Research Article Details

Article ID: A51669
PMID: 35070060
Source: World J Diabetes
Title: Gut microbiota-derived metabolites are novel targets for improving insulin resistance.
Abstract: The gut microbiota plays a key role in metabolic diseases. Gut-microbiota-derived metabolites are found in different dietary sources, including: Carbohydrate (acetate, propionate, butyrate, also known as short-chain fatty acids, as well as succinate); protein (hydrogen sulfide, indole, and phenylacetic acid); and lipids (resveratrol-, ferulic acid-, linoleic acid-, catechin- and berry-derived metabolites). Insulin resistance, which is a global pandemic metabolic disease that progresses to type 2 diabetes mellitus, can be directly targeted by these metabolites. Gut-microbiota-derived metabolites have broad effects locally and in distinct organs, in particular skeletal muscle, adipose tissue, and liver. These metabolites can modulate glucose metabolism, including the increase in glucose uptake and lipid oxidation in skeletal muscle, and decrease in lipogenesis and gluconeogenesis associated with lipid oxidation in the liver through activation of phosphatidylinositol 3-kinase - serine/threonine-protein kinase B and AMP-activated protein kinase. In adipose tissue, gut-microbiota-derived metabolites stimulate adipogenesis and thermogenesis, inhibit lipolysis, and attenuate inflammation. Importantly, an increase in energy expenditure and fat oxidation occurs in the whole body. Therefore, the therapeutic potential of current pharmacological and non-pharmacological approaches used to treat diabetes mellitus can be tested to target specific metabolites derived from intestinal bacteria, which may ultimately ameliorate the hyperglycemic burden.
DOI: 10.4239/wjd.v13.i1.65

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
S06 Regulating intestinal flora intestine gut microbiota; gut microbiota farnesoid X receptor (FXR); fibroblast growth factor-19 (FGF19) Probiotics; Prebiotics; Rifaximin; Yaq-001; Cilofexor; EDP-305; EYP001a; INT-767 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

Target ID Target Name GENE Action Class UniProtKB ID Entry Name

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
D248 Obeticholic Acid Chemical drug DB05990 NR1H4 activator; NR1H4 agonist; FXR agonist Enhance lipid metabolism Approval rejected Details
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D301 Resveratrol Chemical drug DB02709 ALOX15; ALOX5; AHR; NR1I2; NR1I3 Anticancer agent Under clinical trials Details
D182 Insulin Biological drug DB00030 INSR agonist; CPE modulator&product of -- Under clinical trials Details