One of the major challenges for developmental biologists and investigators in the field of diabetes over the last few decades has been to dissect the origin of pancreatic endocrine cells and to accurately understand the mechanisms that regulate islet cell regeneration. While significant advances have been made recently, there continues to be a paucity of knowledge regarding the growth factor signalling pathways that directly regulate the proteins involved in islet cell cycle control. We will discuss recent work in these areas and provide insights from our studies into age-dependent alterations in the expression of growth factor signalling proteins and cell cycle proteins in islet cells.
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"Next, we determined whether the decrease in β-cell mass in p44tg mice (Fig. 3B) was due to changes in β-cell proliferation. Coimmunostaining of pancreas sections with antibodies against insulin and either one of two proliferation markers showed a decrease in the proliferation of β-cells with age in control islets (Fig. 5A and B) as reported previously (29). BrdU labeling demonstrated a virtual absence of replicating β-cells in young and old p44tg mice compared with controls (Fig. 5A). "
[Show abstract][Hide abstract] ABSTRACT: Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice.
We phenotyped metabolic parameters in Δ40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine β-cell proliferation.
Transgenic mice with an ectopic p53 gene encoding Δ40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from ∼14 months of age. Consistent with a dramatic decrease in β-cell mass and reduced β-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased.
These data indicate a significant and novel role for Δ40p53 in β-cell proliferation with implications for the development of age-dependent diabetes.
[Show abstract][Hide abstract] ABSTRACT: The effect of ageing on beta-cell regeneration under hyperglycemia has not been defined and may best be addressed using a unique islet-transplantation model.
Streptozotocin-induced diabetic FVB/NJ mice were rendered normoglycemic with a therapeutic mass of syngeneic islets implanted in the epididymal fat pad, followed by a subrenal capsular implantation of a subtherapeutic mass of 25 islets from young (3 months) or old (24 months) mice. Three weeks after the second transplant, the islet containing fat pad was removed to reintroduce hyperglycemia. Bromodeoxyuridine (BrdU) was provided to mice continuously in drinking water. Islet grafts under the kidney capsule were harvested at different time points and examined for markers of beta-cell regeneration by immunohistochemistry.
After a 7-day labeling, BrdU was detected in 54.2% or 53.0% beta cells of the young or old islet grafts, respectively, under hyperglycemia when compared with 3.3% in grafts under normoglycemia. Ki67-positive beta cells were enhanced from a baseline level of 0.5% to 5.2% (young islets) or 4.0% (old islets) on day 7 of hyperglycemia, then decreased to 2.4% on day 21, at which time point an accumulative 75.3% or 66.8% BrdU-positive beta cells was detected in the young or old grafts, respectively. No statistic difference in the percent BrdU- or Ki67-positive beta cells was detected between the young and aged grafts at any time point studied.
These data reveal that islet beta cells from aged mice can replicate in response to hyperglycemia after transplantation at a capacity and frequencies not significantly different than that of the young adult ones.