4-Phenyl butyric acid does not generally reduce glucose levels in rodent models of diabetes.
1. Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes. The aim of the present study was to investigate the effect of 4-phenyl butyric acid (PBA), a novel chemical chaperone reducing ER stress, on serum glucose level in different strains of normal and diabetic rodents. 2. 4-Phenyl butyric acid (1 g/kg per day, i.g.) was administered to ob/ob Type 2 diabetic mice, alloxan-induced Type 1 diabetic mice and hydrocortisone (HC)-induced Type 2 diabetic mice as well as normal C57BL/6J mice and Kumming mice for 14 days to evaluate its effect on serum glucose levels. In addition, mice were treated simultaneously with PBA (1 g/kg per day) and HC for 9 days to determine its preventive effect against the development of insulin resistance. PBA (0.7 and 1.4 g/kg per day) was administered to non-obese Type 2 diabetic Goto-Kakizaki (GK) and normal Wistar-Kyoto (WKY) rats for 14 and 7 days, respectively, to determine its effects on serum glucose levels. 3. 4-Phenyl butyric acid significantly reduced serum glucose levels in obese Type 2 diabetic ob/ob mice. Normoglycaemia was obtained in ob/ob mice after 4 days of PBA treatment and was maintained for up to 14 days treatment. 4. 4-Phenyl butyric acid had no glucose-lowering effect in alloxan-induced Type 1 diabetic mice, HC-induced Type 2 diabetic mice and non-obese Type 2 diabetic GK rats. In addition, it had no beneficial effects on insulin resistance in HC-treated mice. 5. 4-Phenyl butyric acid did not affect normal serum glucose levels in C57BL/6 J mice, Kunming mice or WKY rats. 6. In conclusion, PBA does not generally reduce glucose levels in rodent models of diabetes, although it can normalize glucose levels in ob/ob diabetic mice, indicating that restoration of ER function as diabetes therapy is limited to conditions under which ER stress is involved in the high glucose levels.
Xu
Tian-Ying
TY
Department of Pharmacology, Second Military Medical University, Shanghai, China.
Chen
Ruo-Hua
RH
Wang
Pei
P
Zhang
Ruo-Yu
RY
Ke
Sen-Fang
SF
Miao
Chao-Yu
CY
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001798:Blood Proteins; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000097:blood; D006031:Glycosylation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000150:complications*; D010654:Phenylbutyrates / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D013045:Species Specificity; D013997:Time Factors; D000093422:Glycated Serum Proteins
D001786:Blood Glucose; D001798:Blood Proteins; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D007328:Insulin; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D000093422:Glycated Serum Proteins