Glucose metabolism in perfused skeletal muscle. Demonstration of insulin resistance in the obese Zucker rat

Abstract

1. The effect of insulin (0.5, 10 and 50 munits/ml of perfusate) on glucose uptake and disposal in skeletal muscle was studied in the isolated perfused hindquarter of obese (fa/fa) and lean (Fa/Fa) Zucker rats and Osborne-Mendel rats. 2. A concentration of 0.5 munit of insulin/ml induced a significant increase in glucose uptake (approx. 2.5 mumol/min per 30 g of muscle) in lean Zucker rats and in Osborne-Mendel rats, and 10 munits of insulin/ml caused a further increase to approx. 6 mumol/min per 30 g of muscle; but 50 munits of insulin/ml had no additional stimulatory effect. In contrast, in obese Zucker rats only 10 and 50 munits of insulin/ml had a stimulatory effect on glucose uptake, the magnitude of which was decreased by 50-70% when compared with either lean control group. Since under no experimental condition tested was an accumulation of free glucose in muscle-cell water observed, the data suggest an impairment of insulin-stimulated glucose transport across the muscle-cell membrane in obese Zucker rats. 3. The intracellular disposal of glucose in skeletal muscle of obese Zucker rats was also insulin-insensitive: even at insulin concentrations that clearly stimulated glucose uptake, no effect of insulin on lactate oxidation (nor an inhibitory effect on alanine release) was observed; [14C]glucose incorporation into skeletal-muscle lipids was stimulated by 50 munits of insulin/ml, but the rate was still only 10% of that observed in lean Zucker rats. 4. The data indicate that the skeletal muscle of obese Zucker rats is insulin-resistant with respect to both glucose-transport mechanisms and intracellular pathways of glucose metabolism, such as lactate oxidation. The excessive degree of insulin-insensitivity in skeletal muscle of obese Zucker rats may represent a causal factor in the development of the glucose intolerance in this species.

Energy Homeostasis, Autonomic Activity and Obesity

“…Alternatively or additionally, the absence of the preabsorptive insulin response and increased baseline insulin concentrations may be explained as a combined consequence of increased vagal activity at younger age and insulin insensitivity during the increase in fat mass during the late phase of obesity (11,12,19,21,49). The increase in baseline glucose concentration in the old Zuckers combined with the steep increase in blood glucose levels during food ingestion (Table 2 and Figure 2) supports this idea of insulin insensitivity.…”

Dysregulation of glucose transport in hearts of genetically obese (fa/fa) Rats

“…post-receptor defects) also contributed to insulin resistance [% 9, 10]. In insulinresistant muscles, several such post-receptor defects have been described [4,7,[10][11][12][13][14]. In isolated soleus muscles of the genetically obese Zucker (fa/fa) rat the following post-receptor abnormalities have been shown: (a) increased utilization of endogenous fatty acids inhibitory to glycolysis [7]; (b) decreased uptake of the D-glucose analogue, 2-deoxy-D-glucose (2-DG) [4,7,12].…”

Insulin-Mediated Hemodynamic Changes Are Impaired in Muscle of Zucker Obese Rats

“…This muscle insulin resistance involves reduced insulin sensitivity as well as a blunted maximal responsiveness to insulin (8). In addition, it is apparent in vivo (7,9), in the perfused hindlimb (2,10), and in individual muscles once they have been isolated and incubated (8). Furthermore, glycolysis, glucose oxidation, and glycogen synthesis are all impaired in obese Zucker rats (8).…”

“…T he obese Zucker rat is a commonly used animal model of insulin resistance that exhibits many of the characteristics that coexist with type 2 diabetes in humans, including hyperinsulinemia (1), dyslipidemia (2), and hypertension (3). Obesity develops as a result of a recessive mutation in the gene for the leptin receptor (4).…”