Insulin resistance is one of the key features of
non-insulin-dependent diabetes mellitus (
NIDDM). Therefore, a
drug that causes an improvement in
insulin sensitivity would be of great interest for the treatment of
NIDDM. In addition to the
insulin-sensitizing
thiazolidinediones, we have found another class of
insulin-sensitizing agents: the alpha-activated carbonic
acids. (-)-
BM 13.0913, a member of this class, was effective in improving
insulin resistance in hyperinsulinemic and hypoinsulinemic
insulin-resistant animal models of
NIDDM. The 50% effective dose (ED50) for the
glucose-lowering action was 4, 2.4, and 8 mg/kg in ob/ob, yellow KK, and db/db mice, respectively. The ED50 for the
insulin-lowering action was 14.5, 5, and 26 mg/kg. This rightward shift of the dose-response curve for
insulin indicates that improving
glucose homeostasis is the primary effect of the
drug, followed by an
insulin-decreasing action. This effect on
glucose homeostasis may be brought about by sensitizing peripheral target tissues to the effects of
insulin. An increase in
deoxyglucose uptake and
glucose oxidation measured in adipocytes from rats that had been treated for 14 days with (-)-
BM 13.0913 supports this conclusion.
Glucose uptake and oxidation was increased at all
insulin concentrations tested, suggesting an improved responsiveness.
Insulin sensitivity in adipocytes was not influenced by the
drug. Studies in the moderately hypoinsulinemic, low-dose
streptozotocin (STZ) diabetic rat with a residual
insulin concentration showed a decrease in
blood glucose concentrations, as well as a decrease in urinary
glucose.(ABSTRACT TRUNCATED AT 250 WORDS)