Small-molecule insulin mimetic reduces hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes.
Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor-gamma agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPARgamma agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.
Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie, Endokrinologie, und Stoffwechsel Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. mathias.strowski@charite.de
Mathias Z
MZ
Strowski
Zhihua
Z
Li
Deborah
D
Szalkowski
Xiaolan
X
Shen
Xiao-Ming
XM
Guan
Stefan
S
Jüttner
David E
DE
Moller
Bei B
BB
Zhang
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006943:Hyperglycemia / Q000188:drug therapy*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
C493136:CPD2 insulin mimetic; D003510:Cyclohexanes; D005230:Fatty Acids, Nonesterified; D007211:Indoles; D007328:Insulin; D045162:Thiazolidinediones; D014280:Triglycerides; D011972:Receptor, Insulin