Incretin Therapies Do Not Expand β-Cell Mass or Alter Pancreatic Histology in Young Male Mice.
The impact of incretins upon pancreatic β-cell expansion remains extremely controversial. Multiple studies indicate that incretin-based therapies can increase β-cell proliferation, and incretins have been hypothesized to expand β-cell mass. However, disagreement exists on whether incretins increase β-cell mass. Moreover, some reports indicate that incretins may cause metaplastic changes in pancreatic histology. To resolve these questions, we treated a large cohort of mice with incretin-based therapies and carried out a rigorous analysis of β-cell turnover and pancreatic histology using high-throughput imaging. Young mice received exenatide via osmotic pump, des-fluoro-sitagliptin, or glipizide compounded in diet for 2 weeks (short-term) on a low-fat diet (LFD) or 4.5 months (long-term) on a LFD or high-fat diet (HFD). Pancreata were quantified for β-cell turnover and mass. Slides were examined for gross anatomical and microscopic changes to exocrine pancreas. Short-term des-fluoro-sitagliptin increased serum insulin and induced modest β-cell proliferation but no change in β-cell mass. Long-term incretin therapy in HFD-fed mice resulted in reduced weight gain, improved glucose homeostasis, and abrogated β-cell mass expansion. No evidence for rapidly dividing progenitor cells was found in islets or pancreatic parenchyma, indicating that incretins do not induce islet neogenesis or pancreatic metaplasia. Contrasting prior reports, we found no evidence of β-cell mass expansion after acute or chronic incretin therapy. Chronic incretin administration was not associated with histological abnormalities in pancreatic parenchyma; mice did not develop tumors, pancreatitis, or ductal hyperplasia. We conclude that incretin therapies do not generate β-cells or alter pancreatic histology in young mice.
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Aaron R
AR
Cox
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Carol J
CJ
Lam
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Matthew M
MM
Rankin
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Jacqueline S
JS
Rios
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Julia
J
Chavez
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Claire W
CW
Bonnyman
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Kourtney B
KB
King
Department of Cellular, Molecular, and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire 03824.|Consulting Tox/Path Services, Kittery, Maine 03904.
Roger A
RA
Wells
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Deepti
D
Anthony
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Justin X
JX
Tu
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Jenny J
JJ
Kim
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Changhong
C
Li
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030.
Jake A
JA
Kushner
D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D054795:Incretins / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology*; D010455:Peptides / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate / Q000627:therapeutic use; D014688:Venoms / Q000627:therapeutic use
D007004:Hypoglycemic Agents; D054795:Incretins; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000068900:Sitagliptin Phosphate