| The International Diabetes Federation(IDF)estimated that roughly 415 million worldwide suffer from diabetes,especially china had the highest number of diabetics in the world with an estimated nearly 100 million sufferers in 2015.The most commonly implicated causes of diabetes are well known: poor diet,lack of physical activity,and changing ways of life.With the development of diabetes diet concept,capsaicin(Trans 8-methyl-N-vanilla base-6-nonene amide),as a kind of alkaloid extracted from chili is widely used in health food,pharmaceutical industry and other fields,especially in treatment of diabetes mellitus.The chronic complications and hypoglycemic effect of capsaicin had caused the wide attention of researchers in biomedical fields.Although a large number of studies have shown that capsaicin has hypoglycemic effect,but its specific hypoglycemic mechanism is not clear;and previous studies showed that islet β cells secrete insulin associated with transient receptor potential vanilloid 1(TRPV1)channels activated by capsaicin,but its increasing role of insulin levels is the way of islet β cells by stimulating or proliferation still has many questions,and TRPV1 receptors as a potential drug targets for a therapy for diabetes is still quite a lot dispute,especially TRPV1 receptors in the mediating role of capsaicin hypoglycemic mechanism still needs to be further defined.In addition,reportedly spicy condiment can change the ultrastructure and the permeability of the ileum,which affects the intestinal absorption of nutrients,and the intestinal absorption capacity of sugar relate to sodium-glucose cotransporter 1(SGLT1)signaling pathways.Thus,the regulation mechanism of capsaicin on the related genes of SGLT1 signaling pathways and the relationship between the hypoglycemic roots of capsaicin and its spicy group remains to be further research.Based on insulin levels increase with the occurrence of insulin resistance in type 2 diabetes,but this phenomenon does not exist in type 1 diabetes.Thus,the aim of this study was to evaluate the cause of the hypoglycemic effect of capsaicin at the molecular level and to provide a basis forhigher value applications and functional assessment of chili peppers.The main conclusions of the research are as follows:(1)To investigate the effect of capsaicinoids on glycometabolism in type 1 diabetic rats,the hypoglycemic mechanism was also discussed.Four-week-old male Sprague–Dawley(SD)rats were randomly categorized into five groups(8 rats/group): control group,model group and Low(D-L),medium(D-M)and high(D-H)dose groups.Dose groups were orally treated with 3,6,and 9 mg/kg·bw of capsaicinoids daily for 28 days.Capsaicinoids treatment significantly increased the body weight,serum insulin level,glycogen content,and fecal sugar excretion of diabetic rats.In particular,insulin levels were increased from 8.17±0.38 mIU/L(model group)to 14.97±0.98 mIU/L(D-H).Meanwhile,fasting blood glucose and glycosylated serum protein contents were substantially decreased,and glucose tolerance was considerably improved.More importantly,significant upregulation of liver X receptor(LXR)and pancreatic duodenal homeobox-1(PDX-1)expression was observed in the liver and pancreas of diabetic rats,which resulted in a significant up-regulated expression of glucose-6-phosphatase(G6Pase),glucokinase(GK),glucose transport protein 2(GLUT2),insulin receptor 1(IRS1)and insulin receptor 2(IRS2).Capsaicinoids significantly downregulated the gene expression of SGLT1,GLUT2,and GLUT5 in the ileum and promoted the excretion of sugar in feces,and upregulated the protein levels of TRPV 1 in the liver and pancreas of rats.Thus,the hypoglycemic mechanism of capsaicinoids may be associated with these changes occurred in different gene and protein expression.The results suggested that capsaicinoids(6 and 9 mg/kg·bw)significantly reduced the blood glucose level via elevation of the insulin level and inhibition of glucose absorption in the ileum.