Hyperglycemic Animals Research Articles

Hypoglycaemic activity of Nelumbo nucifera gaertn. (Fam. Nymphaeaceae) rhizome (methanolic extract) in streptozotocin‐induced diabetic rats

AbstractThe hypoglycaemic effect of the rhizome extract of Nelumbo nucifera was studied in streptozotocin‐induced diabetic rats. A methanol extract of the plant obtained by soxhlet extraction from finely pulverized rhizomes was used. The LD50 of the extract was found to be 2 g/kg. The extract (300 mg/kg and 600 mg/kg, orally) caused a reduction of blood glucose levels in streptozotocin‐induced diabetic rats by 53% (p<0.001) and 55% (p<0.001) respectively at the end of 12 h. The results of this study indicate that the methanol extract of the rhizome possesses favourable hypoglycaemic activity in hyperglycaemic animals taking chlorpropamide as a standard.

Contribution of fructose and lactate produced in placenta to calculation of fetal glucose oxidation rate.

We examined the rate of production of [14C]fructose and [14C]lactate from [U-14C]glucose by the placenta and the contribution of 14CO2 from fetal oxidation of these metabolic products to the calculation of glucose oxidation rate in fetal sheep. During fetal tracer infusions (n = 16), oxidation of fructose contributed 16 +/- 3% of total fetal CO2 production; oxidation of lactate accounted for 3.3 +/- 0.1%. Thus 80% of total fetal CO2 production resulted from direct oxidation of carbon atoms in glucose; the "direct" glucose oxidation fraction was 0.46 +/- 0.04. During maternal tracer infusion (n = 15), CO2 production from fructose was 21 +/- 3, 20 +/- 3, and 30 +/- 4% and from lactate was 16 +/- 3, 13 +/- 3, and 11 +/- 4% in hypo-, normo-, and hyperglycemic animals, respectively; the direct glucose oxidation fraction was 0.40 +/- 0.04, not different from the fraction obtained with the fetal tracer infusion. Fetal oxidation of substrates derived from glucose metabolism in the placenta contributes significantly to fetal CO2 production. Fetal oxidation of placental products of a metabolic substrate tracer should be considered in studies of fetal oxidative metabolism.

Immunocytochemical investigation of insulin secretion by pancreatic beta-cells in control and diabetic Psammomys obesus.

Hyperproinsulinemia is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) caused by pancreatic beta-cell dysfunction through a secretion-related alteration or impaired proinsulin processing. We have investigated the insulin processing and secretion in Psammomys obesus fed with low- and high-energy diets, which represent a model for diet-induced NIDDM. With a high-energy diet the animals develop hyperglycemia and hyperinsulinemia, whereas those maintained on a low-energy diet remain normoglycemic. Although a large amount of insulin immunoreactivity was detected in beta-cells of the normoglycemic compared to hyperglycemic animals, in situ hybridization for insulin mRNA demonstrated a particularly high signal in the beta-cells of the hyperglycemic animals. By electron microscopy, the beta-cells of normoglycemic animals displayed large accumulations of secretory granules, whereas those of the hyperglycemic animals contained very few granules and large deposits of glycogen. These results reflect a secretory resting condition for the cells of the normoglycemic animals in contrast to stimulated synthetic and secretory activities in the cells of the hyperglycemic ones. Using colloidal gold immunocytochemistry at the electron microscopic level, we have examined subcellular proinsulin processing in relation to the convertases PC1 and PC2. Immunolabeling of proinsulin, insulin, C-peptide, PC1, and PC2 in different cell compartments involved in beta-cell secretion were evaluated. Both PC1 and PC2 antigenic sites were detected in beta-cells of hyperglycemic Psammomys, but their labeling intensity was weak compared to the cells of normoglycemic animals. In both groups of animals, higher levels of PC2 were found in the Golgi apparatus than in the immature granules. Major decreases in proinsulin, insulin, PC1, and PC2 immunoreactivity were recorded in beta-cells of the hyperglycemic Psammomys. In addition, all these antigenic sites were detected in lysosome-like structures, revealing a major degradation process. These results suggest that the insulin-secreting cells in hyperglycemic Psammomys obesus are in a chronic secretory state during which impaired processing of proinsulin appears to take place.

