Peripheral insulin resistance in type II diabetes mellitus has been attributed to alterations in skeletal muscle glucose metabolism. However the direct dose-response relationship between insulin and glucose transport has not yet been studied in human skeletal muscle. We investigated 3-0-methylglucose transport in in vitro incubated skeletal muscle strips from eight healthy controls (age 61 +/- 6 yrs) and six lean type II diabetic patients treated with oral antidiabetic medication (age 73 +/- 3 yrs). Rectus abdominis muscle samples (approximately 1 g), obtained during elective abdominal surgery, were clamped at their resting length in vivo, whereupon strips (20-50 mg) were prepared for in vitro incubation. Measurements of high-energy phosphates and glycogen levels revealed that the muscle strips maintained energy levels during the incubation period. Glucose transport responded to insulin in a dose-response manner in the control group, with a 2-fold increase following maximal stimulation. Muscle strips from the diabetic group demonstrated a marked decrease in the insulin dose-response curve (P less than 0.01), when compared to healthy muscle strips. At a maximal insulin concentration (10,000 microU x ml-1), the response of the diabetic muscle tissue was 50% less than that of the healthy control tissue (P less than 0.05). This report demonstrates a dose-response curve for insulin stimulated 3-0-methylglucose transport in in vitro incubated human skeletal muscle strips. Furthermore, in type II diabetic muscle, our results provide evidence for one or several defects at a postreceptor level.

Catecholamine-induced lipolysis in isolated human adipocytes during the first year of life was investigated. During this period fat cell size increased markedly. Basal and catecholamine-induced glycerol release were positively correlated with age when lipolysis was expressed per cell. However, when lipolysis was expressed per unit of cell surface area (micrometer squared), this correlation was observed only for noradrenaline. Basal lipolysis and the effect of the pure beta-agonist, isoprenaline, were identical in infants and adults. From 0 to 2 mo of age noradrenaline had very little lipolytic effect. The addition of the alpha-2-adrenoceptor antagonist, yohimbine, to noradrenaline equalized lipolysis per micrometer squared in infants and adults and the alpha-2-adrenoceptor sensitivity was significantly enhanced in infants. In both groups the lipolytic adrenoceptor was of the beta-l type. In conclusion, adipocytes from infants have a poor lipolytic response to noradrenaline partly because of the small fat cells but mainly because of an enhanced alpha-2-adrenoceptor activity.

Catecholamine-regulation of lipolysis and beta-adrenoceptor binding isoterms were studied in human sc and omental isolated fat cells from 24 subjects undergoing elective cholecystectomy. The lipolytic sensitivity of the nonselective beta-agonists epinephrine and isoprenaline as well as the selective agonists norepinephrine (beta 1) and terbutaline (beta 2) was significantly increased 5-10 times in omental fat cells. On the other hand, no regional difference in antilipolytic sensitivity was seen for the alpha 2 agonist clonidine. No regional difference in lipolytic action was seen when measuring the effect of forskolin, (Bu)2cAMP or enprofylline, which act at different postadrenoceptor steps in the lipolytic cascade. Lipolysis data showed no sex differences. A beta 1-pattern was seen in both regions when lipolysis dose-response curves were arranged in order of potency. Radioligand saturation experiments with the nonselective beta-antagonist 125I-cyanopindolol and competition experiments between this radioligand and the selective antagonists CGP-20,712-A (beta 1) and ICI-118551 (beta 2) showed a 2-fold increase in the amount of beta 1- and beta 2-adrenergic receptors in omental as compared to sc fat cells (P less than 0.02). Competition studies with the same radioligand and the nonselective beta-agonist isoprenaline showed no regional differences in terms of receptor affinity (Kd high 10 nM and Kd low 1 microM) or in relative fraction of receptors in the high affinity state (35%). It is concluded that an increased lipolytic sensitivity for beta 1- and beta 2-agonists can be due to an increase in the amount of the two adrenoceptor subtypes in omental fat cells and thereby explain why catecholamines are more lipolytic in omental cells than in sc fat cells.