Abstract
ARHGAP21 is a RhoGAP protein implicated in the modulation of insulin secretion and energy metabolism. ARHGAP21 transient-inhibition increase glucose-stimulated insulin secretion (GSIS) in neonatal islets; however, ARHGAP21 heterozygote mice have a reduced insulin secretion. These discrepancies are not totally understood, and it might be related to functional maturation of beta cells and peripheral sensitivity. Here, we investigated the real ARHGAP21 role in the insulin secretion process using an adult mouse model of acute ARHGAP21 inhibition, induced by antisense. After ARHGAP21 knockdown induction by antisense injection in 60-day old male mice, we investigated glucose and insulin tolerance test, glucose-induced insulin secretion, glucose-induced intracellular calcium dynamics, and gene expression. Our results showed that ARHGAP21 acts negatively in the GSIS of adult islet. This effect seems to be due to the modulation of important points of insulin secretion process, such as the energy metabolism (PGC1α), Ca2+ signalization (SYTVII), granule-extrusion (SNAP25), and cell-cell interaction (CX36). Therefore, based on these finds, ARHGAP21 may be an important target in Diabetes Mellitus (DM) treatment.
Highlights
Diabetes Mellitus (DM) is a highly prevalent disease, and pancreatic islet dysfunction is crucial for its development [1,2,3]
We found that in the pancreatic islet from Ob/Ob mice the ARHGAP21 expression was significantly reduced (Figure 1A), whereas in the pancreatic islet from endurance-trained mice it was increased, compared to the control (CTL) (Figure 1B). These results corroborate the idea that ARHGAP21 may modulate insulin secretion in adult mice
It was demonstrated that islet from ARHGAP21-knockdown neonatal mice display higher insulin secretion in sub-stimulatory concentrations of glucose (2.8 mM) [6] and ARHGAP21 may control glucose and energy metabolism in adult mice [7, 8]
Summary
Diabetes Mellitus (DM) is a highly prevalent disease, and pancreatic islet dysfunction is crucial for its development [1,2,3]. We reported that isolated pancreatic islet from transgenic heterozygote mice (with around 50% less expression of ARHGAP21) present a reduction in the insulin secretion when compared to the wild-type mice fed on the same diet [7]. The discrepancies between both studies could be explained, at least in part, by the fact that neonate islet are functionally immature, presenting significant physiology differences compared to the islets from adult mice. We measured the ARHGAP21 expression in the pancreatic islet of animal models known to present hyper (B6.V-Lepob/JUnib) and hypo (endurance-trained mice) insulin secretion
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