Impaired microvascular response to graded coronary occlusion in diabetic and hyperglycemic dogs.

The hypothesis that coronary microvascular responses to ischemia are impaired in diabetes was tested in 9 alloxan-treated (60 mg/kg i.v.), 8 hyperglycemic, and 16 control dogs. Arteriolar diameters were measured in intact beating left ventricle by use of stroboscopic epi-illumination and intravital microscopy with fluorescence microangiography. Coronary arterial diameters were measured during graded reductions in mean coronary perfusion pressure to 60 +/- 1 (SE) mmHg (mild stenosis), 39 +/- 1 mmHg (severe stenosis), and 26 +/- 1 mmHg (coronary artery occlusion). Blood glucose levels were 95 +/- 5, 264 +/- 17, and 277 +/- 15 mg/dl in control, diabetic, and hyperglycemic animals, respectively. In control dogs, arteriolar microvessels (< 100 microns) dilated (24 +/- 5, 31 +/- 5, and 26 +/- 6% change in diameter from baseline during mild stenosis, severe stenosis, and coronary occlusion, respectively). Diabetes or hyperglycemia prevented the normal dilatory response and resulted in decreases in microvascular diameter during decreases in perfusion pressure (-2 +/- 3, -4 +/- 3, and -15 +/- 4% change in diameter in diabetic animals and -11 +/- 2, -9 +/- 4, and -8 +/- 5% change in diameter in hyperglycemic animals). Large-vessel (> 100 microns) dilation was also significantly impaired in diabetic and hyperglycemic animals. Myocardial perfusion was significantly lower in the epicardium during a severe stenosis in diabetic and hyperglycemic than in control dogs. Because the ATP-sensitive K+ (KATP) channel mediates this response in normal animals, we tested the hypothesis that KATP channel responsiveness is impaired in diabetes and hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of moderate hyperglycemia on the temporal profile of brain tissue intracellular pH and [Mg 2+] after global cerebral ischemia in rats

In an attempt to understand the mechanisms by which preischemic plasma glucose (pg) worsens neurologic and neuropathologic outcomes, we investigated the effect of moderate preischemic hyperglycemia (200 mg/dl < mean plasma glucose < 360 mg/dl) on postischemic energy metabolism, tissue intracellular pH (pHi) and tissue free intracellular pMg (= −log[Mg 2+]) over a one week period after transient global cerebral ischemia in the rat. In vivo 31P nuclear magnetic resonance spectroscopy was performed prior to and daily up to 1 week (wk) in rats after 12 min of forebrain ischemia, induced by bicarotid occlusion concurrent with systemic hypotension. Preischemic plasma glucose significantly affected 1 wk postischemic survival ( p = 0.05, Fisher's exact test). The temporal profile of the brain tissue pHi was significantly different ( p < 0.03) between the moderate hyperglycemic (H-1wk, n = 7, mean pg = 266.0 ± 47.3 mg/dl) and the normoglycemic (N-1wk, n = 8, mean pg = 91.2 ± 23.7 mg/dl) ischemic animals over 1 wk. Postischemic tissue alkalosis was measured at 24 ( p = < 0.006) and 48h ( p = 0.001) postischemia in the N-1wk group. A single marginally significant ( p = 0.011) mean pHi upshift was measured at 72h postischemia in the H-1wk group. The mean change in pHi at 24h postischemia from the baseline values in moderate hyperglycemic animals that survived only 48h after ischemia (H-48h, n = 6, mean pg = 298.8 ± 70.1 mg/dl) was significantly lower ( p = 0.02) than that of the N-1wk ischemic animals. No differences were detected in the relative area ratios of phosphate metabolites and [Mg 2+] profiles between the N-1wk and H-1wk groups. Scattered dark neurons were present in the cortices of the H-1wk ischemic animals. The present study demonstrates that a mild glucose load, administered 40 min before forebrain ischemia, is detrimental to long term survival and indicates that the pHi regulatory mechanism is sensitive to and has a long term response to a moderate preischemic glucose load, independent of the recovery of cerebral phosphate metabolism and free intracellular [Mg 2+].

