title: Long-term liraglutide treatment is associated with increased insulin content and secretion in β-cells, and a loss of α-cells in ZDF rats.
abstract: The ultimate treatment goal of diabetes is to preserve and restore islet cell function. Treatment of certain diabetic animal models with incretins has been reported to preserve and possibly enhance islet function and promote islet cell growth. The studies reported here detail islet cell anatomy in animals chronically treated with the incretin analog, liraglutide. Our aim was to quantitatively and qualitatively analyze islet cells from diabetic animals treated with vehicle (control) or liraglutide to determine whether normal islet cell anatomy is maintained or enhanced with pharmaceutical treatment. We harvested pancreata from liraglutide and vehicle-treated Zucker Diabetic Fatty (ZDF) rats to examine islet structure and function and obtain isolated islets. Twelve-week-old male rats were assigned to 3 groups: (1) liraglutide-treated diabetic, (2) vehicle-treated diabetic, and (3) lean non-diabetic. Liraglutide was given SC twice daily for 9 weeks. As expected, liraglutide treatment reduced body weight by 15% compared to the vehicle-treated animals, eventually to levels that were not different from lean controls. At the termination of the study, blood glucose was significantly less in the liraglutide-treated rats compared to vehicle treated controls (485.8±22.5 and 547.2±33.1mg/dl, respectively). Insulin content/islet (measured by immunohistochemistry) was 34.2±0.7 pixel units in vehicle-treated rats, and 54.9±0.6 in the liraglutide-treated animals. Glucose-stimulated insulin secretion from isolated islets (measured as the stimulation index) was maintained in the liraglutide-treated rats, but not in the vehicle-treated. However, liraglutide did not preserve normal islet architecture. There was a decrease in the glucagon-positive area/islet and in the α-cell numbers/area with liraglutide treatment (6.5 cells/field), compared to vehicle (17.9 cells/field). There was an increase in β-cell numbers, the β- to α-cell ratio that was statistically higher in the liraglutide-treated rats (24.3±4.4) compared to vehicle (9.1±2.8). Disrupted mitochondria were more commonly observed in the α-cells (51.9±10.3% of cells) than in the β-cells (27.2±4.4%) in the liraglutide-treated group. While liraglutide enhanced or maintained growth and function of certain islet cells, the overall ratio of α- to β-cells was decreased and there was an absolute reduction in islet α-cell content. There was selective disruption of intracellular α-cell organelles, representing an uncoupling of the bihormonal islet signaling that is required for normal metabolic regulation. The relevance of the findings to long-term liraglutide treatment in people with diabetes is unknown and should be investigated in appropriately designed clinical studies.
authors.affiliation: Division of Endocrinology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Schwasinger-Schmidt
authors.forename: David C
authors.initials: DC
authors.lastname: Robbins
authors.forename: S Janette
authors.initials: SJ
authors.lastname: Williams
authors.forename: Lesya
authors.initials: L
authors.lastname: Novikova
authors.forename: Lisa
authors.initials: L
authors.lastname: Stehno-Bittel
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005934:Glucagon / Q000032:analysis / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000069450:Liraglutide; D008297:Male; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon
keywords: ANOVA; BSA; EM; ER; GLP-1; Glucagon; HRP; HbA1c; IACUCI; IF; IHC; IP; Insulin; Islet; LSD; Liraglutide; NDS; PBS; Type 2 diabetes; ZDF; Zucker diabetic fatty; Zucker rat; analysis of variance; bovine serum albumin; electron microscope; endoplasmic reticulum; glucagon-like peptide-1; glycated hemoglobin; horseradish peroxidase; immunofluorescence; immunohistochemistry; intraperitoneal injection; least significant difference; normal donkey serum; nstitutional Animal Care and Use Committee; phosphate buffered solution; α-Cell; β-Cell