Research Article Details
| Article ID: | A09349 |
| PMID: | 31782258 |
| Source: | Physiol Rep |
| Title: | SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model. |
| Abstract: | Nonalcoholic steatohepatitis (NASH) has become the most common cause of chronic liver disease worldwide in recent years. The pathogenesis of NASH is closely linked to metabolic diseases such as insulin resistance, obesity, dyslipidemia, and type 2 diabetes. However, there is currently no pharmacological agent for preventing the progression of NASH. Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption, and improve various pathological conditions of type 2 diabetes, including insulin resistance. In the present study, we examined the effects of ipragliflozin, a SGLT2-selective inhibitor, alone and in combination with pioglitazone on NASH in high-fat diet-fed KK/Ay type 2 diabetic mice. Type 2 diabetic mice with NASH exhibited steatosis, inflammation, and fibrosis in the liver as well as hyperglycemia, insulin resistance, and obesity, features that are observed in human NASH. Four-week repeated administration of ipragliflozin (0.1-3 mg/kg) led to significant improvements in hyperglycemia, insulin resistance, and obesity in addition to hyperlipidemia and liver injury including hepatic steatosis and fibrosis. Moreover, ipragliflozin reduced inflammation and oxidative stress in the liver. Repeated administration of pioglitazone (3-30 mg/kg) also significantly improved various parameters of diabetes and NASH, excluding obesity. Furthermore, combined treatment comprising ipragliflozin (1 mg/kg) and pioglitazone (10 mg/kg) additively improved these parameters. These findings indicate that the SGLT2-selective inhibitor ipragliflozin improves hyperglycemia as well as NASH in type 2 diabetic mice. Therefore, treatment with ipragliflozin monotherapy or coadministered with pioglitazone is expected to be a potential therapeutic option for the treatment of type 2 diabetes with NASH. |
| DOI: | 10.14814/phy2.14286 |
| 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 |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| 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 |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | 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 |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D275 | Pioglitazone | Chemical drug | DB01132 | PPARG agonist | Improve insulin resistance | Advanced in clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D187 | Ipragliflozin | Chemical drug | DB11698 | SGLT2 inhibitor | Improve insulin resistance | Under clinical trials | Details |