Evidence for aerobic glycolysis in lambda-carrageenan-wounded skeletal muscle

Classically, increased lactate production in wounded tissue is ascribed to anaerobic glycolysis although its oxygen consumption has been found to be similar to normal tissue. This apparent inconsistency was studied in a standardized isolated perfused wound model. Male Sprague-Dawley rats were wounded (group W) with intramuscular injections of lambda-carrageenan and fed ad lib.; not wounded and pair fed to the decreased food intake of the wounded animals (group PFC); or not wounded and fed ad lib. (group ALC). After 5 days, the hindlimbs of animals from each group were either perfused using a standard perfusate with added [U-14C]glucose or [1-14C]pyruvate or assayed for the tissue content of lactate and pyruvate. In addition, the effect of a 30% hemorrhage on the tissue lactate and pyruvate concentration was examined. Wounding increased glucose uptake and lactate production by 100 and 96%, respectively, above that seen in ALC animals. Oxygen consumption was unchanged by wounding (5.74, 5.14, and 5.83 mumole/min/100 g in W, PFC, and ALC, respectively). Glucose and pyruvate oxidation were also unaltered among the groups. Hemorrhage resulted in a comparable increase in lactate and pyruvate in tissue from wounded and pair-fed control animals (above those concentrations found in tissue harvested without preexisting hemorrhage). As a consequence, the same relationship in L/P ratio was maintained after hemorrhage. Taken together, these results confirm the presence of aerobic glycolysis in wounded tissue (unchanged oxygen consumption, glucose, and pyruvate oxidation). In addition, pyruvate dehydrogenase activity in the wound was apparently the same as that found in muscle from pair-fed control animals.     

The temporal characteristics of the metabolic and endocrine response to injury

The neuroendocrine and substrate responses immediately after injury have been extensively investigated in man and animals. The purpose of the present study was to examine simultaneously, the temporal, metabolic and endocrine consequences of a single uniform injury induced by the injection of lambda-carrageenan into the hindlimbs of male Sprague-Dawley rats and to compare this response to that observed in semistarved pair-fed control animals. Immediately after injury there was a decrease in the plasma hematocrit, increase in tissue water and peripheral vasoconstriction that suggested hypovolemia. This was followed by a restoration of the blood volume by 1 day as reflected in hemodilution. Alterations in insulin, glucagon, ACTH, corticosterone, epinephrine, norepinephrine, and dopamine in wounded animals occurred during the first 5 days. However, similar changes were observed in pair-fed control animals from days 1 to 5. These findings implied that the early endocrine response observed from 0 to 24 hours after injury arises, primarily as a result of hypovolemia, whereas the response observed from 1 to 5 days appeared to be the result of semistarvation. In contrast to the endocrine alterations observed, alterations in the plasma concentrations of lactate, acetoacetate and beta-hydroxybutyrate persisted for up to 15 days. The presence of these substrate alterations in the absence of hormonal stimuli suggest that nonendocrine mechanisms exist to induce these alterations. The possibility is raised that these substrate alterations may be, at least in part, the result of the inflammatory infiltrate.     

Effect of starvation on the local and systemic metabolic effects of the lambda-carrageenan wound

The contribution that starvation makes to the altered glucose metabolism in injured rats was evaluated. Food intake, weight change, nitrogen balance, and muscle tissue concentrations of glycogen, glucose, and the glycolytic intermediates were determined in these animals. This study concluded that the wounded and pair fed control groups presented adequately represent the metabolic states associated with injury and semistarvation in experimental animals, decreased food intake plays a major role in the weight loss and nitrogen balance in this wound model, wounding overrides two of the controlling steps of glycolysis (hexokinase and phosphofructokinase) in skeletal muscle during starvation, the finding of similar pyruvate dehydrogenase activity after wounding and starvation as demonstrated by tissue lactate to pyruvate ratios and lactate and pyruvate concentrations suggest that lactate production in wounded tissue may not be simply a manifestation of an altered redox state secondary to anaerobic conditions.     

Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury

The metabolic fate of [1,2 13C]-labeled glucose was determined in male control and unilateral controlled cortical impact (CCI) injured rats at 3.5 and 24 h after surgery. The concentration of 13C-labeled glucose, lactate, glutamate and glutamine were measured in the injured and contralateral cortex. CCI animals showed a 145% increase in 13C lactate in the injured cortex at 3.5 h, but not at 24 h after injury, indicating increased glycolysis in neurons and/or astrocytes ipsilateral to CCI. Total levels of 13C glutamate in cortical tissue extracts did not differ between groups. However, 13C glutamine increased by 40% in the left and 98% in the right cortex at 3.5 h after injury, most likely resulting from an increase in astrocytic metabolism of glutamate. Levels of 13C incorporation into the glutamine isotopomers had returned to control levels by 24 h after CCI. The singlet to doublet ratio of the lactate C3 resonances was calculated to estimate the flux of glucose through the pentose phosphate pathway (PPP). CCI resulted in bilateral increases (9-12%) in the oxidation of glucose via the PPP, with the largest increase occurring at 24 h. Since an increase in PPP activity is associated with NADPH generation, the data suggest that there was an increasing need for reducing equivalents after CCI. Furthermore, 13C was incorporated into glutamate and glutamine isotopomers associated with multiple turns of the tricarboxylic acid (TCA) cycle, indicating that oxidative phosphorylation of glucose was maintained in the injured cortex at 3.5 and 24 h after a moderate to severe CCI injury.     

The fate of glucose during the period of decreased metabolism after fluid percussion injury: a 13C NMR study

The present study determined the metabolic fate of [1, 2 13C2] glucose in male control rats and in rats with moderate lateral fluid percussion injured (FPI) at 3.5 h and 24 h post-surgery. After a 3-h infusion, the amount of 13C-labeled glucose increased bilaterally (26% in left/injured cerebral cortex and 45% in right cerebral cortex) at 3.5 h after FPI and in injured cortex (45%) at 24 h after injury, indicating an accumulation of unmetabolised glucose not seen in controls. No evidence of an increase in anaerobic glycolysis above control levels was found after FPI, as 13C-labeled lactate tended to decrease at both time points and was significantly reduced (33%) in the injured cortex at 24 h post-FPI. A bilateral decrease in the 13C-labeling of both glutamate and glutamine was observed in the FPI rats at 3.5 h and the glutamine pool remained significantly decreased in the injured cortex at 24 h, suggesting reduced oxidative metabolism in both neuronal and astrocyte compartments after injury. The percentage of glucose metabolism through the pentose phosphate pathway (PPP) increased in the injured (13%) and contralateral (11%) cortex at 3.5 h post-FPI and in the injured cortex (9%) at 24 h post-injury. Based upon the changes in metabolite pools, our results show an injury-induced decrease in glucose utilization and oxidation within the first 24 h after FPI. Increased metabolism through the PPP would result in increased NADPH synthesis, suggesting a need for reducing equivalents after FPI to help restore the intracellular redox state and/or in response to free radical stress.     

Absence of change in hepatic lactate metabolism after burn injury

In response to severe injury, extraordinary quantities of lactate that are released from the peripheral tissues serve as substrate for hepatic gluconeogenesis. It is possible that as a result of burn injury, reaction kinetics involving lactate could be directly changed within the liver. The metabolic fate of [U-¹⁴C]lactate was examined in vitro in fresh liver slices after a 20 per cent total body surface area injury. Glucose and CO₂ were produced in vitro by the liver tissues after the injury and no differences were seen in the metabolism of these substrates between the injured and control animals. These findings suggest that the intrinsic enzymatic processes within the liver are not directly altered by injury itself or by any of the associated inflammatory mediators which appear early after burns.     

