Enhanced islet expansion by beta-cell proliferation in young diabetes-prone rats fed a protective diet.
Type 1 diabetes is inhibited in diabetes-prone BioBreeding (BBdp) rats fed a low-antigen hydrolyzed casein (HC) diet. In cereal-fed BBdp rats, islet expansion is defective accompanied by a futile upregulation of islet neogenesis without increased islet mass, due to a subtle blockage in islet cell cycle. We hypothesized that islet growth is enhanced before insulitis in HC-fed young BBdp rats and that islet neogenesis could be stimulated by a trophic factor, islet neogenesis-associated protein (INGAP). beta-Cell homeostasis was analyzed using immunohistochemistry, morphometry, laser capture microdissection and RT-PCR in BBdp rats fed HC or cereal diets. beta-cell proliferation in small and medium islets, and the number and area fraction of medium and large islets were increased in HC-fed animals. In situ islet cell cycle analysis revealed an increased proportion of proliferating S + G2 cells in medium and large islets of 25-45 day HC-fed rats. Expression of the cell cycle inhibitor, p16(INK4a) correlated with islet size and the percentage of p16(INK4a+) beta-cells increased in HC-fed BBdp rats, likely reflecting an increase in large islet area fraction. In HC-fed rats, extra-islet insulin(+) clusters (EIC), insulin(+) duct cells, large islet area fraction, and beta-cell mass were increased. Neurogenin-3 and Pdx-1, markers of beta-cell progenitors, were increased in EIC of weanling HC-fed rats. Daily injection of INGAP (30-45 days) increased the number of small islets, total islets, and insulin(+) cells in small ducts. Thus, in BBdp rats fed a protective HC diet, beta-cell expansion is enhanced through increased beta-cell proliferation and stimulation of islet neogenesis.
Wang
Gen-Sheng
GS
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Kauri
Lisa M
LM
Patrick
Christopher
C
Bareggi
Mirella
M
Rosenberg
Lawrence
L
Scott
Fraser W
FW
D000375:Aging / Q000187:drug effects / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002364:Caseins / Q000008:administration & dosage / Q000494:pharmacology; D002449:Cell Aggregation / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D004032:Diet; D004198:Disease Susceptibility / Q000473:pathology; D005247:Feeding Behavior; D018398:Homeodomain Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D002364:Caseins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments; D015534:Trans-Activators; C500438:INGAP peptide; C498696:Neurog3 protein, rat; C000612141:REG3A protein, human; C084010:pancreatic and duodenal homeobox 1 protein