(2)To study the hypoglycemic effects of spicy group in the capsaicin,and use capsiate with no spicy group for comparison,comparative study the effects of capsaicin and capsiate on glycometabolism and hypoglycemic action in T1 D rats.Four-week-old male SD rats were randomly categorized into four groups(8 rats/group): control,model,capsaicin,and capsiate groups.The two treatment groups were treated orally with 6 mg/kg·bw capsaicin and capsiate daily for 28 days.Treatment with capsaicin and capsiate increased body weight,increased glycogen content,and inhibited intestinal absorption of sugar in diabetic rats.Particularly,compared with the insulin level of model group(14.88±0.76 mIU/L),the insulin level of capsaicin group(22.39±1.39 mIU/L)significantly increased by 50.5%,but capsiate group(16.70±0.79 mIU/L)was merely increased by 12.2%.Analysis of the related genes suggested that the TRPV1 receptor was activated by capsaicin.LXR and PDX-1 controlled the glycometabolism balance by regulating the expression levels of GK,GLUT2,PEPCK,and G6 Pase,leading to reduced blood glucose levels in diabetic rats.Meanwhile,hypoglycemic effect were enhanced by the down-regulated expression of SGLT1,GLUT2,and GLUT5 in the intestine.These results indicated that the capsiate although in some ways could improve the symptoms of diabetes,the hypoglycemic effect of capsaicin was much better than capsiate;meanwhile,the results also suggested that significant hypoglycemic effect of capsaicin might cause by its characteristic,and it was speculated that TRPV1–(PDX-1)–(GLUT2/GK)or TRPV1–(PDX-1)–(IRS1/2)signaling pathway may existed in the liver or pancreas of rats.(3)To study the effect of capsaicin on glycometabolism in type 1 diabetic rats by blocking TRPV1 channels,the correlation of the hypoglycemic effect of capsaicin and the blocking of TRPV1 channels were explored randomly electing 40 four-week-old male SD rats divide into 5 groups,each group 8 rats: Control group,Model group,capsazepine group(CPZ),capsaicin group(Cap)and composite group(Cap+CPZ),and the experimental period is 28 days.The results showed that weight,feed intake,fasting blood glucose,insulin level,glycosylated serum protein and glycogen content in CPZ group and model group did not show significant difference.It is interesting that Cap+CPZ group did not show a hypoglycemic effect in diabetic rats.The probable explanation for this phenomenon was that the regulation of glycometabolism and related factors were suppressed by capsazepine,especially significant up-regulation of SGLT1,GLUT2 and GLUT5 expression in the ileum,which promoted the deterioration of diabetes.In addition,these results also verified that the TRPV1 expression were associated with hepatic glycometabolism and insulin secretion,and provided the basis for previous speculation that TRPV1–(PDX-1)–(GLUT2/GK)or TRPV1–(PDX-1)–(IRS1/2)signaling pathway might exist in the liver or pancreas of rats.(4)To explore the regulation mechanism of capsaicin on insulin secretion in pancreas,we studied the the effects of capsaicin on pancreatic tissue of T1 D rats.Meanwhile,to study the effects of capsaicin on βTC-6 cell(mouse insulinoma beta cell of islet)proliferation and apoptosis through the cell experiment,and to evaluate the relations of insulin secretion with the change of intracellular calcium concentration.More importantly,we verified the speculation of the existence of signaling pathways(TRPV1–(PDX-1)–(GLUT2)or TRPV1–(PDX-1)–(IRS1/2)through the TRPV1 control experiment.The results showed that the structure of pancreas was improved significantly by medium dose of capsaicin,and it was found that intracellular calcium concentration and insulin secretion increased at the same time after added right amount of capsaicin(50 μmol/L).In the TRPV1 control experiments,we measured the related protein expression level,the results showed that TRPV1–(PDX-1)–(GLUT2/IRS1)signaling pathway might exist in the pancreas,but this corollary still needs further research.In addition,the effect of capsaicin on the pancreas and βTC-6 cell showed that hypoglycemic effect of capsaicin derived from the stimulation of normal islet cells and repair function of dysfunction cells,rather than the proliferation of islet cells. |
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