and his group identified multiple roles for heparanase in islet damage (originally-in the setting of type 1 diabetes) (32,(78)(79)(80). The islet-damaging heparanase actions include promotion of the leukocyte migration from pancreatic blood vessels and their passage across the islet basement membrane, as well as depletion of heparan sulfate which is required for beta cell survival (32,(78)(79)(80).…”

“…Given the secreted nature of the enzyme and its involvement in beta cell injury [via depletion of heparan sulfate (32,(78)(79)(80) and through tissue-damaging effects of the adverselyactivated islet-infiltrating macrophages, similarly to those demonstrated in other pathologies (17,26,28,50,90)], it is conceivable that in hyperglycemic patients elevated levels of heparanase, originating from the tumor of exocrine pancreas (i.e., PDAC), can exert pathogenic effects within the endocrine compartment (i.e., islets), further impairing glucose metabolism and leading to the onset/aggravation of diabetes.…”

Expression of Matrix Metalloproteinases in Ameloblastomas and Ameloblastic Carcinoma: Systematic Review and Meta-analysis

“…ECM is a dynamic reticulated structure present between cell to cell, which plays a crucial role in both physiological and pathological processes, such as tumor invasion, angiogenesis, wound healing, and inflammation. 36,37 MMPs are capable of ECM remodeling, favoring the invasion and proliferation of tumor cells. 38,39 MMPs have been detected in both cyst fluids and wall tissue extracts of various odontogenic cysts and odontogenic tumors, including ABs, suggesting that these enzymes play a key role in regulation of tumor and cyst growth.…”