We have examined the effect of chronic (20 days)
oral administration of
benfluorex (35 mg/kg) in a rat model of
NIDDM, induced by injection of STZ 5 days after birth and characterized by frank
hyperglycemia, hypoinsulinemia, and hepatic and peripheral
insulin resistance. We assessed the following: 1) basal
blood glucose and
insulin levels, 2)
glucose tolerance and
glucose-induced
insulin release in vivo and in vitro, and 3) basal and
insulin-stimulated in vivo
glucose production and
glucose utilization, using the
insulin-clamp technique in conjunction with isotopic measurement of
glucose turnover. The in vivo
insulin response of several individual tissues also was evaluated under the steady-state conditions of the clamp, using the uptake of the
glucose analogue
2-deoxy-D-glucose as a relative index of
glucose metabolism. In the
benfluorex-treated diabetic rats, postabsorptive basal plasma
glucose levels were decreased (8.1 +/- 0.2 mM compared with 10.5 +/- 0.5 mM in the pair-fed untreated diabetic rats and 6.1 +/- 0.2 mM in the
benfluorex-treated nondiabetic rats), whereas the basal and
glucose-stimulated intravenous
glucose tolerance test plasma
insulin levels were not improved. Such a lack of improvement in the
glucose-induced
insulin release after
benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the pair-fed untreated diabetic rats, the basal
glucose production and overall
glucose utilization were significantly increased, and during
hyperinsulinemia both liver and peripheral tissues revealed
insulin resistance. In the
benfluorex-treated diabetic rats, the basal
glucose production and basal overall
glucose utilization were normalized. After
hyperinsulinemia,
glucose production was normally suppressed, whereas overall
glucose utilization was not significantly improved.(ABSTRACT TRUNCATED AT 250 WORDS)