Ovine uteroplacental glucose and oxygen metabolism in relation to chronic changes in maternal and fetal glucose concentrations

We tested whether uterine glucose uptake rate (UtGU), placental glucose transport rate to the fetus (PGT) and uteroplacental glucose consumption rate (UPGC) were altered in chronically catheterized pregnant sheep after 2–5 week intravenous infusions of glucose or insulin that produced sustained maternal and fetal hyper- or hypoglycemia. In the hyperglycemic animals, UtGU was greater than that of controls; the excess UtGU was partitioned into non-oxidative UPGC rather than PGT. The ‘normal’ rate of PGT observed in the hyperglycemic animals is probably related to suppression of fetal insulin concentration which would decrease fetal glucose clearance and thus the transplacental glucose concentration gradient. The increase in UPGC may help prevent an excessive supply of glucose to the fetus. In the hypoglycemic animals, weight-specific UPGC and uteroplacental oxygen uptake were not different from controls; placental weight also was reduced, an adaptation that maintained normal placental metabolism per unit tissue and did not disproportionately deprive the fetus of glucose supply.

Hypoglycaemic effect of Momordica charantia extracts in normoglycaemic or cyproheptadine-induced hyperglycaemic mice

The hypoglycaemie effect of orally administered extracts of Momordica charantia L. fruits was examined in normoglycaemic or cyproheptadine-induced hyperglycaemic mice. The aqueous extract reduced the fasting glucose levels of hyperglycaemic or normoglycaemic mice. However, the ethanol extract did not affect the fasting or nonfasting glucose levels significantly in both groups of mice. There was no significant difference between the glucose-loaded and glucose-loaded plus aqueous extract given group. On the other hand, oral glucose-loading of the cyproheptadine-induced hyperglycaemic animals reduced the fasting glucose levels significantly. These results showed that aqueous extract of M. charantia fruits has a hypoglyeaemic activity without improving the tolerance to glucose in cyproheptadine-induced diabetic mice.

Preischemic hyperglycemia leads to delayed postischemic hyperthermia.

Temperature alterations are known to influence the outcome of transient ischemia, even when instituted in the postischemic period. Since preischemic hyperglycemia aggravates ischemic brain damage, the question of whether hyperglycemic animals become hyperthermic arose. To explore this possibility, we measured body temperature telemetrically in normoglycemic and hyperglycemic rats subjected to 10 minutes of forebrain ischemia at a body (and brain) temperature of 37 degrees C. Isoflurane-anesthetized animals were subjected to 10 minutes of forebrain ischemia under normoglycemic or hyperglycemic conditions. Temperature changes after ischemia were measured by means of a telemetric temperature coil. In normoglycemic animals, temperature decreased to 35.6 +/- 1.1 degrees C (mean +/- SD) during the first 4 hours of recovery, after which it gradually increased to normal values (38 degrees C). Hyperglycemic animals behaved differently in that they remained normothermic for approximately 10 hours during recovery and later became hyperthermic, with core temperatures rising above 39 degrees C. The rise in temperature was not due to the osmotic load of the glucose administered because infusion of mannitol, which gave a comparable increase in plasma osmolality, failed to cause delayed postischemic hyperthermia. Excessive hypercapnia during ischemia in normoglycemic animals, which produces cerebral acidosis of a magnitude similar to that of hyperglycemia and is known to aggravate ischemic lesions, likewise failed to induce hyperthermia. When post-ischemic seizures ensued in hyperglycemic subjects, temperature was 39.8 +/- 0.6 degrees C. Animals with seizures invariably died. To evaluate the influence of postischemic hyperthermia on the outcome, an additional series of experiments was performed in which delayed hyperthermia was avoided by gentle cooling (n = 6) or by acetaminophen administration (n = 5). Although these procedures prevented delayed hyperthermia, they neither blocked seizure induction nor affected the fatal outcome. Postischemic seizures developed when the core temperatures of animals were 37.9 +/- 0.1 degrees C and 37.8 +/- 0.2 degrees C in the cooled and acetaminophen-treated groups, respectively. The results suggest that both delayed hyperthermia and delayed seizures in hyperglycemic animals are caused by the aggravated damage incurred by these animals during or immediately after the ischemic insult.

Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals

The concentration of extracellular glucose in anesthetized rat brain was measured continuously with two types of substrate-specific microelectrodes in a number of physiological and pathological conditions. Extracellular glucose level increased in hyperglycemia and decreased in hypoglycemia, paralleling the changes in blood sugar. Increased neuronal activity and in particular spreading depression, evoked triphasic alterations in extracellular glucose concentration: an initial rapid fall was followed by an equally swift overshoot above the baseline and a subsequent return to it. Limitation in O2 supply led to a decline in extracellular content of glucose: respiration with 5% O2 reduced the level by 7-20% and that with 3% O2 by 75-85%. Decreases to undetectable concentrations were seen in ischemia despite the use of an oxygen-insensitive microglucose sensor. Restoration of oxygen supply to the brain was accompanied by increases in extracellular glucose content above the original normoxic level, which returned to baseline values after 10-15 min. In hyperglycemic animals ischemia-induced leakage of K+ was delayed while the rate of recovery to control levels after restitution of blood flow was enhanced. It is concluded that continuous monitoring of glucose with glucose-specific microelectrodes provides a new and important insight into brain energy metabolism.

The influence of pH on cellular calcium influx during ischemia

The objective of this study was to explore how alterations in tissue pH during ischemia influence cell calcium uptake, as this is reflected in the extracellular calcium concentration (Ca e 2+). Variations in pH were achieved by making animals hypo-, normo- or hyperglycemic prior to cardiac arrest ischemia or by increasing preischemic PCO 2 in normoglycemic animals. For comparison, the N-methyl- d-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) was given prior to induction of ischemia. In some experiments the effect of acidosis on K + efflux and Na + influx were studied as well. In hypoglycemic subjects, the reduction of Ca e 2+ during ischemia was very rapid, 90% of the reduction occurring within 4.7 s. Normoglycemic animals showed a slower rate of reduction of Ca e 2+. Hyperglycemic animals displayed an even slower rate of reduction and a biphasic response in which the initial, faster influx of Ca 2+ was followed by a conspicuously slow one. This second phase led to a very gradual decrease in Ca e 2+, a stable level being reached first after 6–7 min. This marked delay in calcium influx during ischemia was very similar in hypercapnic animals, who showed an extracellular pH during ischemia as low as hyperglycemic subjects. The effect of acidosis was duplicated by MK-801, suggesting that low pH reduces calcium influx by blocking NMDA-gated ion channels.

The VMH-dietary obese rat: a new model of non-insulin-dependent diabetes mellitus.

A model of non-insulin-dependent diabetes mellitus (NIDDM) has been developed in adult rats by combining bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) and high fat-high sucrose diets. VMH-dietary obese rats showed fasting hyperinsulinemia (> or = 540 pM) and hypertriglyceridemia (> or = 180 mg/dl) generally within 3 wk on the protocol. Fasting hyperglycemia (> or = 10 mM) was observed in the majority of animals in seven consecutive experiments. Hyperglycemic animals showed impaired glucose tolerance despite high prevailing insulin levels. Pancreatic islets isolated from VMH-dietary obese rats showed a loss of insulin secretory response to glucose by week 5, before the onset of hyperglycemia. Islets from hyperglycemic rats no longer responded to an increase in glucose concentration and failed to suppress insulin release normally in response to 15 nM norepinephrine or to a decrease in glucose concentration. This model mimics the major characteristics of obesity-associated human NIDDM as well as several stages of its progression, rendering it useful for studying the etiology of the metabolic and secretory defects in the syndrome.

Moderate hyperglycemia affects ischemic brain ATP levels but not intracellular pH.

We used 31P nuclear magnetic resonance (NMR) spectroscopy to study the effect of moderate hyperglycemia on brain ATP and intracellular pH in a model of severe incomplete forebrain ischemia. Plasma glucose in the hyperglycemic rats was 277 +/- 9 mg/100 ml compared with 115 +/- 10 mg/100 ml in the normoglycemic rats at the onset of ischemia. After 15 min of ischemia, brain ATP levels decreased to 31 +/- 8% in normoglycemic rats vs. 63 +/- 11% in hyperglycemic rats (P < 0.05). Phosphocreatine levels were 31 +/- 9 and 55 +/- 8% for normoglycemic and hyperglycemic rats, respectively. Intracellular pH decreased to the same level (approximately 6.5) in both normoglycemic and hyperglycemic animals after 15 min of ischemia. In summary, we found that moderate hyperglycemia during severe incomplete forebrain ischemia significantly increases ischemic brain ATP levels but does not have a significant effect on intracellular pH. These results support the hypothesis that alterations in brain ATP and adenosine concentrations may be important in the pathogenesis of ischemic tissue injury under moderate hyperglycemic conditions, whereas alterations in tissue pH may be less important.

