Functional properties of iminosugar 1-deoxynojirimycin: main focus on its insulin-sensitizing effect for maintenance of healthy metabolic and brain functions

概要

Deleterious dietary choices and sedentary lifestyles have led to the rising incidence of obesity and associated “metabolic syndrome (MetS)”, a term that has been used to describe a co-existing abnormalities–generally include excess adiposity, hyperlipidemia, high blood glucose, impaired glucose tolerance, and insulin resistance–that together increase the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver, and interestingly, neurodegenerative diseases at later age [1]. A reciprocal relationship between insulin sensitivity/resistance and insulin release, in particular, serves as the major driver in development of T2DM, whereby pancreatic β-cells compensate for the decline in systemic insulin sensitivity through proportionate adjustment in insulin secretion. Further decline in insulin sensitivity exhausts β-cells, resulting in persistent hyperglycemia and eventually, T2DM [2]. Recent evidence has also shown how defective insulin signaling in the brain region may give rise to neuronal dysfunction and cognitive deficits that are commonly associated with Alzheimer’s disease (AD) [3], which opens up new avenues for therapeutic strategies that are able to simultaneously resolve metabolic disturbances and neurodegenerative pathologies. In this regard, regular intake of bioactive compounds, especially the ones deriving from foods, serve as a viable option as they generate less adverse reactions compared to other procedures (e.g., drugs or surgery), can be easily incorporated into daily diet, and are more accessible in the market.

1-Deoxynojirimycin (DNJ) is an iminosugar and glucose-mimetic with anti-hyperglycemic and anti-obesity properties, commonly found in mulberry leaves [4] and in growth medium of some microorganisms, such as Bacillus and Streptomyces [5]. Efficacy studies in animals and human subjects have offered the mechanistic insights into the health benefits of DNJ and mulberry leaf-derived products containing DNJ, including its potent ability to inhibit intestinal α- glucosidase activities [6], restoring insulin sensitivity [7], accelerating hepatic glucose metabolism [8], and modulating lipid metabolism pathways [9], among others. Recent evidence has also indicated the neuroprotective capacity of DNJ in AD-like SAMP8 mice [10], though the responsible mechanism for this function has yet to be fully elucidated. It is important to note that most of the available studies rely on mulberry leaf-derived DNJ; meanwhile, utilization of DNJ- containing products from microbial sources are still lower compared to its mulberry leaves counterpart, despite the ability of some microorganism to yield higher amount of DNJ compared to mulberry leaves. For this reason, the first and second part of this dissertation were aimed to develop a production method for microbial-derived product containing DNJ in form of Bacillus amyloliquefaciens AS385 fermented medium powder (FMP), followed with assessment of its impact on the physiological aspects of lean and high-fat diet (HFD)-fed C57BL/6J mice. The organ distribution of DNJ following prolonged intake of FMP were also a subject of interest, as this knowledge would provide a better insight into the cause-effect relationship between DNJ uptake with its reported benefits in specific organs/tissues. In the third part of the study, we aimed to explore the mechanism that may be involved in the neuroprotective capacity of DNJ, particularly in relation to neuronal insulin signaling regulation; the rationale of this study was based on the insulin-sensitizing effect of DNJ in liver and peripheral tissues [7,11,12] and its purported delivery into the brain region following oral intake [12,13]. For this purpose, we first developed an insulin-resistant neuronal model using SK-N-SH human neuroblastoma and studied the changes in insulin signaling response and tau pathology following treatment with DNJ. Pure DNJ, instead of FMP, was opted for this experiment as DNJ appears to be the main active component in FMP. Collectively, the results that are presented in this dissertation may hopefully provide a better mechanistic understanding into the activities of DNJ and DNJ-based product (i.e., FMP) in an effort to promote their therapeutic use for maintenance of healthy metabolic and brain functions.