title: Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro.
abstract: Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Meghan F
authors.initials: MF
authors.lastname: Hogan
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meier
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Sakeneh
authors.initials: S
authors.lastname: Zraika
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Templin
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Mellati
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Leissring
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition (M.F.H., D.T.M., S.Z., A.T.T., M.M., R.L.H., S.E.K.), Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Institute for Memory Impairments and Neurological Disorders (M.A.L.), University of California, Irvine, Irvine, California 92697.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D007339:Insulysin