Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice.
Templin, Andrew T.; Mellati, Mahnaz; Soininen, Raijaet al.
2019 • In Protein Engineering, Design and Selection, 32 (2), p. 95-102
[en] Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation in vitro. We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition in vivo. hIAPP transgenic mice were crossed with Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/Δ3), and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/Δ3 mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP;Hspg2Δ3/Δ3 mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition in vivo through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Templin, Andrew T.; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Mellati, Mahnaz
Soininen, Raija
Hogan, Meghan F.
Esser, Nathalie ; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Castillo, J. Josh
Zraika, Sakeneh
Kahn, Steven E.
Hull, Rebecca L.
Language :
English
Title :
Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice.
Abedini, A., Tracz, S.M., Cho, J.-H., Raleigh, D.P. (2006) Characterization of the heparin binding site in the N-terminus of human pro-islet amyloid polypeptide: implications for amyloid formation. Biochemistry, 45, 9228-9237.
Andrikopoulos, S., Verchere, C.B., Terauchi, Y., Kadowaki, T., Kahn, S.E. (2000) Beta-cell glucokinase deficiency and hyperglycemia are associated with reduced islet amyloid deposition in a mouse model of type 2 diabetes. Diabetes, 49, 2056-2062.
Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J.R., Yamada, Y. (1999) Perlecan is essential for cartilage and cephalic development. Nat. Genet., 23, 354-358.
Aston-Mourney, K., Subramanian, S.L., Zraika, S., Samarasekera, T., Meier, D.T., Goldstein, L.C. et al. (2013) One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice. Am. J. Physiol. Endocrinol. Metab., 305, E475-E484.
Castillo, G.M., Cummings, J.A., Yang, W., Judge, M.E., Sheardown, M.J., Rimvall, K. et al. (1998) Sulfate content and specific glycosaminoglycan backbone of perlecan are critical for perlecan's enhancement of islet amyloid polypeptide (amylin) fibril formation. Diabetes, 47, 612-620.
Chargé, S.B., Esiri, M.M., Bethune, C.A., Hansen, B.C., Clark, A. (1996) Apolipoprotein E is associated with islet amyloid and other amyloidoses: implications for Alzheimer's disease. J. Pathol., 179, 443-447.
Celie JW, Rutjes NW, Keuning ED, Soininen R, Heljasvaara R, Pihlajaniemi T. et al. (2007) Subendothelial heparan sulfate proteoglycans become major L-selectin and monocyte chemoattractant protein-1 ligands upon renal ischemia/reperfusion. Am J Pathol., 170, 1865-78.
Clark, A., Wells, C.A., Buley, I.D., Cruickshank, J.K., Vanhegan, R.I., Matthews, D.R. et al. (1988) Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res., 9, 151-159.
Cooper, G.J., Willis, A.C., Clark, A., Turner, R.C., Sim, R.B., Reid, K.B. (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc. Natl. Acad. Sci. U. S. A., 84, 8628-8632.
Costell, M., Gustafsson, E., Aszódi, A., Mörgelin, M., Bloch, W., Hunziker, E. et al. (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J. Cell Biol., 147, 1109-1122.
Cross, S.E., Vaughan, R.H., Willcox, A.J., McBride, A.J., Abraham, A.A., Han, B. et al. (2017) Key matrix proteins within the pancreatic islet basement membrane are differentially digested during human islet isolation. Am. J. Transplant., 17, 451-461.
D'Alessio, D.A., Verchere, C.B., Kahn, S.E., Hoagland, V., Baskin, D.G., Palmiter, R.D. et al. (1994) Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse. Diabetes, 43, 1457-1461.
Guardado-Mendoza, R., Davalli, A.M., Chavez, A.O., Hubbard, G.B., Dick, E.J., Majluf-Cruz, A. et al. (2009) Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons. Proc. Natl. Acad. Sci., 106, 13992-13997.
Hao, R.-H., Guo, Y., Dong, S.-S., Weng, G.-Z., Yan, H., Zhu, D.-L. et al. (2016) Associations of plasma FGF2 levels and polymorphisms in the FGF2 gene with obesity phenotypes in Han Chinese population. Sci. Rep., 6, 19868.