Effects of theophylline and cyclohexyladenosine on brain injury following normo- and hyperglycemic ischemia: a histopathologic study in the rat.

The present study was designed to determine the effects of theophylline, an adenosine receptor antagonist, and cyclohexyladenosine (CHA), an adenosine receptor agonist, on ischemic brain injury following normo- and hyperglycemic ischemia and reperfusion in fasted male Wistar rats. Moderate hyperglycemia was achieved by administering 17% D-glucose (3 g/kg i.p.), whereas normoglycemic animals received an equal volume of saline. The animals were further divided into two groups: One group was pretreated with either theophylline (0.20 mumol/g i.p.) or an equal volume of saline; the second group received either intraventricular CHA (6.25 nmol) or mock CSF prior to the onset of ischemia. During ischemia, pericranial temperature was maintained at 36 degrees C and EEG was monitored. Cerebral ischemia was induced for 15 min, after which flow was restored and the animals were allowed to recover completely. There were no significant differences in physiologic parameters among the groups studied. Five days following the ischemic episode, the rats were perfused with formalin and the brains subserially sectioned (8 microns) in the coronal plane and stained with celestine blue/acid fuchsin. Histopathologic analysis was performed in a blinded fashion to determine percentage of dead neurons. Hyperglycemic animals had significantly greater ischemic injury in CA1, cortex, and caudate than the normoglycemic group (p < 0.01). Moreover, rats pretreated with theophylline had a significantly (p < 0.01) higher percentage of dead neurons in CA1, cortex, and caudate than corresponding controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic changes associated with altering blood glucose levels in short duration forebrain ischemia

31P nuclear magnetic resonance spectroscopy was used to follow changes in cerebral pH and high-energy phosphate metabolites during forebrain ischemia in hypo-, normo- and hyperglycemic rats, and during reperfusion in animals in which the blood glucose level was altered post-ischemia. Pre-ischemia, no differences in the levels of inorganic phosphate (P i) and adenosine triphosphate (ATP) relative to phosphocreatine (PCr) or in tissue pH between blood glucose groups were observed. During ischemia, the decrease in tissue pH was found to be dependent on the pre-ischemic blood glucose concentration, being greatest in hyperglycemic and least in hypoglycemic animals. The increase of P i, a consequence of the hydrolysis of high-energy phosphate metabolites, also depended on the blood glucose concentration, being greatest in hypoglycemic and least in hyperglycemic animals. ATP and PCr decreased more rapidly in hypoglycemic rats compared to normo- or hyperglycemic animals, which showed no differences in the rates of depletion. Post-ischemic hyperglycemia resulted in delayed recovery of tissue pH in all groups and of PCr and ATP in animals hyperglycemic throughout the experiment. Insulin administration immediately following ischemia increased the rate of recovery of pH, ATP and PCr in hyperglycemic animals. ATP remained significantly below pre-ischemia level in all subgroups at 1 h post-ischemic, while PCr was lower than it was pre-ischemia only in those subgroups hyperglycemic prior to and/or following ischemia. In animals maintained severely hypoglycemic throughout the experiment, erratic blood pressure and cerebral energy failure during the reperfusion interval were observed.

Coupling of Energy Failure and Dissipative K+ Flux during Ischemia: Role of Preischemic Plasma Glucose Concentration

