Potential benefit of inhibitors of advanced glycation end products in the progression of type II diabetes: a study with aminoguanidine in C57/BLKsJ diabetic mice.
Prolonged hyperglycemia in type II diabetic patients is linked both with diabetic complications and with further impairment of glucose homeostasis, possibly due to glucose toxicity of the beta cell. While the connection between the accumulation of extracellular advanced glycation end products (AGEs) and the development of complications is well established, it has only recently been suggested that intracellular glycation may be equally adverse and could be involved in the pathogenesis of glucose toxicity in vitro. Aminoguanidine is a recognized inhibitor of the formation of both extracellular and intracellular AGEs. In this study, we show that the development of diabetes, measured by increased water intake and concomitant midday blood glucose levels in type II genetically diabetic mice, is reduced by treatment with aminoguanidine at a dosage of 500 mg/kg/d for 12 weeks in the diet. In addition, at the end of the study, aminoguanidine reduced the decline in serum and pancreatic insulin levels and the degree of pancreatic islet morphological degeneration, all of which are associated with pancreatic insufficiency following prolonged hyperglycemia in this animal model. These results suggest that AGEs may be involved in the aggravation of type II diabetes in vivo and aminoguanidine may be beneficial in its treatment.
Piercy
V
V
Department of Vascular Biology and Safety Assessment, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Toseland
C D
CD
Turner
N C
NC
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D010179:Pancreas / Q000378:metabolism / Q000473:pathology
D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D006146:Guanidines; D007328:Insulin; C004479:pimagedine