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  • The changes seen in the

    2019-07-30

    The changes seen in the expression and distribution of TH, GAD and SYP establish neuroendocrine connection of diabetes in R6/2 mice. In the pancreas, TH positive gamma-Glu-Cys coexpress insulin, SST and glucagon, whereas TH decreases glucose induced insulin secretion in rat islets. We found the loss of TH immunoreactivity in the islet cells and nerve fibers, implicating an impaired regulation of insulin, glucagon as well as SST. TH is believed to be a marker of aging β cells and studies in TH ko mice show the loss of β cells during development [28]. TH positive cells may differentiate to β and α cells postnatally and studies have shown that during aging, β and α cells exhibit diminished TH immunoreactivity [34]. This speculation is further strengthened with the loss of TH immunoreactivity described here in R6/2 mice. Future studies at pre-and post embryonic stages of R6/2 mice are warranted to establish morphological and physiological relations between TH and insulin, glucagon as well as SST. Furthermore, it will be important to determine which SSTR subtypes colocalize with TH in individual islet cells. The colocalization of TH with SSTR subtypes in the hypothalamus as described earlier [61] and the selective distribution of TH in the islet cells and nerve fibers as presented here indicate the endocrine/paracrine role of secreted TH in the pancreas. Furthermore, neuroendocrine changes in experimental models and HD patients with the release of several neuroendocrine factors to the CSF and blood cannot be avoided from this discussion. The elucidation of such complex molecular mechanism might establish a critical association between neuronal degeneration and progression of diabetes with SST and its cognate receptors. Increased GAD auto-antibodies are often associated with type I diabetes due to the loss of β cells and previous study has also suggested the involvement of GAD in type 2 diabetes [62]. What role GAD might play in the development and progression of diabetes in HD patients and experimental models of disease is not well understood. Increased GAD expression in α cells of islets in R6/2 mice is not surprising, instead it establishes a functional and physiological role of the CNS in diabetes. In addition to perturbed β cell function and metabolic state, studies have shown increased oxidative damage in a hyperglycemic condition due to an interruption in the GABA network. We speculate that GABA mediated inhibition of glucagon secretion might be associated with increased GAD and subsequent loss of SST dependent inhibitory input on GABA. SYP is a well established marker of presynaptic terminals in the CNS and a marker of endocrine cells, which colocalize with β, α, δ and PP cells in the islets of Langerhans [27], [63]. SYP serves as a marker of pancreatic neuroendocrine neoplasm due to its selective expression in islet cells [64]. The loss in protein turnover and glycolysis of SYP has been shown in the retina of STZ induced rat models of diabetes [43]. The loss of SYP immunoreactivity and insulin secretion seen in the pancreas of R6/2 mice suggests a direct association between insulin and SYP. The loss of SYP also causes behavioral changes such as impaired spatial learning and memory [65]. With such profound changes, the role of SYP in impaired learning and memory in neurodegenerative diseases associated with diabetes cannot be excluded from the discussion. We propose that with the loss of SYP in R6/2 mice, neuronal activity and neurotransmitter release is possibly perturbed and contribute to diabetes associated impaired learning and memory in HD patients [66]. Furthermore, future studies are warranted to determine whether the changes seen in R6/2 mice are comparable to other models of HD such as YAC mice. The elucidation of the molecular mechanism for the role of TH, GAD and SYP in addition to their colocalization with SST/SSTR subtypes, will establish a crucial connection between neuronal loss in the brain and the development of diabetes in HD patients and experimental models of disease.