The present experiments were undertaken to assess the influence of preischemic hypo- or hyperglycemia on the coupling among changes in extracellular K+ concentration (K+e) and in cellular energy state, as the latter is reflected in the tissue concentrations of phosphocreatine (PCr), Cr, ATP, ADP, and AMP, and in the calculated free ADP (ADPf) concentrations. The questions posed were whether the final release of K+ was delayed because the extra glucose accumulated by hyperglycemic animals produced enough ATP to continue supporting Na(+)-K(+)-driven ATPase activity, and whether the additional acidosis altered the ionic transients. As expected, preischemic hypoglycemia shortened and hyperglycemia prolonged the phase before K+e rapidly increased. This was reflected in corresponding changes in tissue ATP content. Thus, hypoglycemia shortened and hyperglycemia prolonged the time before the fall in ATP concentration accelerated. When tissue was frozen at the moment of depolarization, the tissue contents of ATP were similar in hypo-, normo-, and hyperglycemic groups, approximately 30% of control. This suggests that hyperglycemia retards loss of ion homeostasis by leading to production of additional ATP. However, hyperglycemia did not reduce the rate at which the PCr concentration fell, and the ATP/ADPf ratio decreased. There were marked differences in the amount of lactate accumulated between the groups. Thus, massive depolarization in hypoglycemic groups occurred at a tissue lactate content of approximately 4 mM kg-1. This corresponds to a decrease in intracellular pH (pHi) from approximately 7.0 to approximately 6.9. In the hyperglycemic groups, depolarization occurred at a lactate content of about 12 mm kg-1, corresponding to a pHi of approximately 6.4.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperglycemia increases cerebral intracellular acidosis during circulatory arrest

Phosphorus 31 nuclear magnetic resonance spectroscopy was used to assess cerebral high-energy phosphate metabolism and intracellular pH in normoglycemic and hyperglycemic sheep during hypothermic circulatory arrest. Two groups of sheep (n = 8 per group) were placed in a 4.7-T magnet and cooled to 15 °C using cardiopulmonary bypass. Spectra were acquired before and during circulatory arrest and during reperfusion and rewarming. Intracellular pH and adenosine triphosphate levels decreased during circulatory arrest. Compared with the normoglycemic animals, the hyperglycemic group was significantly more acidotic with the greatest difference observed during the first 20 minutes of reperfusion (6.40 ± 0.08 versus 6.08 ± 0.06; p < 0.001). Intracellular pH returned to baseline after 30 minutes of reperfusion in the normoglycemic group but did not reach baseline until 1 hour of reperfusion in the hyperglycemic animals. Adenosine triphosphate levels were significantly higher in the hyperglycemic group during circulatory arrest. Repletion of adenosine triphosphate during reperfusion was similar for both groups. These results support the hypothesis that hyperglycemia during cerebral ischemia drives anaerobic glycolysis and thus leads to increased lactate production and a decrease in the intracellular acidosis normally associated with ischemia.

Forebrain ischemia in diabetic and nondiabetic BB rats studied with 31P magnetic resonance spectroscopy.

In spontaneously diabetic BB rats, the effect of chronically maintained blood glucose levels on the degree of energy failure and brain pH change during an ischemic insult, and on subsequent recovery after reperfusion, was studied with in vivo 31P magnetic resonance spectroscopy. Short duration forebrain ischemia (10-min carotid occlusion plus hypotension of 50 mmHg) was induced in diabetic and nondiabetic male BB rats whose blood glucose levels were maintained with insulin. Spectra were obtained in 1-min blocks before, during, and for 1 h after ischemia. Before ischemia, hypoglycemic (blood glucose less than 3 mM) diabetic rats had an increased Pi peak intensity, with no significant pH change, compared with other groups. During ischemia, the rate and extent of hydrolysis of high-energy phosphate metabolites (as measured by an increase in Pi) decreased, and the severity of tissue acidosis increased as preischemia blood glucose concentration increased. Among hyperglycemic BB rats, similar ischemia-induced changes were found for subgroups with blood glucose levels of 13.7 +/- 1.2 and 20.3 +/- 0.6 mM, in keeping with the known decrease in hexose binding sites associated with chronic hyperglycemia. Decline in PCr level during ischemia was not significantly different between groups. With reperfusion, both Pi and pH values rapidly returned to preischemia values. PCr levels, however, did not recover in hyperglycemic diabetic animals, with the degree of residual impairment dependent on the preischemia glucose level. Results suggest that optimal management of diabetes may lessen the degree of injury within the ischemic penumbra in diabetic patients who suffer a stroke.

Influence of experimental hyperglycemia on microvascular blood perfusion of pancreatic islet isografts.

