Troglitazone and D-chiroinositol have been shown to exert
antidiabetic effects by either potentiating or mimicking
insulin action. We studied whether pretreatment with these compounds can prevent the deleterious effects of
glucosamine on
insulin action that may play an important role in
hyperglycemia-induced
insulin resistance. Normal Wistar rats were pretreated with
troglitazone (100 mg/kg/
d), D-chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days.
Glucosamine (50 micromol/kg/min) was then infused for 210 minutes, and a euglycemic
glucose clamp was performed during the last 120 minutes. Pretreatment with
troglitazone or D-chiroinositol had no effect on fasting plasma
glucose or
insulin or basal hepatic
glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L) clamp condition, HGO in
glucosamine-infused placebo-treated rats was not suppressed, but instead was increased over the basal level, indicative of hepatic
insulin resistance. In contrast, HGO failed to increase during
glucosamine infusion in rats pretreated with
troglitazone but was not normally suppressed. This may indicate a partial improvement in the hepatic
insulin resistance. D-Chiroinositol pretreatment had no effect on the
glucosamine-induced increase in HGO. The
glucose disposal rate (GDR) was 25% lower in rats infused with
glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min), indicative of peripheral
insulin resistance. Pretreatment with D-chiroinositol (34.5+/-2.3 mg/kg/min) prevented the
glucosamine-induced decrease in the GDR, indicating an improvement in peripheral
insulin resistance.
Troglitazone (25.2+/-3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats,
glucosamine infusion induced hepatic and peripheral
insulin resistance; (2) D-chiroinositol, but not
troglitazone, pretreatment prevented
glucosamine-induced peripheral
insulin resistance; and (3)
troglitazone, but not D-chiroinositol, partially blocked the
glucosamine-induced hepatic
insulin resistance. D-Chiroinositol may provide a novel pharmacological approach to
hexosamine-induced peripheral
insulin resistance.