INTERACTION BETWEEN BTBR AND C57BL 6J GENOMES PRODUCES AN INSULIN-RESISTANCE SYNDROME IN (BTBR X C57BL/6J) F1-MICE/

Insulin resistance is a common syndrome that often precedes the develo pment of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR and C57B L/6J (B6) mice have normal insulin responsiveness and normal fasting p lasma insulin levels. However, a cross between these two strains yield ed male offspring with severe insulin resistance. Surprisingly, on a b asal diet (6.5% fat), the insulin resistance was not associated with f asting hyperinsulinemia. However, a 15% fat diet produced significant hyperinsulinemia in the male mice (twofold at 10 weeks; P < .05). At 1 0 weeks of age, visceral fat contributed approximately 4.3% of the tot al body weight in the males versus 1.8% in females. In the males, leve ls of plasma triacylglycerol and total cholesterol increased 40% and 3 0%, respectively, compared to females. Plasma free fatty acid concentr ations were unchanged. Oral glucose tolerance tests revealed significa nt levels of hyperglycemia and hyperinsulinemia 15 to 90 minutes after oral glucose administration in the male mice. This was particularly d ramatic in males on a 15% fat diet. Glucose transport was examined in skeletal muscles in (BTBRxB6)F-1 mice. In the nonhyperinsulinemic anim als (females), insulin stimulated 2-deoxyglucose transport 3.5-fold in the soleus and 2.8-fold in the extensor digitorum longus muscles. By contrast, glucose transport was not stimulated in the hyperinsulinemic male mice. Hypoxia stimulates glucose transport through an insulin-in dependent mechanism. This is known to involve the translocation of GLU T4 from an intracellular pool to the plasma membrane. In the insulin-r esistant male mice, hypoxia induced glucose transport as effectively a s it did in the insulin-responsive mice. Thus, defective glucose trans port in the (BTBRXB6)F-1 mice is specific for insulin-stimulated gluco se transport. This is similar to what has been observed in muscles tak en from obese NIDDM patients. These animals represent an excellent gen etic model for studying insulin resistance and investigating the trans ition from insulin resistance in the absence of hyperinsulinemia to in sulin resistance with hyperinsulinemia.