In 1980 we described an in vivo method for estimating the rate of glucose uptake among selected tissues during an acute insulin response. The method was based upon the same principles as Sokoloff's 2-deoxyglucose (2DG) method. We now report further examination of the basic assumptions of the model and validation of its general applicability by comparing the response of brain and other tissues to prolonged insulin infusion (while glucose is held constant) with their response to a single injection of insulin. The method provides a reproducible estimate of relative insulin response in any tissue that can be anatomically separated at death. Tissues that are minimally sensitive to insulin such as spleen, lung, skin, and gut do not display increments in the calculated value for net rate of tissue uptake of 2DG. Insulin-sensitive tissues display increased rates of uptake that are characteristic for each specific tissue, ranging in magnitude from 1.7- to 17.9-fold over basal among an array of insulin-sensitive tissues. The duration of a unit response to a sub-maximal dose of insulin also varied among the tissues, persisting for 20-30 min after plasma insulin had returned to basal in heart and for 10-20 min in the other insulin-sensitive tissues. The method provides a reproducible measure of glucose metabolism in vivo and has been validated as a means of quantifying relative insulin sensitivity among the peripheral tissues. During steady-state conditions with plasma glucose held constant, brain glucose metabolism was unaffected by a 60-min infusion of insulin.
We have tested the hypothesis that insulin affects the metabolism of the hypothalamus by examining the uptake of labeled insulin by rat brain structures in vivo and the responsiveness of the metabolism of rat brain to the addition of insulin in vitro. The uptake of immunoprecipitable [ I25 I]-iodoinsulin by ventral medial, lateral and far lateral segments of hypothalamus, median eminence, basal ganglia, and cerebral cortex was compared to that of two insulin-sensitive tissues, pituitary and heart muscle. Of the brain tissues only median eminence, in the region of the primary plexus, displayed significant uptake over background. Heart muscle displayed an uptake of insulin 3 times greater than median eminence and 10 to 20 times greater than the brain tissues.The uptake, oxidation and formation of lipid from [ 14 C]glucose in slices of anterior and posterior hypothalamus and cortical grey matter failed to respond to insulin in vitro while diaphragm muscle from the same rats responded to insulin under identical conditions. The data fail to support the hypothesis and suggest that insulin does not directly interact with the neurons in hypothalamic nuclei but rather acts indirectly to affect hypothalamic function. The data suggest that insulin may interact with receptors in the median eminence, or other circumventricular organs, transmitting information via neuronal pathways to deeper brain centers. Alternatively, we cannot exclude the possibility that insulin might directly alter the permeability of the blood-brain barrier for nutrients in the hypothalamic region. {Endocrinology 101: 605, 1977) S EVERAL investigations have provided indirect evidence that control systems integrated within the hypothalamus are influenced by insulin. Mayer (1) was the first to postulate that the glucoreceptors of the hypothalamus concerned with feeding behavior were insulin-sensitive structures. This hypothesis was tested by Debons et al.(2), who demonstrated that diabetic mice were resistant to hypothalamic damage by gold thioglucose unless they were treated with insulin. Insulin injected directly into the hypothalamus also restored sensitivity to gold-thioglucose (3). Szabo and Szabo (4) have shown that intracarotid injection of insulin results in a change of peripheral blood glucose which they ascribe to an effect of insulin within the central nervous system upon glucoregulatory systems. A number of investigators have demonstrated
The hypothesis that insulin might promote increased glucose metabolism in putative glucoreceptor areas of the brain was investigated in the rat. Using tritiated 2-deoxyglucose (2-DG), unanesthetized fasted rats were injected with 0.1 U insulin and studied 30 min later. The local uptake of 2-DG into discrete brain areas was examined in serial frozen 400-micrometer sections. Areas 1.1 mm in diameter were punched from the region of the ventral medial, ventral lateral, and dorsal hypothalamus and from a control area from the cerebral cortex. The punched tissue segments were analyzed for total radioactivity and protein content. The results showed that insulin failed to influence the pattern of 2-DG uptake into these discrete brain regions. When the data were analyzed with a simple kinetic model to determine the net fractional rate of uptake of 2-DG by the tissues, brain tissues displayed a 75% rate increase compared to saline-treated controls. Heart muscle collected from the same rats showed a 700% increase after insulin, while lung, an insulin insensitive tissue, displayed a 30% increase. Because the nonsteady state conditions of the model dictate a number of assumptions, the modest increase in the calculated rate of uptake in brain tissue must be verified by a steady state model before it can be accepted as representing a real effect of insulin upon the overall metabolism of glucose in the brain. Regardless of these reservations, it may be concluded from the pattern of response, that insulin does not selectively increase glucose uptake or metabolism in the putative glucoreceptor areas of the hypothalamus under the conditions of these experiments.
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