Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

Abstract

We reported previously that young BioBreeding diabetes-prone (BBdp) rats display increased neogenic extra-islet insulin þ clusters (EICs, o4 insulin þ cells) without an increase in b-cell mass. Therefore, we investigated the possibility that abnormal islet expansion occurs in BBdp rats before the appearance of islet inflammation. Islet expansion was analyzed in pancreata from 14 to 45 day BBdp and control (BioBreeding control, BBc) rats using immunohistochemistry, morphometry, laser capture microdissection and reverse transcriptase-PCR. mRNA expression for Neurogenin-3, a developmental marker of endocrine progenitors, was three-fold greater in EIC of weanling BBdp and BBc rats compared with islet cells. With increasing age (14-30 days), Neurogenin-3 expression decreased in EIC and increased in islets. In BBdp rats, EIC number and b-cell proliferation within EIC was greater compared with BBc animals; apoptosis did not differ. The area of small and medium islets in BBdp rats was greater than BBc rats between 14 and 30 days, but this did not result in increased total islet area or b-cell mass. In addition, the number and area of very large islets was low at 45 days. The frequency of proliferating b-cells decreased with increasing islet size in BBdp but was constant in BBc rats. Cell cycle analysis of islets revealed more G1 cells and fewer G2 cells in BBdp rats. The ratio of cyclinD2/Cdkn1a, genes that respectively promote or inhibit cell cycle progression, was decreased in BBdp islets. These results suggest that despite increased islet neogenesis, the capacity for islet expansion in diabetes-prone rats is compromised possibly due to decreased proliferative capacity with increasing islet size associated with a partial block at the G1/S cell cycle boundary in islet cells.

Cathelicidin Antimicrobial Peptide: A Novel Regulator of Islet Function, Islet Regeneration, and Selected Gut Bacteria

“…4D) in BBdp rats, but not in BBc rats. The observation that this occurred in BBdp rats but not in BBc rats is consistent with that from a previous study (27) from our group indicating that BBdp rats display signs of neogenesis more frequently than control rats, possibly as a response to early diabetes-promoting changes in the islet microenvironment. Thus, CAMP/LL-37 treatment may be further potentiating this phenomenon.…”

Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

“…Apparently, in view of our results, even increased b-cell neogenesis and decreased b-cell apoptosis are insufficient to restore normal b-cell mass when proliferation and b-cell mass are already affected. Recently, increased islet neogenesis in diabetes-prone rats without increased islet mass has also been reported (Kauri et al 2007). The loss of regenerative capacity may be caused by the lack of one or more rate-limiting trophic stimuli.…”

Postnatal development of the endocrine pancreas in mice lacking functional GABABreceptors

“…An increase in cluster number was described previously in young diabetes-prone BBdp rats together with an increase in cluster ␤-cell proliferation (38). An increase in very small islets was also observed in 1-and 7-day-old NOD mice together with an increase in glucagon-positive cells, which was reminiscent of immature islets and suggested increased islet neogenesis (51).…”