title: One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice.
abstract: The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve β-cell mass. However, sitagliptin also increases β-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated β-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing β-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and β-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, β-cell mass, insulin release, and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid-induced β-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups, and no evidence of pancreatitis, ductal metaplasia, or neoplasia were observed. Therefore, long-term sitagliptin treatment stimulates β-cell secretion without increasing amyloid formation and protects against amyloid-induced β-cell loss. This suggests a novel effect of sitagliptin to protect the β-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Aston-Mourney
authors.forename: Shoba L
authors.initials: SL
authors.lastname: Subramanian
authors.forename: Sakeneh
authors.initials: S
authors.lastname: Zraika
authors.forename: Thanya
authors.initials: T
authors.lastname: Samarasekera
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meier
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Goldstein
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000009:adverse effects; D057898:Hemizygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000139:chemically induced; D010195:Pancreatitis / Q000139:chemically induced; D058225:Plaque, Amyloid / Q000517:prevention & control*; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000068900:Sitagliptin Phosphate; D013997:Time Factors; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D011719:Pyrazines; D011994:Recombinant Proteins; D014230:Triazoles; D008687:Metformin; D000068900:Sitagliptin Phosphate
keywords: DPP-4 inhibitor; IAPP; amyloid; exocrine pancreas pathology; β-cell mass