Abstract
1-Deoxynojirimycin (DNJ) is widely used for the treatment of diabetes mellitus as an inhibitor of intestinal α-glucosidase. However, there are few reports about its effect on insulin sensitivity improvement. The aim of the present study was to investigate whether DNJ decreased hyperglycemia by improving insulin sensitivity. An economical method was established to prepare large amounts of DNJ. Then, db/db mice were treated with DNJ intravenously (20, 40 and 80 mg·kg−1·day−1) for four weeks. Blood glucose and biochemical analyses were conducted to evaluate the therapeutic effects on hyperglycemia and the related molecular mechanisms in skeletal muscle were explored. DNJ significantly reduced body weight, blood glucose and serum insulin levels. DNJ treatment also improved glucose tolerance and insulin tolerance. Moreover, although expressions of total protein kinase B (AKT), phosphatidylinositol 3 kinase (PI3K), insulin receptor beta (IR-β), insulin receptor substrate-1 (IRS1) and glucose transporter 4 (GLUT4) in skeletal muscle were not affected, GLUT4 translocation and phosphorylation of Ser473-AKT, p85-PI3K, Tyr1361-IR-β and Tyr612-IRS1 were significantly increased by DNJ treatment. These results indicate that DNJ significantly improved insulin sensitivity via activating insulin signaling PI3K/AKT pathway in skeletal muscle of db/db mice.
Highlights
Type 2 diabetes mellitus, the fourth leading cause of death worldwide, is a chronic metabolic disorder characterized by impaired homeostasis of lipid and carbohydrate metabolism, and results in insulin resistance and subsequent hyperglycemia [1]
Howe2v1e7r0,6treatment with DNJ remarkably enhanced the phosphorylation of IR-β and insulin receptor substrate-1 (IRS1) (Figure 7C,D). These results clearly indicated that DNJ increased glucose transporter 4 (GLUT4) translocation to the plasma membrane via up-regulating the phosphorylation of IR-β, IRS1, AKT and phosphatidylinositol 3 kinase (PI3K) rather than increasing the expression of total IR-β, IRS1, AKT and PI3K
Treatment with DNJ remarkably enhanced the phosphorylation of IR-β and IRS1 (Figure 7C,D). These results clearly indicated that DNJ increased GLUT4 translocation to the plasma membrane via up-regulating the phosphorylation MofolIeRcu-lβes,2I0R15S,12,0A, pKagTe–apnagdePI3K rather than increasing the expression of total IR-β, IRS1, AKT and PI3K
Summary
Type 2 diabetes mellitus, the fourth leading cause of death worldwide, is a chronic metabolic disorder characterized by impaired homeostasis of lipid and carbohydrate metabolism, and results in insulin resistance and subsequent hyperglycemia [1]. The current study aimed to investigate whether DNJ could improve insulin sensitivity. PreparationAsofshDoNwnJ, DNJ was first extracted from dried mulberry leaves with boiling water; The atFhninetaielhlxyyt,rpaDceNtrwJgwalysacpseuomrbitfaiieicndeedbfyfaefctacettrioconryfesxtmaclhliuaznelbdgeeinrrre9ys5in%l,eaeanthvioaennsoel.xiWcsheaandtgtereteirbremusiitnneeaddndDmNsialJiicbnaylgyHeilgtHoh sPDuecrNfcoersJms, iavhneoclyew. Ever the amount of DNJ in mulberry leaves is very low, the content is only 0.1%, and it is difficult to prepare [12,25]. We established an economical method to prepare large amounts of DNJ. DNJ was first extracted from dried mulberry leaves with boiling water; the extract was purified by cation exchange resin, anion exchange resin and silica gel H successively. The product purified by silica gel H looMkeoldecupleus 2r0e1r5,t2h0,a2n170th0–a21t7o14nly purified by exchange resin After these steps, the recovery of DNJ was over 50%.
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