Research Article Details
| Article ID: | A08928 |
| PMID: | 31935149 |
| Source: | Crit Rev Clin Lab Sci |
| Title: | Fructose and hepatic insulin resistance. |
| Abstract: | Excessive caloric intake in a form of high-fat diet (HFD) was long thought to be the major risk factor for development of obesity and its complications, such as fatty liver disease and insulin resistance. Recently, there has been a paradigm shift and more attention is attributed to the effects of sugar-sweetened beverages (SSBs) as one of the culprits of the obesity epidemic. In this review, we present the data invoking fructose intake with development of hepatic insulin resistance in human studies and discuss the pathways by which fructose impairs hepatic insulin action in experimental animal models. First, we described well-characterized pathways by which fructose metabolism indirectly leads to hepatic insulin resistance. These include unequivocal effects of fructose to promote de novo lipogenesis (DNL), impair fatty acid oxidation (FAO), induce endoplasmic reticulum (ER) stress and trigger hepatic inflammation. Additionally, we entertained the hypothesis that fructose can directly impede insulin signaling in the liver. This appears to be mediated by reduced insulin receptor and insulin receptor substrate 2 (IRS2) expression, increased protein-tyrosine phosphatase 1B (PTP1b) activity, whereas knockdown of ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, increased insulin sensitivity. In summary, dietary fructose intake strongly promotes hepatic insulin resistance via complex interplay of several metabolic pathways, at least some of which are independent of increased weight gain and caloric intake. The current evidence shows that the fructose, but not glucose, component of dietary sugar drives metabolic complications and contradicts the notion that fructose is merely a source of palatable calories that leads to increased weight gain and insulin resistance. |
| DOI: | 10.1080/10408363.2019.1711360 |
| 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 |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | 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 |
| 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 | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D545 | Pig placenta extract | Biological extract | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |