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  • In the present study using weeks old

    2019-07-30

    In the present study, using 11weeks old HD tg mice (R6/2) and age matched control littermates, we determined the distributional pattern of β, α and δ cells. Second, we sought to determine the subcellular distribution of SSTR subtypes and their colocalization with β, α and δ N,N-Dimethylsphingosine in the pancreas of R6/2 mice. Third, to establish the neuroendocrine connection of diabetes with HD, we sought to elucidate the expression and subcellular distribution of GAD, TH and SYP in the pancreas. Fourth, we determined the status of the downstream signaling effectors, including PKA, STAT3, AKT and ERK1/2. Together, these observations provide novel insight for the role of SST and SSTRs in the development and progression of diabetes in experimental models of HD.
    Material and methods
    Results
    Discussion The present study aimed to establish a functional and physiological relation between hormone producing cells and SSTR subtypes in the pancreatic tissue of 11weeks old R6/2 and age matched wt mice. We also demonstrate the status of downstream signaling pathways and dissected out the changes in key CNS enzymes, including TH and GAD, as well as a marker of synaptic vesicle protein SYP in the pancreas of R6/2 mice. SSTR1 and 5 are the prominent receptor in β cells that involve in the regulation of insulin [14], [46]. SSTR2 is the subtype, which is expressed in α cells and regulates glucagon secretion. In R6/2 mice, α cells were devoid of SSTR2 expression, indicating the withdrawal of inhibitory input of SSTR2. SSTR3 mediated cytotoxic effect induces apoptosis, however the role of SSTR3 in the islet of Langerhans is not well understood [53]. Diabetes in R6/2 mice is associated with the degeneration of β cells and linked to apoptosis therefore SSTR3 in R6/2 mouse pancreas might involve in a loss of islet cells [54]. It was interesting to note that SSTR4, which is a predominant receptor subtype in neurodegenerative disease, is also decreased in the pancreas of R6/2 mice. Consistent with the notion that SSTR4 ablated mice are highly susceptible to pain and inflammation, such a role of SSTR4 is highly predictable in diabetes [55]. Previous studies using SSTR subtypes ko mice have shown changes in insulin and glucagon release, enhanced fasting glucose in response to insulin and changes in islet size as well as insulitis [12], [13], [14], [24], [56]. Such effects of SSTRs are further supported by our recent observations describing comparable neurochemical changes in SSTR1/5 double ko and R6/2 mice brain [19]. These observations suggest that SSTRs ko and R6/2 mice represent a true model to study the development and progression of diabetes and might serve as an experimental tool to delineate the molecular mechanism associated with the pathogenesis of diabetes in neurological diseases. To our knowledge, this is the first comprehensive study describing the distribution of SSTR subtypes, their colocalization with β, α and δ cells and signal transduction pathways in islets of Langerhans of wt and R6/2 mice. The loss of insulin, glucagon and SST at the level of mRNA and protein is consistent with a previous study [7]. The expression and distribution of SSTR subtypes in β, α and δ cells in the islets of Langerhans are critical determinants in assigning the role of SST in regulation of insulin and glucagon secretion. The results described here support that impaired β cell function may be regulated by SST via five different SSTR subtypes in a receptor dependent manner as described earlier [14], [57], [58], [59]. In addition, the disparity in the expression of SSTRs mRNA and protein is the indication of impaired translation of selective SSTR subtypes in R6/2 mice. Taken together, with the well established role of SST in the regulation of insulin and glucagon secretion, the loss of SST and diminished SSTRs expression might account for the loss of SST mediated inhibitory inputs in the pancreas and progression of diabetes in neurological diseases [60]. However, the argument that reduced insulin secretion in the islets could directly influence SST expression levels as a compensatory mechanism cannot be avoided from the discussion [7].