Enhanced islet neogenesis and beta‐cell proliferation in pre‐insulitic diabetes‐prone rats fed a hydrolyzed casein diet

Abstract

Diabetes incidence is reduced in diabetes-prone BioBreeding (BBdp) rats fed a hydrolyzed casein (HC) diet compared with a standard cereal-based rodent diet such as NTP-2000 (NTP). To further characterize the basis of this protective effect, islet neogenesis, apoptosis and cell proliferation were analyzed using immunohistochemistry, morphometry, Laser Capture Microdissection, and RT-PCR in BBdp rats weaned onto an NTP or HC diet at 23 d and sacrificed at 25, 30, and 45 d. Islet area fraction was greater in medium and large islets of HC-fed rats at 30 d and in large islets only at 45 d. There were more small islets in HC-fed rats both at 30 and 45 d and β-cell mass was significantly greater at 45 d. Cell cycle analysis revealed an increased ratio of S+G2/G0+G1 in HC-fed animals between 25 and 45 d. PDX-1+ clusters (<4 cells) were increased in HC-fed rats, whereas extra-islet insulin+ clusters (EIC) and insulin+ cells in ducts, representative of islet neogenesis, were increased at 45 d. Ngn3 mRNA was higher in EIC of HC-fed rats at 24 d. Glucagon-like peptide-1 receptor protein and mRNA were increased in islets of HC-fed rats. In summary, the protective HC diet increased β-cell mass in diabetes-prone rats through upregulation of islet neogenesis and β-cell proliferation. (GSW and LMK contributed equally; Supported by Canadian Diabetes Association and Canadian Institutes of Health Research)