Enhanced diabetogenic effect of streptozotocin in mice overexpressing UCP-3 in skeletal muscle.
Diabetic patients exhibit varying degrees of increased muscle UCP-3 expression in skeletal muscle and, in rodents, the pancreatoxin streptozotocin (STZ) upregulates UCP-3 mRNA in skeletal and cardiac muscles. We have investigated the development of STZ-induced diabetes in transgenic mice overexpressing UCP-3 in skeletal muscle in order to provide further insight on the functional role of muscle UCP-3. UCP-3 transgenic mice treated with STZ (UCP3-STZ) showed a significant increase in blood glucose concentration 3 days after the last dose of STZ with a progressive induction of diabetes, attaining blood glucose concentrations of 24.7 +/- 1.5 mmol/L on day 17. Wild-type mice treated with STZ (WT-STZ) only started to show an increase in blood glucose concentration 6 days after the last dose of STZ and peaked on day 17 at a lower concentration than in the UCP-STZ mice. The pancreatic insulin content of UCP-3 control mice (UCP3-CON) was decreased relative to wild-type control mice (WT-CON), and STZ reduced the total pancreatic insulin content by 72% in WT-STZ mice and by 88% in UCP3-STZ mice. In an insulin tolerance test, blood glucose concentrations declined more in the UCP-3 transgenic mice than in the wild-type mice. Mice overexpressing UCP-3 in skeletal muscle have a lower pancreatic insulin content, but tend to be more insulin-sensitive. These twin actions result in an increased susceptibility to STZ-induced diabetes in UCP-3 transgenic mice.
Wang
Steven
S
Clore Laboratory, University of Buckingham, United Kingdom. steven.wang@buckingham.ac.uk
Cawthorne
Michael A
MA
Clapham
John C
JC
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007473:Ion Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D010179:Pancreas / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology*; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D013311:Streptozocin