title: Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice.
abstract: Obesity and metabolic diseases appear as clusters, often featuring high risk for insulin resistance and type 2 diabetes, and constitute a major global health problem with limited treatment options. Previous studies have shown that double-stranded RNA-dependent kinase, PKR, plays an important role in the nutrient/pathogen-sensing interface, and acts as a key modulator of chronic metabolic inflammation, insulin sensitivity, and glucose homeostasis in obesity. Recently, pathological PKR activation was also demonstrated in obese humans, strengthening its prospects as a potential drug target. Here, we investigate the use of two structurally distinct small-molecule inhibitors of PKR in the treatment of insulin resistance and type 2 diabetes in cells and in a mouse model of severe obesity and insulin resistance. Inhibition of PKR reduced stress-induced Jun NH2-terminal kinase activation and insulin receptor substrate 1 serine phosphorylation in vitro and in vivo. In addition, treatment with both PKR inhibitors reduced adipose tissue inflammation, improved insulin sensitivity, and improved glucose intolerance in mice after the establishment of obesity and insulin resistance. Our findings suggest that pharmacologically targeting PKR may be an effective therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Nakamura
authors.forename: Alessandro
authors.initials: A
authors.lastname: Arduini
authors.forename: Brenna
authors.initials: B
authors.lastname: Baccaro
authors.forename: Masato
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D015075:2-Aminopurine / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007093:Imidazoles; D007211:Indoles; C587358:imoxin; D015075:2-Aminopurine; D019892:eIF-2 Kinase; D005947:Glucose