Hopping, G., Kellock, J., Barnwal, R.P., Law, P., Bryers, J., Varani, G. et al. (2014) Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers. Elife, 3, e01681.
Howard, C.F. (1986) Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia, 29, 301-306.
Hull, R.L., Andrikopoulos, S., Verchere, C.B., Vidal, J., Wang, F., Cnop, M. et al. (2003) Increased dietary fat promotes islet amyloid formation and betacell secretory dysfunction in a transgenic mouse model of islet amyloid. Diabetes, 52, 372-379.
Hull, R.L., Westermark, G.T., Westermark, P., Kahn, S.E. (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J. Clin. Endocrinol. Metab., 89, 3629-3643.
Hull, R.L., Shen, Z.-P., Watts, M.R., Kodama, K., Carr, D.B., Utzschneider, K.M. et al. (2005) Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide. Diabetes, 54, 2235-2244.
Hull, R.L., Zraika, S., Udayasankar, J., Kisilevsky, R., Szarek, W.A., Wight, T.N. et al. (2007) Inhibition of glycosaminoglycan synthesis and protein glycosylation with WAS-406 and azaserine result in reduced islet amyloid formation in vitro. Am. J. Physiol. Cell Physiol., 293, C1586-C1593.
Hull, R.L., Peters, M.J., Perigo, S.P., Chan, C.K., Wight, T.N., Kinsella, M.G. (2012) Overall sulfation of heparan sulfate from pancreatic islet β-TC3 cells increases maximal fibril formation but does not determine binding to the amyloidogenic peptide islet amyloid polypeptide. J. Biol. Chem., 287, 37154-37164.
Irving-Rodgers, H.F., Ziolkowski, A.F., Parish, C.R., Sado, Y., Ninomiya, Y., Simeonovic, C.J. et al. (2008) Molecular composition of the peri-islet basement membrane in NOD mice: a barrier against destructive insulitis. Diabetologia, 51, 1680-1688.
Jurgens, C.A., Toukatly, M.N., Fligner, C.L., Udayasankar, J., Subramanian, S.L., Zraika, S. et al. (2011) β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am. J. Pathol., 178, 2632-2640.
Kahn, S.E., D'Alessio, D.A., Schwartz, M.W., Fujimoto, W.Y., Ensinck, J.W., Taborsky, G.J. et al. (1990) Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. Diabetes, 39, 634-638.
Kahn, S.E., Andrikopoulos, S., Verchere, C.B. (1999) Islet amyloid: a longrecognized but underappreciated pathological feature of type 2 diabetes. Diabetes, 48, 241-253.
Kerever, A., Mercier, F., Nonaka, R., de Vega, S., Oda, Y., Zalc, B. et al. (2014) Perlecan is required for FGF-2 signaling in the neural stem cell niche. Stem Cell Res., 12, 492-505.
de Koning, E.J., Höppener, J.W., Verbeek, J.S., Oosterwijk, C., van Hulst, K.L., Baker, C.A. et al. (1994) Human islet amyloid polypeptide accumulates at similar sites in islets of transgenic mice and humans. Diabetes, 43, 640-644.
Lorenzo, A., Razzaboni, B., Weir, G.C., Yankner, B.A. (1994) Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature, 368, 756-760.
Matveyenko, A.V. and Butler, P.C. (2006) Islet amyloid polypeptide (IAPP) transgenic rodents as models for type 2 diabetes. ILAR J., 47, 225-233.
Meng, F., Abedini, A., Plesner, A., Middleton, C.T., Potter, K.J., Zanni, M.T. et al. (2010) The sulfated triphenyl methane derivative acid fuchsin is a potent inhibitor of amyloid formation by human islet amyloid polypeptide and protects against the toxic effects of amyloid formation. J. Mol. Biol., 400, 555-566.
Montane, J., de Pablo, S., Castaño, C., Rodríguez-Comas, J., Cadavez, L., Obach, M. et al. (2017) Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment. FASEB J., 31, 5296-5306.
Ornitz, D.M. and Itoh, N. (2015) The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol., 4, 215-266.
