An Investigative Study of Pancreatic Exocrine Biomarkers, Histology, and Histomorphometry in Male Zucker Diabetic Fatty (ZDF) Rats Given Dulaglutide by Subcutaneous Injection Twice Weekly for 13 Weeks.
Glucagon-like peptide-1 (GLP-1) receptor agonist therapy has been implicated as a possible risk factor for acute pancreatitis in patients with type 2 diabetes. Dulaglutide is a long-acting GLP-1 receptor agonist in development for treatment of type 2 diabetes. The effects of dulaglutide were evaluated in male Zucker diabetic fatty (ZDF) rats to examine whether dulaglutide may induce or modulate pancreatitis. Rats were randomized to dose groups receiving twice-weekly subcutaneously administered dulaglutide 0.5, 1.5, and 5.0 mg/kg/dose (corresponding human plasma exposures following twice-weekly dosing are 3-, 8-, and 30-fold, respectively) for 13 weeks or to vehicle control. Following termination, serially trimmed sections of pancreases were stained with hematoxylin and eosin or co-stained with an epithelial marker and a marker of either proliferation or apoptosis. Efficacious reductions in glucose and hemoglobin A1c occurred at all dulaglutide doses. Lipase activity was unaffected, and there were modest increases in total and pancreatic amylase activities at all doses without individual microscopic inflammatory correlates. Microscopic dulaglutide-related pancreatic changes included increased interlobular ductal epithelium without ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased incidence/severity of neutrophilic acinar pancreatic inflammation (5.0 mg/kg). In summary, dulaglutide treatment was associated with mild alterations in ductal epithelium and modest exacerbation of spontaneous lesions of the exocrine pancreas typically found in the ZDF rat model.
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA usborne_amy_l@lilly.com.
Amy
A
Usborne
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
Richard A
RA
Byrd
Charles River Laboratories, Preclinical Services Montreal, Senneville, Quebec, Canada.
James
J
Meehan
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
Jamie L
JL
Blackbourne
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
John
J
Sullivan
Charles River Laboratories, Preclinical Services Montreal, Senneville, Quebec, Canada.
Florence
F
Poitout-Belissent
Charles River Laboratories, Preclinical Services Montreal, Senneville, Quebec, Canada.
Annick
A
Prefontaine
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
Jennifer A
JA
Martin
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
John L
JL
Vahle
D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008297:Male; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D015415:Biomarkers; D001786:Blood Glucose; D004763:Glucagon-Like Peptides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C555680:dulaglutide
GLP-1; dulaglutide; pancreas; rat