题名：Long-term liraglutide treatment is associated with increased insulin content and secretion in beta-cells, and a loss of alpha-cells in ZDF rats.
作者：SCHWASINGER-SCHMIDT T; ROBBINS DC; WILLIAMS SJ; NOVIKOVA L; STEHNO-BITTEL L;
来源：Pharmacol Res. 2013 Oct;76:58-66. doi: 10.1016/j.phrs.2013.07.005. Epub 2013 Jul [ IF= 0.00 ] ]
摘要：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 alpha-cell
numbers/area with liraglutide treatment (6.5cells/field), compared to vehicle
(17.9cells/field). There was an increase in beta-cell numbers, the beta- to
alpha-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 alpha-cells (51.9+/-10.3% of cells) than in the
beta-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 alpha- to beta-cells was decreased and there was an absolute reduction
in islet alpha-cell content. There was selective disruption of intracellular
alpha-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.