Influence of oxygen therapy on glucose-lactate metabolism after diffuse brain injury

OBJECT: Severe traumatic brain injury (TBI) imposes a huge metabolic load on brain tissue, which can be summarized initially as a state of hypermetabolism and hyperglycolysis. In experiments O2 consumption has been shown to increase early after trauma, especially in the presence of high lactate levels and forced O2 availability. In recent clinical studies the effect of increasing O2 availability on brain metabolism has been analyzed. By their nature, however, clinical trauma models suffer from a heterogeneous injury distribution. The aim of this study was to analyze, in a standardized diffuse brain injury model, the effect of increasing the fraction of inspired O2 on brain glucose and lactate levels, and to compare this effect with the metabolism of the noninjured sham-operated brain. METHODS: A diffuse severe TBI model developed by Foda and Maramarou, et al., in which a 420-g weight is dropped from a height of 2 m was used in this study. Forty-one male Wistar rats each weighing approximately 300 g were included. Anesthesized rats were monitored by placing a femoral arterial line for blood pressure and blood was drawn for a blood gas analysis. Two time periods were defined: Period A was defined as preinjury and Period B as postinjury. During Period B two levels of fraction of inspired oxygen (FiO2) were studied: air (FiO2 0.21) and oxygen (FiO2 1). Four groups were studied including sham-operated animals: air-air-sham (AAS); air-O2-sham (AOS); air-air-trauma (AAT); and air-O2-trauma (AOT). In six rats the effect of increasing the FiO2 on serum glucose and lactate was analyzed. During Period B lactate values in the brain determined using microdialysis were significantly lower (p < 0.05) in the AOT group than in the AAT group and glucose values in the brain determined using microdialysis were significantly higher (p < 0.04). No differences were demonstrated in the other groups. Increasing the FiO2 had no significant effect on the serum levels of glucose and lactate. CONCLUSIONS: Increasing the FiO2 influences dialysate glucose and lactate levels in injured brain tissue. Using an FiO2 of 1 influences brain metabolism in such a way that lactate is significantly reduced and glucose significantly increased. No changes in dialysate glucose and lactate values were found in the noninjured brain.     

The effects of naloxone on glucose uptake and metabolism in the isolated perfused hindlimb of the rat

Naloxone, an opiate antagonist, is reported to reverse hypotension and to improve survival in hemorrhaged and septic animals. We have found recently that naloxone also blunts the hyperglycemic response to hemorrhage. This could result from a naloxone-induced diminution of the hypotensive stimulus to hyperglycemia, from a naloxone-induced diminution of hormonal secretion or action, from a naloxone-mediated decrease in glucose production, or from a direct action of naloxone on glucose uptake in skeletal muscle and other peripheral tissues. In order to examine the direct effect of naloxone on glucose uptake in skeletal muscle, male Sprague-Dawley rats were perfused in a standardized isolated perfused hindlimb system with or without naloxone (0.5 microgram/ml of perfusate). No insulin was added to the perfusate. Glucose uptake in animals treated with naloxone was 30.2% greater than that of control animals (p less than 0.05). This increase was not dependent on insulin. Although no significant differences were noted in the individual products of glucose utilization, the total tissue glucose that could be accounted for by these intermediates was increased in naloxone-treated hindlimbs (p less than 0.05). Thus the increase in glucose uptake by skeletal muscle noted in these experiments may explain, in part, the blunted hyperglycemic response to hemorrhage that occurs after naloxone administration. These results also suggest the possibility that endogenous opiates may be important in regulating glucose metabolism after hemorrhage.     

Can lactate be used as a fuel by wounded tissue?

The role of lactate in the metabolism of the healing wound is poorly understood. The purpose of the present studies was to determine if despite a net lactate production, wounded (Wx) tissue could metabolize lactate and use it as an oxidative fuel. The extensor digitorum longus muscles (EDL) of weanling, male, Fischer rats were injured with lambda-carrageenan or injured thermally, and 5 and 3 days later, respectively, were incubated in a standard incubate that contained varying amounts of lactate (0 to 6 mmol/L added). Lactate uptake and oxidation, occurred in lambda-carrageenan Wx EDL, thermally injured EDL and non-Wx EDL in a dose-dependent manner. At lactate concentrations of less than 3 mmol/L in the incubate, there was net lactate production, but at lactate concentrations of 6 mmol/L there was no net lactate production by both Wx and non-Wx EDL. The increase in lactate oxidation was not associated with an alteration in the tissue content of adenosine triphosphate or creatine phosphate. It was associated with a reduction in glucose oxidation in Wx and non-Wx EDL and by a decrease in glucose uptake by Wx EDL. These data suggest that lactate may be used as an oxidative fuel by wounded tissue and in this regard may substitute for glucose.     

