Research Article Details
| Article ID: | A14053 |
| PMID: | 29608898 |
| Source: | Eur J Pharmacol |
| Title: | Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation. |
| Abstract: | Elevated blood glucose and insulin resistance are triggering factors for non-alcoholic steatohepatitis (NASH). We investigated the effects of the Sodium Glucose co-Transporter 2 (SGLT2) inhibitor canagliflozin on NASH development in rats with type 2 diabetes mellitus as well as the possible underlying mechanisms and for the first time the effect of canagliflozin on the hepatic zinc-α2-glycoprotein (ZAG) levels. Rats were treated with nicotinamide and streptozotocin to reduce the insulin secretory capacity then fed high fat diet for 8 weeks. The diabetic high fat diet rats were divided into three groups; untreated group, canagliflozin 10 mg/kg treated group and canagliflozin 20 mg/kg treated group during this period. The elevated blood glucose and glycated haemoglobin (HbA1c) levels in the diabetic high fat diet rats were significantly reduced by canagliflozin. Moreover, the diabetic high fat diet induced NASH development as evidenced by liver weight gain, hepatic lipid accumulation and low hepatic ZAG expression as well as increased serum alanine aminotransferase; all these changes were reversed in rats treated with canagliflozin. Additionally, canagliflozin succeeded to upregulate the hepatic ZAG levels in both normal and diabetic high fat fed rats, lower the serum and hepatic inflammatory cytokines levels as well as lower the serum caspase-3 levels and enhanced hepatic Bcl-2 expression. Also, canagliflozin attenuated hepatic oxidative stress and elevated the antioxidant enzymes activity as well as the total antioxidant capacity. All these effects of canagliflozin were dose dependant. CONCLUSION: SGLT2 inhibitor-canagliflozin- has beneficial effects in treatment of NASH associated with diabetes mellitus. |
| DOI: | 10.1016/j.ejphar.2018.03.043 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T02 | Sodium/glucose cotransporter 2 | SLC5A2 | inhibitor | Transporter | P31639 | SC5A2_HUMAN | Details |
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T11 | Caspase-3 | CASP3 | inhibitor | Enzyme | P42574 | CASP3_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D549 | SGLT2 inhibitor | Chemical drug | -- | SGLT2 inhibitor | -- | Under clinical trials | Details |
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D395 | Zinc | Chemical drug | DB01593 | PSPH; CCS; HDAC1 cofactor; HDAC4 cofactor; INS; UTRN; ASPA cofactor; TP73 cofactor; A2M; AGT; APOBR; APOE; APOL1; C3; C5; CFB; CFH; CFI; CLU; CP; CPN2; DSP; F12; F13B; FGA; GSN; HBB; HPR; JUP; SELENOP; TTR; VTN | -- | Under clinical trials | Details |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D240 | Nicotinamide | Chemical drug | DB02701 | PARP inhibitor | Metabolic disorder drug | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D058 | Canagliflozin | Chemical drug | DB08907 | SGLT2 inhibitor | Improve insulin resistance | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |