Hormone Regulation of Glucose Metabolism in the Genetically Obese-Diabetic Mouse (db/db): Glucose Metabolism in the Perfused Hindquarters of Lean and Obese Mice

Abstract

Glucose metabolism and insulin sensitivity in the skeletal muscle of genetically obese-diabetic mice (db/db) 5-6 wk of age (an early stage of the diabetes-obesityc syndrome) were examined using an in situ perfused hindquarter preparation. Rates of glucose uptake, 14CO2 production from (U-14C) glucose, and lactate production from glucose were all lower in muscles from dbldb mice than those from their lean littermates. Lactate production in muscle perfused without exogenous glucose was similar in both lean and obese mouse hindquarters. Likewise, epinephrine, which activated phosphorylase equally in both lean and obese mouse muscle, also elevated the tissue glucose-6-phosphate level and lactate production from endogenous source(s) to a similar degree in the two preparations. However, epinephrine was less effective In stimulating glucose uptake in the db/db mouse preparation. Glucose uptake was lower in the obese mouse hindquarter at all insulin concentrations tested (0-1000 μU/ml). The half-maximally effective dose of insulin (50 μU/ml) remained unaltered, however, indicating a decrease in insulin responsiveness rather than sensitivity. Both basal and insulin (1 mU/ml)-stimulated (3H)-D-allose uptake In the dbldb mouse hindquarter were below normal. No difference in assayed hexokinase activity was observed. Muscle pyruvate dehydrogenase and glycogen synthase activities were elevated by insulin (1 mU/ml) to a similar extent in both lean and obese mice. These findings suggest that at an early phase of development when obesity, hyperglycemia, and hyperinsulinemia are moderate, a defect in glucose transport plays a major role in the “insulin resistance” of the skeletal muscles of dbldb mice.