Regional Spinal Cord Blood Flow and Energy Metabolism in Rats after Laminectomy and Acute Compression Injury

Many data are available concerning spinal cord blood flow (SCBF) and metabolism on various models and timing after spinal cord injury, however, detailed information on their exact relationship in the same injury model is lacking. This relationship is a crucial factor in the understanding of the pathophysiology of spinal cord trauma. Rats were subjected to lumbar laminectomy or lumbar spinal cord compression trauma. 3 hours later, changes in SCBF were evaluated autoradiographically and changes in ATP, glucose and lactate levels were analyzed using substrate-specific bioluminescence techniques. Measurements were performed at the lesion site (segment L4), adjacent segments (L3 and L5) and at remote thoracic segments (Th8 to Th9). Laminectomy alone did not change SCBF, both in thoracic and lumbar segments. In contrast, ATP levels were significantly reduced and lactate levels were increased at the lesion site and in adjacent lumbar segments at 3 hours after laminectomy, whereas glucose levels were not significantly changed. In animal subjected to additional compression trauma, SCBF was significantly reduced in segments L3, L4 and L5 paralleled by a significant ATP reduction and lactate increase. Glucose levels did not differ significantly from controls 3 hours after compression injury. This metabolic profile was also reflected in the remote thoracic segments. In contrast, SCBF was not reduced in thoracic segments of traumatized animals. The observation that ATP was already significantly reduced and lactate increased in laminectomized segments and in remote thoracic regions after trauma signals that metabolic changes are sensitive indicators to spinal stress. The fact that posttraumatic metabolic profile differs from the pattern of hemodynamic and metabolic changes induced by ischemia, suggests posttraumatic mediators may be involved in the different regulation of the energy producing machinery.     

Metabolic response in microvascular flaps during partial pedicle obstruction and hypovolemic shock

To investigate tissue metabolism during suboptimal blood perfusion, we used in situ microdialysis in an experimental model of myocutaneous flaps. We assessed concentrations of glucose, lactate, and pyruvate in flaps subjected to partial pedicle obstruction and to hemorrhagic shock. When the arterial flow was restricted, the glucose concentration decreased in the flap muscle, and the lactate concentration increased in all flap components. The restriction ofvenous outflow resulted in lactate overproduction and a decrease of glucose in skin and muscle. The lactate-to-pyruvate ratio remained normal during arterial obstruction but increased during venous obstruction. During hypovolemic shock, the lactate production increased and the glucose concentration decreased or remained normal. The metabolic changes occurring during partial pedicle obstruction and hypovolemic shock are moderate and different from those seen in total pedicle obstruction. Microdialysis is a feasible method for assessing local tissue metabolism and can be used to monitor flap ischemia.     

Captopril-induced glutamate release at the start of reperfusion after cold cardioplegic storage of pig hearts

OBJECTIVE: We sought to evaluate the effects of captopril on glucose-related metabolism during hypothermic cardioplegic storage and subsequent reperfusion. METHODS: We compared hearts from control pigs with hearts from pigs treated with increasing oral doses of captopril for 3 weeks (12.5-150 mg daily), an intravenous bolus (25 mg) before operation, and captopril-containing cardioplegic solution (1 mg/L). The hearts were excised after infusion of cold crystalloid cardioplegic solution and stored in saline solution (4 degrees C-6 degrees C). In one series we studied myocardial blood flow and arteriovenous differences in oxygen, glucose, lactate, glutamate, and alanine during 60 minutes of postcardioplegic blood reperfusion. In this series captopril-treated hearts were reperfused with captopril-containing blood (1 mg/L). In another series we obtained biopsy specimens from the left ventricle throughout 30 hours of hypothermic cardioplegic storage and monitored tissue content of energy-rich phosphates, glycogen, glutamate, and alanine. RESULTS: Captopril increased glutamate and alanine release 11- to 17-fold at the start of reperfusion (P <.001). Furthermore, captopril increased myocardial oxygen and glucose uptake during reperfusion (P <.001 for both), whereas lactate release and myocardial blood flow were unaffected by captopril. At the start of reperfusion, there was a positive correlation between glutamate release and glucose uptake in captopril-treated hearts (r = 0.66, P =.05). We found no statistically significant differences between captopril and control hearts in tissue content of adenosine triphosphate, glycogen, glutamate, alanine, or lactate during 30 hours of cardioplegic storage. CONCLUSIONS: The metabolic effects of captopril are strictly related to reperfusion, during which oxidative metabolism of glucose is improved. The captopril-induced increase in glutamate and alanine release at the start of reperfusion after cardioplegic storage may reflect a switch in metabolism of glucose-related amino acids.     

