Background and aim: According to the so-called “nutrition overflow hypothesis”, type 2 diabetes results
from nutrition-induced local tissue inflammation leading to insulin resistance, insulin
secretory dysfunction and finally pancreatic beta cell loss. Free fatty acids acting
through toll-like receptors are key mediators of this lipotoxic inflammatory response.
We previously demonstrated that the intracellular protein p8 exerts potent anti-inflammatory
and anti-diabetogenic effects in pancreatic beta cells in vivo. Here we investigated
the anti-lipotoxic potential of p8 ex vivo in pancreatic islets of transgenic mice
with beta cell-specific p8 overexpression.
Materials and methods: Islets were obtained from transgenic mice with beta cell-specific p8 overexpression
under the control of the rat insulin 1 promoter (RIP1) or syngeneic wild type mice
for control. Islets were then exposed to 0.15 mM palmitate for 24h (LD50 in INS-1E
beta cells). Cell viability was assessed by MTS assay and insulin secretion was analysed
by ELISA. Both values were normalised to protein concentrations.
Results: Untreated p8-Tg islets demonstrated increased viability at baseline as compared to
Wt islets. Palmitate exposure reduces viability of both Tg and Wt islets. Importantly,
palmitate-treated p8-Tg islets demonstrated a preserved viability which was significantly
enhanced above wild type levels. Moreover, the preserved viability of Tg islets was
associated with in parallel enhanced insulin secretion as compared to wild type controls.
Conclusions: Beta cell specific overexpression of p8 in transgenic pancreatic islets preserves
viability and insulin secretory capacity in response to lipotoxic injury by palmitate
ex vivo. These results suggest that p8 bears potent anti-inflammatory capacity to
protect insulin biosynthesis in nutrition-induced lipotoxic type 2 diabetes mellitus.
