Chronic administration of theophylline to rats induces a post-insulin binding defect in adipocyte glucose transport

Abstract

To determine whether adenosine is involved in long-term regulation of glucose transport in adipose tissue, we have investigated effects of administration of an adenosine receptor antagonist (theophylline) on adipocyte glucose transport. Rats were injected with theophylline (30 mg/kg, dissolved in 0.9% NaCl) daily for 7 days. Controls were injected with saline. The rats were then killed, and epididymal adipocytes were isolated. Insulin-stimulated glucose transport rates were decreased by about 25%-30% in the cells from theophylline-treated rats at all insulin concentrations tested. The half-maximally effective concentration of insulin was not altered (6.5 +/- 0.5 and 6.7 +/- 0.5 mU/l in control and treated cells respectively), suggesting a post-insulin binding defect. This was confirmed by the finding that 125I-insulin binding to the cells was not altered. Adenosine receptor number and affinity (measured on detergent-solubilized adipocyte extracts using 125I-hydroxyphenylisopropyl adenosine) was also not changed by theophylline treatment. We conclude that theophylline administration causes decreased glucose transport rates in rat adipocytes at a post-insulin binding level. Thus, chronic adenosine receptor blockade impairs adipocyte glucose transport, suggesting that adenosine is involved in long-term regulation of glucose metabolism in adipose tissue.

Adenosine and the regional differences in adipose tissue metabolism in women

“…Therefore, the change in total tissue content of adenosine probably re¬ flects the changes in the effective extracellular concentration of the nucleoside. The higher ade¬ nosine concentration in femoral adipose tissue in menstruating women could explain its higher lipoprotein lipase activity and tendency to accu¬ mulate fat, as adenosine is known to inhibit lipolysis (Ohisalo et al 1984) and to stimulate lipopro¬ tein lipase activity (Ohisalo et al 1981) and glu¬ cose uptake (Schwabe et al 1973;Joost & Stein¬ felder 1982;Green 1987). During lactation, the lower extracellular adenosine concentration would allow lipid mobilization preferentially from the femoral site.…”

“…It is known to inhibit cAMP accumulation and lipolysis in human adipocytes (Ohisalo et al 1984) and to stimulate lipoprotein lipase activity in rat adipose tissue (Ohisalo et al 1981). Adenosine has also been shown to stimulate glucose uptake (Schwabe et al 1973;Joost & Steinfelder 1982;Green 1987). It exerts its effects via specific plasma membrane receptors (Londos & Wolff 1977;Londos et al 1980;Daly 1985).…”

Direct Effects of Caffeine and Theophylline on p110δ and Other Phosphoinositide 3-Kinases

“…These compounds have been the subject of intense study to determine how they act at physiological concentrations, and a number of effects have been ascribed to these compounds at such concentrations including stimulation of muscle contraction levels (1), anti-inflammatory and immunomodulatory effects (2), alterations in glucose metabolism (3)(4)(5)(6)(7)(8), attenuation of the antilipolytic effect of insulin (3), and induction of apoptosis (9,10). Several mechanisms of action have been identified for these methylxanthines, and these can explain some of the pleiotropic effects these compounds have on cells at their physiologically achievable concentrations.…”

Caffeine's impairment of insulin‐mediated glucose disposal cannot be solely attributed to adrenaline in humans

“…While caffeine has been reported to decrease the activity of a number of insulin signalling intermediates (e.g. PI3K and Akt), without affecting insulin binding within adipose tissue (Green, 1987; Akiba et al 2004), this does not seem to occur in human skeletal muscle (Thong et al 2002). Nevertheless as observed with adrenaline, a decrease in both the number and accessibility in GLUT4 transporters has been documented in both adipose (Steinfelder & Petho‐Schramm, 1990; Akiba et al 2004) and skeletal muscle tissues (Han et al 1998).…”