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  • These findings raise the question of what mechanism of beta


    These findings raise the question of what mechanism of beta cell proliferation is induced by short-term HF diet feeding. Gene expression profiling of isolated islets from mice fed a HF diet for 1 week revealed that expression levels of downstream genes of Foxm1 were coordinately upregulated (Fig. 5). Foxm1 is a transcription factor that stimulates cell proliferation and exhibits a proliferation-specific expression pattern [36]. It also appears to be a key transcriptional regulator of cell-cycle progression in pancreatic beta cells. Indeed, it has been reported that Foxm1 is necessary for adult beta cell proliferation in response to pancreatectomy, pregnancy and obesity [[37], [38], [39]]. Foxm1 stimulates the transcription of many mitotic genes, including Plk1, Aurkb, Survivin, Cenpa, Cenpb, Cenpf, and Cdc20, to ensure correct regulation of mitosis [39]. These increased gene expression levels were confirmed by real-time quantitative PCR in our study. Recently, it has been reported that Foxm1 acts via Plk1 to regulate Cenpa expression and deposition on centromeres, and that Cenpa deficiency impairs adaptive beta cell proliferation [40]. The transcription factor Foxm1 is thought to play a role in all phases of the cell cycle, including G1/S-phase and G2/M-phase transitions. Our results show that expression of Ccna2 and Ccnb1, but not Ccnd, was significantly upregulated in islets from mice fed an HF diet for 1 week compared with those fed SC (Fig. 5d). The effect of Foxm1 on N6-Methyl-ATP family members has been explored previously: Ccna2 and Ccnb1 expression levels were increased in isolated mouse islets overexpressing Foxm1b, whereas Foxm1b overexpression had no effect on Ccnd1, Ccnd2 nor Ccnd3 expression [39]. Moreover, increased expression levels of Foxm1, Ccna2 and Ccnb1, but not Ccnd2, were observed in mouse islets after partial pancreatectomy [13,37]. These results are consistent with our data. In contrast, Irs2-mediated signalling, which is enhanced by glucokinase, is linked with Ccnd2 [17], indicating that the cyclin expression profiles in islets from mice fed an HF diet for 1 week are quite different from those induced by the enhancement of the glucokinase- and Irs2-dependent pathway. Thus, the pancreatic beta cell proliferation induced by short-term and long-term HF diet feeding might be mediated by different pathways. The mechanism of Foxm1 upregulation by short-term HF diet feeding remains unknown. Rapamycin has been shown to block increases in Foxm1 signalling and beta cell proliferation in response to a 72-hour coinfusion of glucose and intralipid in Wister rats [41], which is in accordance with our results for short-term HF diet-induced beta cell proliferation (Fig. 6d). Given that the mTOR complex 1 (mTORC1) signalling pathway integrates signals from growth factors and nutrients [42], further studies are underway to identify the factors augmenting this mTORC1/Foxm1 pathway. Basal beta cell proliferation decreases with age in mouse models [43,44] as well as in humans [10]. Moreover, adaptive beta cell proliferation is strongly restricted with age in mice [44]. Our results show that HF diet feeding for 1 week stimulated beta cell proliferation with upregulation of Foxm1, Ccna2 and Ccnb1 not only in 8-week-old mice, but also in 48-week-old mice (Fig. 7). In support of this finding, Galson and colleagues [45] demonstrated that expression of activated Foxm1 in aged beta cells triggers cell-cycle progression, leading to elevated beta cell proliferation. From a clinical point of view, given that the onset of type 2 diabetes increases with age in humans, the ability to increase beta cell proliferation in aged islets is particularly important.
    Introduction Myo-inositol (inositol), also called cyclohexanehexol, is broadly distributed in mammalian cells, higher plants, fungi and some bacteria as an essential growth factor [[1], [2], [3]]. The metabolism of inositol and its derivatives has been extensively studied [[4], [5]]. Inositol has been reported to be effective in treating depression, panic disorder, Alzheimer’s disease, fatty liver and diabetes, as well as to be useful in pediatric respiratory depression syndrome [[6], [7], [8]]. Inositol is widely applied in the cosmetics industry to improve cell growth and prevent cell aging, the pharmaceutical industry as an adulterant, and the functional food industry as a nutritional supplement [[9], [10], [11]]. Inositol is predominately obtained by acid hydrolysis of phytate (inositol hexakisphosphate), a phosphate-esterified inositol derivative extracted from bran and plant seeds [[12], [13], [14]]. Commonly, phytate is hydrolyzed to inositol using harsh chemical conditions (low pH, high temperature and pressure). Alternatively, phytate has been enzymatically hydrolyzed to inositol using phytase and acid phosphatase [[15], [16], [17], [18]]. Additionally, inositol has been produced from glucose by a fermentation process in metabolically engineered microorganisms, but with a low yield [[19], [20]]. Recently, an in vitro enzymatic synthesis of inositol from starch involving four enzymes (alpha-glucan phosphorylase, phosphoglucomutase, inositol 1-phosphate synthase [IPS] and inositol monophosphatase [IMP]) was reported [21].