Thiazolidinediones for the prevention of diabetes in the non-obese diabetic (NOD) mouse: implications for human type 1 diabetes.
BACKGROUND
Thiazolidinediones (TZDs) are a recently introduced generation of drugs acting as receptor agonists to reduce insulin resistance and used currently in combination with other hypoglycaemic agents for the treatment of type 2 diabetes. In addition, TZDs possess anti-inflammatory properties that make them of interest for reducing the T-cell inflammation occurring in the islets in type 1 diabetes.


METHODS
The action of TZD treatment on diabetes incidence in the non-obese diabetic (NOD) mouse was studied by investigating the effect of rosiglitazone (RGL) (400 mg/kg body weight by gavage) from 3 weeks of age (soon after weaning) onwards and comparing its effect to that of troglitazone (TGL) given by the same route.


RESULTS
We found that RGL and TGL both significantly reduced diabetes incidence by >50% in the NOD mouse compared to litter-matched control NOD mice (p<0.05 and p<0.01, respectively). However, the withdrawal of TGL from the market due to hepatotoxicity led us to re-analyse our data for toxic liver effects. We found that TGL was more toxic to mice than RGL (causing ten deaths as compared with one death).


CONCLUSIONS
RGL reduces diabetes incidence in the NOD mouse model of type 1 diabetes. This may be an effect resulting from its action as on inhibitor of pro-inflammatory genes such as cytokines and metabolic proteases. Its use may be considered for trials designed to protect beta-cell function in humans, especially in patients with latent autoimmune diabetes of adults (LADA) and also for disease prevention.
Beales
Philip E
PE
Department of Diabetes and Metabolism, St Bartholomew's Hospital, London, UK.
Pozzilli
Paolo
P
D000818:Animals; D002839:Chromans / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D015994:Incidence; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; D000077288:Troglitazone