The influence of hyperglycemia on the microvascular blood perfusion of pancreatic islet isografts of Syrian golden hamsters was analyzed by direct visualization of the islet's microvasculature by means of in vivo fluorescence microscopy. The experiments were performed using the hamster dorsal skinfold preparation, which allows for quantitative analysis of the microcirculation of islets grafted on the striated skin muscle. Islets were isolated from inbred hamsters by collagenase digestion and subsequently transplanted in normoglycemic (controls; n = 8) and hyperglycemic (65 mg/kg streptozotocin intravenously; n = 10) recipients. In both groups, revascularization of the islet grafts was completed on day 10 after transplantation. Quantitative analysis of capillary blood perfusion on days 6, 10, and 14 revealed no differences in functional capillary density and capillary red blood cell velocity of islets grafted into normoglycemic as compared to hyperglycemic animals. However, islet capillaries were significantly wider in hyperglycemic recipients (11.9 +/- 1.3 microns, P < 0.01) as compared to normoglycemic controls (8.9 +/- 0.4 microns). The increase of capillary diameters resulted in a significant rise (P < 0.01) of mean capillary blood perfusion from 1.76 +/- 0.39 nl/min in controls to 2.88 +/- 0.63 nl/min in hyperglycemic recipients, indicating an increase in microvascular blood perfusion due to hyperglycemia. From these results it is concluded that hyperglycemia is associated with higher capillary blood perfusion in revascularized islet isografts, similarly as known for pancreatic islets in situ.

Influence of preischemic hyperglycemia on osmolality and early postischemic edema in the rat brain.

Preischemic hyperglycemia, which raises tissue lactate content during ischemia, is known to aggravate ischemic brain damage. To explore the possibility that the enhanced lactic acidosis gives rise to osmotic damage, we studied the influence of a varied preischemic plasma glucose concentration on the early postischemic edema. Brain edema was measured by the specific-gravity technique. Brain and plasma osmolality were measured with a vapor pressure osmometer. We examined different brain regions in hyperglycemic and moderately hypoglycemic rats subjected to 15 min of forebrain ischemia, followed by recirculation for 5, 15, and 30 min. The decrease in specific gravity was compared with the increase in osmolality, to study whether the edema formation in the different groups correlated to the increase in tissue osmolality. We found edema formation to be most pronounced in frontoparietal cortex. In this structure and in hippocampus, statistically significant decreases of specific gravity were seen at all recirculation times studied. In caudoputamen, significant edema was seen only in the groups with 5 and 15 min of recirculation. Contrary to expectations, no difference was found between hyperglycemic and hyperglycemic animals. Tissue osmolality increased during ischemia in both the low and high glucose groups, but to a higher level in the latter (hypoglycemia 311 +/- 1 mmol kg-1, hyperglycemia 328 +/- 10 mmol kg-1; mean +/- SD, p less than 0.05). In the hyperglycemic group, brain osmolality remained elevated for the first 15 min of recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum glucose: effects on tumor and normal tissue accumulation of 2-[F-18]-fluoro-2-deoxy-D-glucose in rodents with mammary carcinoma.

The positron-emitter-labeled glucose analogue 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) accumulates into many cancers after intravenous injection, but the effect of serum glucose levels on FDG uptake in the tumor has not been extensively studied. In vitro, elevated media glucose levels markedly diminished FDG and FDG 6-phosphate uptake and retention in human adenocarcinoma cells, while insulin had no effect. Mammary cancers were established subcutaneously in 12 rats. Six control rats with mammary tumors were fasted overnight. Hyperglycemia was established in six rats by means of continuous glucose infusion (glucose clamp). All animals were then intravenously administered 50 microCi of FDG. Serum glucose levels were 87 mg/dL (4.83 mmol/L) in the control animals and more than 900 mg/dL (49.9 mmol/L) in the hyperglycemic animals. One hour after injection of FDG, mean F-18 uptake in the tumor, brain, small bowel, and ovaries was 2.7-9.7 times lower in the hyperglycemic animals (P less than .02). Mean F-18 activity in the kidneys tended to be somewhat higher in the hyperglycemic animals. FDG uptake in other tissues was comparable between the control and hyperglycemic groups. These data suggest that high serum glucose levels may substantially impair visceral tumor imaging with FDG positron emission tomography.