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- Title
Plasminogen Activator Inhibitor-1 (PAI-1) Exerts Differential Effects on Hyperglycemia vs Obesity in Leptin Receptor-Deficient db/db Mice.
- Authors
Fogo, Agnes B.; Zhou, Jun; Declerck, Paul J.; Ma, Lijun
- Abstract
We have shown previously that deficiency of PAI-1 prevents obesity in a high fat diet-induced obesity model (Diabetes, 2004). In the present study, we explored whether manipulation of PAI-1 (pharmaceutical inhibition of PAI-1 or genetic PAI-1 deficiency) has metabolic effects in a genetic model of obesity and diabetes, the leptin-receptor-deficient mice (db/db). Male db/db mice (at age 6 wks) were treated for 8 wks with a neutralizing anti-PAI-1 antibody (MA-33H1F7, 5 mg/kg body weight) or a class-matched non-inhibitory control antibody (MA-32K3, 5 mg/kg) twice a week, and were sacrificed at age 14 wks. Metabolic parameters were measured in mice. For genetic deficiency of PAI-l, PAI-l-/- mice were crossbred with db/db mice to generate double knockout mice (PAI-1-/-,db/db), and were compared to their littermate control with intact PAI-1 till age 32 wks. Treatment with PAI-1 antibody for 8 wks in db/db mice attenuated the increase in blood glucose levels that developed in db/db mice receiving control antibody (239±31 mg/dl vs 301±35 mg/dl, p<0.05). PAI-1 antibody treatment had no effects on body weight (53.9±1.1 vs 54.0±1.0 g, p=NS). PAI-1 deficiency in db/db mice (PAI-l-/-,db/db) resulted in lower blood glucose levels at age 32 wks compared to control PAI-1 intact db/db mice (205±44 vs 527±46 mg/dl, p<0.01), but paradoxically even increased body weight (72.7±3.2 vs db/db 51.4±2.1 g, p<0.01). We conclude that inhibition of PAI-1, whether pharmaceutical or genetic, improved hyperglycemia in a genetic obese db/db model. These results were in contrast to effects on obesity, which even increased in PAI-1-/-. These data further confirm that inhibition of PAI-1 might offer a novel therapeutic approach to ameliorate the diabetic state, and that mechanisms are not linked to effects on obesity. ADA-Funded Research
- Publication
Diabetes, 2007, Vol 56, pA452
- ISSN
0012-1797
- Publication type
Academic Journal