Oskarsson, M.E., Singh, K., Wang, J., Vlodavsky, I., Li, J.-P., Westermark, G.T. (2015) Heparan sulfate proteoglycans are important for islet amyloid formation and islet amyloid polypeptide-induced apoptosis. J. Biol. Chem., 290, 15121-15132.
Oskarsson, M.E., Hermansson, E., Wang, Y., Welsh, N., Presto, J., Johansson, J. et al. (2018) BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proc. Natl. Acad. Sci. U. S. A., 115, E2752-E2761.
Pepys, M.B., Rademacher, T.W., Amatayakul-Chantler, S., Williams, P., Noble, G.E., Hutchinson, W.L. et al. (1994) Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure. Proc. Natl. Acad. Sci. U. S. A., 91, 5602-5606.
Potter, K.J., Werner, I., Denroche, H.C., Montane, J., Plesner, A., Chen, Y. et al. (2015) Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase. Am. J. Transplant., 15, 1519-1530.
Potter-Perigo, S., Hull, R.L., Tsoi, C., Braun, K.R., Andrikopoulos, S., Teague, J. et al. (2003) Proteoglycans synthesized and secreted by pancreatic islet beta-cells bind amylin. Arch. Biochem. Biophys., 413, 182-190.
Rossi, M., Morita, H., Sormunen, R., Airenne, S., Kreivi, M., Wang, L. et al. (2003) Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J., 22, 236-245.
Sherwin, R.S., Shamoon, H., Hendler, R., Saccà, L., Eigler, N., Walesky, M. (1980) Epinephrine and the regulation of glucose metabolism: effect of diabetes and hormonal interactions. Metabolism, 29, 1146-1154.
Shu, C., Smith, S.M., Melrose, J. (2016) The heparan sulphate deficient Hspg2 exon 3 null mouse displays reduced deposition of TGF-β1 in skin compared to C57BL/6 wild type mice. J. Mol. Histol., 47, 365-374.
Verchere, C.B., D'Alessio, D.A., Palmiter, R.D., Weir, G.C., Bonner-Weir, S., Baskin, D.G. et al. (1996) Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide. Proc. Natl. Acad. Sci. U. S. A., 93, 3492-3496.
Vidal, J., Verchere, C.B., Andrikopoulos, S., Wang, F., Hull, R.L., Cnop, M. et al. (2003) The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice. Diabetologia, 46, 71-79.
Walz, A., McFarlane, S., Brickman, Y.G., Nurcombe, V., Bartlett, P.F., Holt, C.E. (1997) Essential role of heparan sulfates in axon navigation and targeting in the developing visual system. Development, 124, 2421-2430.
Wang, F., Hull, R.L., Vidal, J., Cnop, M., Kahn, S.E. (2001) Islet amyloid develops diffusely throughout the pancreas before becoming severe and replacing endocrine cells. Diabetes, 50, 2514-2520.
Westermark, P. (1972) Quantitative studies on amyloid in the islets of Langerhans. Ups. J. Med. Sci., 77, 91-94.
Westermark, P., Wilander, E., Westermark, G.T., Johnson, K.H. (1987) Islet amyloid polypeptide-like immunoreactivity in the islet B cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia, 30, 887-892.
Westermark, P., Engström, U., Johnson, K.H., Westermark, G.T., Betsholtz, C. (1990) Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc. Natl. Acad. Sci. U. S. A., 87, 5036-5040.
Westwell-Roper, C.Y., Chehroudi, C.A., Denroche, H.C., Courtade, J.A., Ehses, J.A., Verchere, C.B. (2015) IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice. Diabetologia, 58, 575-585.
Wijesekara N, Kaur A, Westwell-Roper C, Nackiewicz D, Soukhatcheva G, Hayden MR. et al. (2016). ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice. Diabetologia, 59, 1242-6.
Young, I.D., Ailles, L., Narindrasorasak, S., Tan, R., Kisilevsky, R. (1992) Localization of the basement membrane heparan sulfate proteoglycan in islet amyloid deposits in type II diabetes mellitus. Arch. Pathol. Lab. Med., 116, 951-954.
Zraika, S., Aston-Mourney, K., Marek, P., Hull, R.L., Green, P.S., Udayasankar, J. et al. (2010) Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation. J. Biol. Chem., 285, 18177-18183.