The effect of tumor bulk on the metabolic response to cancer.

The derangements in energy/substrate metabolism seen in oncology patients are similar regardless of the tumor's site of origin, and in advanced disease these metabolic derangements can be manifested as cancer cachexia. The relationship between tumor size and the degree of metabolic abnormality, however, remains unclear. Using primed constant infusions of stable and radiolabeled isotopes and indirect calorimetry, the authors have determined the rates of net protein catabolism (NPC), glucose oxidation, Cori cycling of glucose, and oxygen consumption in 85 patients with cancer. They have assessed the association between bulk of tumor and metabolic abnormality using regression analysis. A positive correlation was found between tumor bulk and the rates of NPC (r2 = 0.8), plasma glucose appearance (r2 = 0.72), plasma glucose clearance (r2 = 0.70), the percentage of tissue glucose uptake recycled to lactate (r2 = 0.62), and oxygen consumption (r2 = 0.79). The percentage of tissue glucose uptake oxidized was negatively correlated with tumor bulk (r2 = 0.75). The data indicate that the degree of metabolic abnormality seen in cancer patients is closely related to the quantity of malignant tissue present. Progressive increase in tumor size is associated with an increase in peripheral substrate mobilization, an increase in the rate of hepatic glucose production, an increase in tissue glucose uptake, an increase in energy-expensive glucose cycling to lactate, and an increase in protein loss.     

Measured energy expenditure and plasma substrate and hormonal changes after severe head injury.

The influence of head trauma on the pattern of response to injury has been studied. Metabolic and hormonal data from brain injured patients over 20 days following injury were compared with an existing data base from non-head-injured patients and control subjects. The results demonstrated elevated concentrations of plasma glucose, lactate, non-esterified fatty acids (NEFA), cortisol, glucagon and insulin above that of control values in both groups after injury. Head injury as a separate factor did not affect the concentrations of any of these plasma substrates and hormones independently of its contribution to the Injury Severity Score (ISS). However, plasma catecholamine concentrations were higher in the head injured initially and at 7 days after injury. All head-injured patients showed an increase in metabolic rate (above predicted values) at some stage after injury. It should be noted, however, that there were some features of head injury (and its treatment) such as paralysis, ventilation and fasting which were not matched in the non-head-injured group. It was concluded that the metabolic changes occurring after head injury are similar to those occurring after extracranial injury and that therapeutic intervention has a major effect on the level of energy expenditure seen in these patients.     

Lactate and pyruvate metabolism in injured cat spinal cord before and after a single large intravenous dose of methylprednisolone

The lactate content and the lactate/pyruvate ratio of the acutely traumatized cat spinal cord have been studied and were found to rise rapidly following a 400 gm-cm injury. Lactate levels rose nearly twofold within 5 minutes after injury, peaked at 2 hours after injury, and remained significantly elevated for at least 8 hours compared to an adjacent uninjured segment of traumatized cord. Pyruvate levels, on the other hand, fell acutely in the injured section of cord during the 1st hour after injury then rose slowly over an 8-hour period. The changes in tissue lactate and pyruvate metabolism in the spinal cord following injury are consistent with a marked injury-induced reduction in blood flow. The elevation in lactate and the fall in pyruvate levels observed at 1 hour after injury were completely prevented by the intravenous administration of a single 30-mg/kg dose of methylprednisolone sodium succinate at 30 minutes after injury. Lower or higher doses of methylprednisolone were far less effective. The effects of the 30-mg/kg dose of methylprednisolone on tissue lactate content were associated with high tissue levels of the glucocorticoid and were short-lived, paralleling the accumulation and elimination pattern of steroid from the injured tissue. The results suggest that, in addition to other reported beneficial actions of large intravenous doses (30 mg/kg) of methylprednisolone on the injured cord, the glucocorticoid may also improve blood flow to the injured segment as has been suggested by others. The use of high glucocorticoid doses, early therapy initiation, and rigorous maintenance dosing is discussed.     

