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

Abstract

Summary. Overall D-glucose metabolism and 3-0-methylglucose transport were measured in the perfused heart preparation of lean and genetically obese (fa/fa) rats. Absolute values of basal and insulin-stimulated glucose metabolism were decreased in hearts of 15-week-old obese rats when compared to lean age-matched controls. Basal and maximally stimulated (i. e., by the combined addition of insulin and increasing perfusion pressure) 3-0-methylglucose transport was normal in hearts from young obese rats (5-week-old). However, when only one stimulus was used (insulin or increasing perfusion pressure alone), 3-0-methylglucose transport was stimulated to values that were lower than those of lean rats. Basal 3-0-methylglucose transport was four times lower in hearts from older obese rats (15-week-old) than in lean ones of the same age. At this age, stimulation of 3-0-methylglucose transport by insulin alone, by increasing perfusion pressure alone or by the combination of both stimuli, reached values in obese rats that were only half those of lean animals. It is concluded that: (a) in the early phase of the syndrome, the basal glucose transport system in hearts of obese rats is normal, but its response to stimulation becomes abnormal and; (b) at a later phase of obesity, the glucose transport system becomes abnormal even under basal conditions and its responsiveness to various stimuli is markedly impaired.Key words: Perfused heart; genetically obese rats; glucose transport; insulin; perfusion pressure.Obesity in man and laboratory animals is usually associated with hyperinsulinaemia and insulin resistance [1]. It was initially thought that the major cause of insulin resistance in obese hyperinsulinaemic animals was the decreased ability of plasma membranes of liver [2][3][4][5], adipose tissue [6] and muscle [4,7] to bind insulin, an abnormality that could be accounted for by a decrease in specific insulin receptor number [8]. Subsequent studies have suggested that additional defects unrelated to the insulin receptors (i.e. 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]. In the perfused hindquarter of obese hyperglycaemic (db/db) mice the existence of a post-receptor defect at the level of glucose transport (again measured with 2-DG) has been proposed to be the major cause of insulin resistance [15]. Thus the evidence that insulin resistance could be partly attributed to defectual glucose handling has been indirect, based either on overall glucose metabolism or on 2-DG glucose uptake.Studies carried out with 2-DG have two major drawbacks: (a) 2-DG is not only taken up but phosphorylated [16]; (b) t...

Dysregulation of glucose transport and transporters in perfused hearts of genetically obese (fa/fa) rats

“…1). These findings corroborate those of others made in other muscle types [4][5][6] and suggest that, although the heart is not representative of the muscle mass, it may undergo -upon the occurrence of insulin resistance -changes that are analogous to those seen in other muscles. This strengthens the observations made during the present study, with regard to the state of the glucose transporters as assessed by the cytochalasin B-binding assay.…”

“…With regard to glucose uptake, it has been shown that basal, as well as insulin-stimulated glucose uptake, was decreased in most obesity syndromes studied [2,[4][5][6]. As is now well established in adipocytes [8,9] and also described in muscle [10], glucose transporting molecules (glucose transporters) are present both in the plasma and in some intracellular (microsomal) membranes.…”

“…It has been demonstrated to be present in vitro as well as in vivo (reviewed in 1), and bears on insulin receptor number [2]; insulin receptor autophosphylation [3]; glucose uptake [4,5]; glycolysis [4][5][6] and glycogen synthesis [7].…”

Effect of work-induced hypertrophy on muscle glucose metabolism in lean and obese mice

“…Thus, work-induced hypertrophy was able to compensate for decreased insulin responsiveness observed in GTG-obese muscles. Additive effects of insulin and work induced by pressure were also observed in perfused hearts from obese Zucker rats [29]. The mechanisms of such effects of exercise are unknown.…”

Insulin‐dependent translocation of the small GTP‐binding protein rab3C in cardiac muscle: studies on insulin‐resistant Zucker rats

“…Fhe genetically obese OCa/fa) Zucker rat is a well-documented animal model for insulin resistance in skeletal [1,2] and cardiac m~tscle [3,4]. It has been suggested that a defect of the glucose ur take itself may contribute besides other defects to this insulin re,4stance [5,6].…”