ROLE OF A1 ADENOSINE RECEPTORS IN INSULIN RESISTANCE OF THE OBESE

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The long range goal of the proposed studies is to understand the molecular basis for insulin resistance frequently observed in obese hypertensive individuals. The nature of the connection between obesity and insulin resistance is unclear, despite intensive investigation of the problem. The first specific aim of this proposal is to find out whether an A1 Adenosine antagonist, theophilline improves insulin sensitivity in obese insulin-resistant individuals. A second aim is to evaluate the correlation between interstitial adenosine levels and insulin resistance in lean and obese individuals. The third aim is to evaluate the source of possible high levels of adenosine in the extracellular space of obese diabetic individuals. One source may be sympathetic synaptic vesicles that contain high levels of ATP that then break down to adenosine in the extracellular space. To accomplish these aims, we plan to microdialyze muscles of obese individuals, formerly obese individuals who have lost more than fifty pounds, and lean control individuals. Thus far (February 1998), we have microdialyzed muscles of four lean (control) individuals, three males and one female. To achieve specific aim 1, glucose uptake into muscle from microdialysis tubing has been measured in the presence and absence of theophilline and in the presence and absence of saturating insulin in the dialysate. At the same time, to achieve specific aim 2, adenosine and norepinepherine levels in dialysate emerging from the muscle have been measured. To achieve specific aim 3, patients have performed rhythmic arm exercise as the protocol is repeated. Arm exercise evokes sympathetic excitation, thereby increasing norepinephrine and ATP release. The ATP is converted to adenosine by enzymes in the interstitium. Adenosine and norepinephrine then diffuse into the dialysate fluid where they can be measured by HPLC techniques. To facilitate achievement of these aims, we have devised an innovated sheme to measure insulin stimulated glucose uptake from microdialysis probes. The scheme takes advantage of the availability of radiolabeled L-glucose, the stereoisomer of naturally occurring D-glucose as a control for metabolite disappearance from the probe, unrelated to metabolism. Data from control individuals demonstrate the utility of this method for quantitating in vivo muscle insulin dependent glucose uptake and demonstrate a very significant stimulation of insulin dependent glucose by theophilline, however, thus far no increase in interstitial adenosine with exercise has been observed.