Cerebral metabolic response to traumatic brain injury sustained early in development: a 2-deoxy-D-glucose autoradiographic study

Following fluid percussion (FP) traumatic brain injury (TBI), adult rats exhibit dynamic regional changes in cerebral glucose metabolism characterized by an acute (hours) increase and subsequent chronic (weeks) decrease in metabolic rates. The injury-induced hyperglycolysis is the result of ionic fluxes across cell membranes and the degree and extent of metabolic depression is predictive of neurobehavioral deficits. Given that younger animals appear to exhibit similar physiological responses to injury yet show an improved rate of recovery compared to adults, we wanted to determine if this injury-induced dynamic metabolic response to TBI is different if the injury is sustained early in life. Local cerebral metabolic rates for glucose (ICMRglc: micromol/100 g/min) using [14C]2-deoxy-D-glucose were measured immediately, 30 min, 1 day, and 3 days following a mild to moderate level of lateral FP injury in postnatal day 17 (P17) rats. Even though gross morphological damage was not evident, injured pups exhibited ipsilateral hyperglycolysis immediately after injury, predominantly in cortical regions (ranging from 59.2% to 116.5% above controls). This hyperglycolytic state subsided within 30 min, and by 1 day all cerebral structures, except the ipsilateral cerebellar cortex, showed lower rates of glucose metabolism (ranging from 5.7% to 63.0% below controls). This period of posttraumatic metabolic depression resolved within 3 days for all structures measured. Compared to previous adult studies these results suggest that the young rat pup, although exhibiting acute hyperglycolysis, is not subjected to a prolonged period of metabolic depression, which supports the findings that at this level of injury severity, these young animals show remarkable neurological sparing following TBI.     

Elevated energy expenditure in hepatocytes from tumor-bearing rats

Mechanisms for the development of cancer cachexia are not well defined. Oxygen consumption and the capacity of the host liver to metabolize lactate were studied in isolated hepatocytes from sarcoma-bearing rats (TIH) and pair-fed controls (CH). Basal oxygen consumption (without exogenous substrate) is significantly increased by 65% in the TIH as compared to the CH. The addition of a physiologic concentration of lactate stimulated oxygen consumption over the already stimulated basal state by 13% in the TIH compared to 5% in the CH. When the hepatocytes are incubated with 1.5 mM of [U-14C]lactate, glucose production, lactate oxidation, and entry of lactate carbons into nonsecretory protein are significantly increased in the TIH. Associated with this stimulation is a significant decrease in lactate incorporation into glycogen and lipid in the TIH. This study suggests that the tumor-influenced liver utilizes lactate at an increased rate and its intermediary metabolism is directed toward energy utilization rather than energy storage. The enhanced metabolic processes in the tumor-influenced liver are associated with an increased oxygen consumption which may be a contributory factor to the negative energy balance, a characteristic of cancer cachexia.     

Regional changes in cerebral extracellular glucose and lactate concentrations following severe cortical impact injury and secondary ischemia in rats

Traumatic brain injury (TBI) causes the brain to be more susceptible to secondary insults, and the occurrence of a secondary insult after trauma increases the damage that develops in the brain. To study the synergistic effect of trauma and ischemia on brain energy metabolites, regional changes in the extracellular concentrations of glucose and lactate following a severe cortical impact injury were measured employing a microdialysis technique. Three microdialysis probes were placed in center of the impact site, in an area adjacent to the impact site, and in the contralateral parietal cortex, and perfused with artificial cerebrospinal fluid (CSF) at 2 microl/min. Rats were assigned to one of the following experimental groups (n = 7 per group): (1) combined impact injury and secondary insult, (2) impact injury with sham secondary insult, (3) sham impact with secondary insult, or (4) sham impact and sham secondary insult. The impact injury was produced with a pneumatic impactor (5 m/sec, 3-mm deformation). One hour following the impact injury, a secondary insult was produced by bilateral carotid occlusion for 1 h. The impact injury resulted in a three- to fivefold global increase in dialysate lactate concentrations, with a corresponding fall in dialysate glucose concentration by 50% compared to no change in lactate or glucose concentrations in sham-injured animals (p < .0001 for both lactate and glucose). The secondary insult resulted in a second increase in dialysate lactate and decrease in dialysate glucose concentration that was significantly greater in the animals that had suffered the impact injury than in the sham-injured animals. Ischemia and traumatic injury have synergistic effects on lactate accumulation and on glucose depletion in the brain that probably reflects persisting ischemia, but may also indicate mitochondrial abnormalities and inhibition of oxidative metabolism.     

