November 12, 2014
BMJ Case Rep. 2013 Apr 22;2013. pii: bcr2013008550. doi: 10.1136/bcr-2013-008550.
Author Address: Department of Internal Medicine, Reading Health System, West Reading, Pennsylvania 19612, USA.
Reference Type: Journal Article
Record Number: 5184Author: Aston-Mourney, K., Subramanian, S. L., Zraika, S., Samarasekera, T., Meier, D. T., Goldstein, L. C. and Hull, R. L.
Title: One year of sitagliptin treatment protects against islet amyloid-associated beta-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice
Journal: Am J Physiol Endocrinol Metab
Date: Aug 15
Short Title: One year of sitagliptin treatment protects against islet amyloid-associated beta-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice
Alternate Journal: American journal of physiology. Endocrinology and metabolism
ISSN: 1522-1555 (Electronic)
Accession Number: 23736544
Diabetes Mellitus, Type 2/*drug therapy/metabolism/pathology
Dipeptidyl-Peptidase IV Inhibitors/adverse effects/*therapeutic use
Drug Therapy, Combination/adverse effects
Hypoglycemic Agents/adverse effects/therapeutic use
Insulin-Secreting Cells/*drug effects/metabolism/pathology
Islet Amyloid Polypeptide/*biosynthesis/genetics/metabolism
Metformin/adverse effects/therapeutic use
Pancreatic Neoplasms/chemically induced
Plaque, Amyloid/*prevention & control
Pyrazines/adverse effects/*therapeutic use
Triazoles/adverse effects/*therapeutic use
Abstract: The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve beta-cell mass. However, sitagliptin also increases beta-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 beta-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing beta-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 beta-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, beta-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 beta-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 beta-cell secretion without increasing amyloid formation and protects against amyloid-induced beta-cell loss. This suggests a novel effect of sitagliptin to protect the beta-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas.