The role of metabolism in the generation of plasma insulin oscillations was investigated by simultaneous in vivo recordings of oxygen tension (pO 2 ) in the endocrine and exocrine pancreas and portal blood insulin concentrations in the anesthetized rat. At the start of the experiment, the blood glucose concentration of seven rats was 6.2 ؎ 0.1 mmol/l and the arterial blood pressure was 116 ؎ 5 mmHg. These values did not differ from those obtained at the end of the experiment. Islet pO 2 was measured by impaling superficially located islets with a miniaturized Clark electrode. The pO 2 measurements revealed slow (0.21 ؎ 0.03 min ؊1 ) with superimposed rapid (3.1 ؎ 0.3 min ؊1 ) oscillations. The average pO 2 was 39 ؎ 5 mmHg. Simultaneous recordings of pO 2 in the exocrine pancreas were significantly lower (16 ؎ 6 mmHg), but showed a slow and a rapid oscillatory activity with similar frequencies as seen in the endocrine pancreas. Corresponding measurements of portal insulin concentrations revealed insulin oscillations at a frequency of 0.22 ؎ 0.02 min ؊1 . The results are the first in vivo recordings of an oscillatory islet parameter with a frequency corresponding to that of plasma insulin oscillations; they support a primary role of metabolic oscillations in the induction of plasma insulin oscillations. Diabetes 51:699 -703, 2002 T he regular variations in blood concentrations of insulin, with a typical duration of 5-10 min (1-4), are critical to the hormone's effect in lowering blood glucose (5-10). Despite this importance of insulin oscillations, their generation is still unclear. Oscillations of similar duration have been detected in the secretion of insulin from single isolated islets (11,12). Regular plasma insulin variations are therefore believed to be the result of coordinated secretory activities of the islets of Langerhans in the pancreas (10,13-16). In addition, oscillations in the cytoplasmic Ca 2ϩ concentration ([Ca 2ϩ ] i ) and oxygen tension (pO 2 ) have been shown to be correlated with pulsatile insulin release from isolated islets (12,(17)(18)(19)(20)(21). Therefore, rhythmic changes in ionic fluxes and metabolism are considered to be important for the regulation of plasma insulin oscillations. However, so far these slow in vitro oscillations of [Ca 2ϩ ] i and pO 2 have not been demonstrated in vivo. In the present study, we performed in vivo measurements of pO 2 in rat pancreatic islets and in adjacent exocrine tissue and simultaneously determined portal vein insulin concentrations.
RESEARCH DESIGN AND METHODS
Materials.Reagents of analytical grade and water purified by a Milli-Q filter (Millipore, Bedford, MA) were used. Tetramethylbenzidine and insulin peroxidase were purchased from Sigma (St. Louis, MO); aprotinin (Trasylol), from Bayer (Leverkusen, Germany); and heparin, from Leo/Løvens (Ballerup, Denmark). The rat insulin standard was obtained from Novo Nordisk (Bagsvaerd, Denmark). IgG-certified microtiter plates were purchased from Nunc (Roskilde, Denmark). The antibodies to insulin...