Age- and diabetes-related changes in tissue glucose uptake and estradiol accumulation in the C57BL/KsJ mouse

The effect of the diabetes (db/db) mutation on the age-related changes in glucose uptake and estradiol incorporation in peripheral tissues were investigated in C57BL/KsJ mice between 2 and 16 wk of age. Glucose uptake in the uterus, ovaries, pancreas, lung, liver, heart, kidney, and spleen were markedly increased in diabetic mice after the development of the hyperglycemic condition, as compared with control mice. The age-related increase in glucose uptake observed in control mice was enhanced in hyperglycemic (i.e., greater than or equal to 4 wk of age) animals. In contrast, the diabetes mutation caused a decreased estradiol uptake by the uteri, ovaries, and mesometrial fat pads at 16 wk, while having little effect in nontarget tissues of diabetic mutants. These data indicate that the diabetes mutation enhances glucose uptake, especially in estradiol target tissues (i.e., uterus, ovary), at the same time that estradiol incorporation is depressed. These results suggest that an alteration in glucose utilization by steroid-sensitive reproductive tract tissue may underlie the impaired reproductive ability in these animals. Other peripheral tissues did not demonstrate any remarkable changes in estradiol uptake, but the enhanced carbohydrate metabolism observed may relate to the subsequent age- and diabetes-related changes in tissue structure and function in these animals.     

Effects of tromethamine and hyperventilation on brain injury in the cat

The metabolic brain acidosis after trauma has been thought to be harmful and to contribute to neurological deterioration. Amelioration of the brain acidosis either by systemic buffering agents or by hyperventilation has been proposed as a method of treatment. The objective of this study was to explore with magnetic resonance (MR) spectroscopy the metabolic changes in brain that occur with the use of hyperventilation, THAM (tromethamine; tris[hydroxymethyl]aminomethane), and a combination (THAM and hyperventilation) therapy in experimental fluid-percussion injury. Brain lactate, brain pH, inorganic phosphate (Pi), and adenosine triphosphate levels were measured by 1H and 31P MR spectroscopy. Arterial and cerebrovenous lactate and water content in brain tissue was determined in 29 cats using the specific gravimetric technique. Following injury, the phosphocreatine (PCr)/Pi ratio, which is an index of cerebral energy depletion, decreased to 76% in four untreated animals, to 79% in 11 THAM-treated animals, to 68% in seven animals receiving hyperventilation, and to 66% in seven animals with combination THAM and hyperventilation therapy. The PCr/Pi ratio returned to a normal level in 8 hours in animals treated with THAM and THAM in combination with hyperventilation. The brain lactate index increased to 157% in the hyperventilation group after trauma. In cats receiving THAM plus hyperventilation, the brain lactate index was reduced to 142%, while the minimum rise of 126% was associated with treatment of THAM alone. In the THAM-treatment and combination-treatment groups, the water content of the white and gray matter was significantly decreased compared with that in untreated cat brains. Prolonged hyperventilation provided relative ischemia in brain tissue and promoted more production of brain lactate, no recovery of the PCr/Pi ratio, and no decrease in brain edema. On the other hand, administration of THAM decreased production of brain lactate and brain edema and promoted the recovery of cerebral energy dysfunction. It was found that THAM ameliorates the deleterious effects of hyperventilation by minimizing energy disturbance and that it also decreases brain edema. The authors conclude that THAM may be effective in reducing brain tissue acidosis and helpful as a metabolic stabilizing agent following severe head injury.