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The regulation of net hepatic glucose uptake in vivo occurs by way of the hormonal milieu (insulin and glucagon), the glucose level, and the route of glucose delivery. Hyperglycemia in the absence of changes in pancreatic hormones (i.e., increased insulin and/or decreased glucagon) does not elicit significant glucose uptake by the liver. Net hepatic glucose uptake is augmented in a dose-dependent manner by a rise in insulin and is further stimulated by the presence of a "portal signal." The presence of coordinated changes in insulin, glucagon, and the glucose level in combination with the "portal signal" ensures adequate glucose uptake by the liver in response to a meal.
During cerebral ischemia, hyperglycemia has a deleterious effect upon the adult brain but not the neonatal brain. This phenomenon may be related to the fact that hyperglycemia in adult animals subjected to cerebral ischemia raises the ischemic accumulation of lactate by as much as 10-fold. The purpose of this study was to determine whether hyperglycemia during cerebral ischemia produces a similar increase in the rate of lactic acid accumulation in developing animals. Data from in vivo proton magnetic resonance spectroscopic experiments showed that blood glucose concentration did not affect the rate of lactic acid accumulation during cerebral ischemia in either the neonatal dog or juvenile rabbit. The lack of increase in the ischemic rate of lactic acid accumulation during hyperglycemia in the developing animal contrasts sharply with the marked effect of blood glucose concentration upon the rate of lactic acid accumulation in the adult animal. Differences in the total amount of lactic acid formed and the rate at which it is accumulated may contribute, in part, to the greater tolerance of the young animal to cerebral ischemia.
Increases in the glucose level in the absence of the portal signal or changes in insulin elicits little if any glucose uptake by the liver. NHGU is augmented by a rise in insulin (or drop in glucagon) and is further stimulated by the presence of a portal signal. Under postprandial conditions, NHGU will depend on the dynamic interaction between the pancreatic hormones, glucose and the portal signal. Moreover, in a simulated postprandial environment, the quantitative impact of the portal signal is at least as important as that of insulin. The presence of the portal signal should be of physiologic benefit because it will allow adequate net removal of glucose by the liver without requiring excessive excursions of insulin and glucose. The metabolic fate of ingested glucose within the liver is still controversial. It appears that the liver will remove 30-40% of the glucose that enters the portal vein following an oral glucose load and will replete its glycogen stores by both direct and indirect pathways. Whether the three-carbon precursors utilized by the indirect route are of hepatic or peripheral origin remains a matter of debate. Studies are under way to elucidate whether the hepatic response to the portal signal involves the autonomic nervous system, the nature of the interaction of the portal signal and insulin, and the metabolic fate of glucose removed by the liver in response to this signal.
The content and distribution of the 26-to 38-kDa surfactant protein (SP-A) and its mRNA were determined in fetuses of control and streptozotocin (STZ)-treated Sprague-Dawley rats using immunohistochemistry, RNA blotting, and in situ hybridization. Female rats were treated with 50 mg/kg STZ before mating, and the fetuses were killed at fetal days 18-21 or on neonatal days 1 and 2 (day of birth = end of day 22). SP-A was barely detectable on fetal day 18 in controls and easily detected by fetal day 21. In the STZ group, SP-A was decreased compared with controls at fetal days 18-21. However, by neonatal days 1-2, there were no significant differences in SP-A levels between groups. SP-A mRNA was detectable at fetal day 18 in controls, but it was decreased in the STZ group at day 18-21 (P less than 0.02) and differences were no longer detected by neonatal days 1-2. SP-A and SP-A mRNA accumulated with advancing gestational age in both groups until neonatal days 1-2. The differences in SP-A and SP-A mRNA levels in the two groups diminished with advancing age but remained significant at fetal day 21. These data suggest that STZ-induced diabetes interferes with normal expression of SP-A in the developing fetal lung.
The aim of the present experiments was to determine the effects of basal glucagon on glucose production after induction of prolonged insulin lack in normal conscious dogs fasted overnight. A selective deficiency of insulin or a combined deficiency of both pancreatic hormones was created by infusing somatostatin alone or in combination with an intraportal replacement infusion of glucagon. Glucose production (GP) was measured by a primed constant infusion of [3H-3]glucose, and gluconeogenesis (GNG) was assessed by determining the conversion rate of circulating [14C]alanine and [14C]lactate into [14C]glucose. When insulin deficiency was induced in the presence of basal glucagon the latter hormone caused GP to double and then to decline so that after 4 h it had returned to the conrol rate. The conversion of alanine and lactate into glucose, on the other hand, increased throughout the period of insulin lack. Withdrawal of glucagon after GP had normalized resulted in a 40% fall in GP, a 37% decrease in GNG, and a marked decrease in the plasma glucose concentration. Induction of insulin deficiency in the absence of basal glucagon resulted in an initial (30%) drop in GP followed by a restoration of normal GP after 2--3 h and moderately enhanced glucose formation from alanine and lactate. It can be concluded that (a) the effect of relative hyperglucagonemia on GP is short-lived; (b) the waning of the effect of glucagon is attributable solely to a diminution of glycogenolysis because GNG remains stimulated; (c) basal glucagon markedly enhances the GNG stimulation apparent after induction of insulin deficiency; and (d) basal glucagon worsens the hyperglycemia pursuant on the induction of insulin deficiency both by triggering an initial overproduction of glucose and by maintaining the basal production rate thereafter.
We examined the effect of hyperglycemia per se on net splanchnic glucose balance. In 2 groups of normal postabsorptive men who had undergone hepatic vein catheterization, somatostatin was administered to block endogenous insulin and glucagon secretion. Exogenous glucose was infused in both groups to maintain euglycemia for 2 h in one group (n = 7) and to induce hyperglycemia of 220-240 mg/dl after 30 minutes of euglycemia in the second group (n = 4). In both groups the induction of insulinopenia and glucagonopenia with euglycemia maintained resulted in an initial 75% fall in net splanchnic glucose production (NSGP). In the group in which euglycemia was maintained NSGP returned to basal rates (157 +/- 31 mg/min) within 2 h. However, in the group in which hyperglycemia was induced, NSGP did not return to basal rates but remained suppressed (28 +/- 4 mg/min) for the duration of the study. These data in normal man indicate that hyperglycemia per se with insulin and glucagon acutely withdrawn can suppress splanchnic glucose production but does not induce net splanchnic glucose storage.