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  • 2-Guanidinoethylmercaptosuccinic Acid In R mice the reduced

    2019-07-30

    In R6/2 mice, the reduced number of hormone producing 2-Guanidinoethylmercaptosuccinic Acid and islet mass is probably due to apoptosis triggered by multiple signaling pathways. Whether disrupted signaling pathways in the pancreas of R6/2 mice are due to mHtt induced toxicity, an imbalance in hormonal secretion, or perturbed SSTR subtypes expression is not known. Studies have shown the activation of PKA by glucagon via activation of its receptor and adenylyl cyclase [67]. cAMP via activating PKA exerts insulin secretagouge action and modulates the exocytosis of insulin in β-cells [68], [69]. cAMP/PKA activity is also associated with β-cell glucose responsiveness as well as in the regulation of insulin secretion [70]. Consistent with these results, the loss in PKA seen in the present study suggests that reduced glucagon in R6/2 mice might be a factor for PKA suppression. Activation of the PKA/CREB pathway increases β cell proliferation and cell mass, thus, the loss in PKA in R6/2 mice in part may be associated with decreased islet mass [71]. Further studies are warranted to characterize the islet cell types expressing PKA, and the role of SSTRs in the regulation of PKA activity. Furthermore, the distributional pattern of PKA in islets suggests that these cells might also be positive to SSTR2 or glucagon, however such speculations need to be confirmed. Activated PI3K is essential for insulin action on glucose transport and glucose dependent β cell mitogenesis [72]. AKT is upstream effector to PI3K and regulate its functional activity, suggesting that AKT might be involved in the regulation of glucose transport as well [73]. Consistent with these observations, the decreased AKT seen in the present study along with suppressed PI3K (data not shown) might be linked to impaired glucose transport. The activation of AKT also protects neurons from toxicity, thus the loss of AKT in HD pancreas might also be associated with apoptosis and decreased cell mass [74], [75]. Previous studies have shown that MAPK signal transduction pathways are implicated in suppressing production and secretion of insulin along with insulin resistance, leading to apoptosis [76]. Hepatic activation of ERK induces β cell proliferation through the neuronal mediated relay of metabolic signals. It has also been reported that the selective activation of ERK1/2 in the liver of the insulin deficient diabetes model increases β cell mass and normalize serum glucose levels [77]. STAT3 is one of the critical regulators of cell proliferation and apoptosis, and studies have suggested that the loss in STAT3 activation or expression triggers caspase dependent cell death [78]. Similarly, inhibition of the JAK-STAT3 pathway is also associated with the induction of cell cycle arrest and apoptosis [79]. Consistent with these studies, we found loss in ERK1/2 and STAT3 expression and phosphorylation in R6/2 mice. Whether changes in the status of signaling molecules are directly due to impaired insulin or indirectly due to the changes in SSTR subtypes is not known. However, our results support the fact that signal transduction pathways might play a determinant role in the abnormal islet function in diabetes associated with HD pathogenesis. The occurrence of diabetes in HD and experimental models of disease is well established [80]. The lack of inflammatory cells in R6/2 mice does not support the occurrence of type 1 diabetes, but emphasizes its resemblance with maturity onset diabetes of the young (MODY) patients [8]. These observations are of specific interest for the role of SSTR subtypes which are developmentally regulated. Therefore, it will be interesting to analyze SSTR subtypes expression at the level of mRNA/protein in MODY patients and the use of the R6/2 model may serve as an experimental tool to delineate the physiological significance of SSTR subtypes in diabetes. In conclusion, our morphological, biochemical and molecular characterization provides evidence that not only insulin producing β cells, but the loss of SST might play a crucial role in the progression of diabetes in HD. To what extent the brain might play a role in regulation of diabetes in HD patients' warrants further studies. We propose that the selective loss in SSTR subtypes expression, distributional organization and signal transduction pathways might be associated with impaired memory and cognitive function in the CNS with diabetes and that SSTR might serve as a novel therapeutic target in this direction.