INTRACEREBROVENTRICULAR ADMINISTRATION OF SOMATOSTATIN OCTAPEPTIDE COUNTERACTS THE HORMONAL AND METABOLIC RESPONSES TO STRESS IN NORMAL ANDDIABETIC DOGS

Intracerebroventricular (ICV) injection of carbachol elicits hormonal and metabolic responses similar to moderate stress. In normal dogs, IC V carbachol stimulated marked counterregulatory hormone release, but a ltered plasma glucose only marginally because the marked increment in glucose production (R(a)) was almost matched by the increment of utili zation (R(d)), even though plasma insulin was unchanged. In alloxan-di abetic dogs, R(d) did not match R(a) and plasma glucose increased subs tantially. Since somatostatin octapeptide (ODT8-SS) inhibits some symp athetic mechanisms of the stress response, we explored the extent to w hich ODT8-SS can alleviate the counterregulatory responses to stress i nduced by carbachol, and particularly whether it can restore glycemic control in diabetes. ODT8-SS (20 nmol) was ICV-injected (1) in normal dogs (n = 5), and (2) prior to ICV carbachol before (n = 7) and after (n = 6) the induction of alloxan-diabetes. ODT8-SS did not affect basa l values, but when administered before ICV carbachol there were no sig nificant increments in plasma epinephrine, cortisol, arginine vasopres sin (AVP), insulin, glucose, or lactate. There were significant increa ses in norepinephrine, glucagon, R(a), R(d), and the glucose metabolic clearance rate (MCR), although they were much smaller than seen previ ously with ICV carbachol alone. After induction of alloxan-diabetes, R (d) and MCR did not change with ICV ODT8-SS and carbachol as in normal dogs, but norepinephrine, epinephrine, glucagon, lactate, plasma gluc ose, and R(a) increased, although with the exception of glucagon these increases were much smaller than seen previously with ICV carbachol a lone. ODT8-SS administered before ICV carbachol in normal or diabetic animals resulted in increased free fatty acid (FFA) levels. The increa ses in glycerol were less than and those in FFA greater than seen prev iously with ICV carbachol alone. Since ODT8-SS does not alter basal co unterregulatory hormone release but suppresses the release during stre ss, this is a useful probe to analyze some of the metabolic responses to stress. When the response to carbachol from our previous report is compared with the responses to carbachol + ODT8-SS. it is indicated th at the stress-related increase in R(a) was consistent with stimulation of the sympathetic nervous system, whereas increased R(d) is related to an unknown stress-related neuroendocrine mechanism that requires a permissive effect of insulin. since it was not seen in the frankly dia betic animals. We hypothesize that the stress-induced increase in R(d) occurs not only in muscle but also in adipocytes, and that the somato statin-induced attenuation of R(d) decreased FFA re-esterification and consequently markedly increased stress-induced FFA release. Although ODT8-SS substantially decreased the R(a) response in diabetic dogs, th e hyperglycemic effect of carbachol is only partially attenuated. Thus , in diabetes moderate stress can disturb glucose homeostasis substant ially even when the sympathetic nervous system has been markedly suppr essed. Copyright (C) 1994 by W.B. Saunders Company