Effects of insulin-induced hypoglycemia on somatostatin level and binding in rat cerebral cortex and hippocampus

The effects of severe insulin-induced hypoglycemia on somatostatin level and specific binding in the cerebral cortex and hippocampus were examined using 125I-Tyr11-somatostatin as a ligand. Severe insulin-induced hypoglycemia did not affect the level of somatostatin-like immunoreactivity in the brain areas studied. However, the number (but not the affinity) of specific somatostatin receptors was significantly decreased in membrane preparation from the hippocampus but not in the cerebral cortex at the onset of hypoglycemic coma (5-10 min). Administration of glucose at the onset of hypoglycemic coma brought about extensive recovery of hippocampal somatostatin receptor number. These results suggest that glucose modulates the somatostatin receptor in the rat hippocampus. The physiological significance of these findings remains to be clarified.     

Effects of d-3-hydroxybutyrate treatment on hypoglycemic coma in rat pups

d-3-Hydroxybutyrate (3OHB) is an alternative energy substrate for the brain during hypoglycemia, especially in infancy. Knowledge of the capacity and limits of 3OHB to compensate for cerebral glucose depletion during hypoglycemia in developing brain is important for its potential clinical use, but is scarce. We studied the effect of 3OHB treatment during insulin-induced hypoglycemia in 13-day-old rat pups. 3OHB treatment resulted in increased 3OHB plasma levels in hypoglycemic animals (3–4 mM vs. 0.5–1 mM untreated), and delayed the onset of clinical coma by 70 min and of burst-suppression coma by 90 min. 3OHB treated animals did not survive after resuscitation with glucose, compared to 80% survival of untreated hypoglycemic pups. Cleaved-caspase-3 immunohistochemistry and double labeling studies demonstrated a 20-fold increase of apoptotic mature oligodendrocytes in white matter of 3OHB treated animals. 3OHB treatment delays the onset of clinical and burst-suppression coma during hypoglycemia, but the prolonged duration of hypoglycemia is associated with increased mortality after resuscitation and cellular white matter injury.     

Effects of fasting and insulin-induced hypoglycemia on brain cell membrane function and energy metabolism during hypoxia-ischemia in newborn piglets.

This study was done to determine the effects of 12 h fasting-induced mild hypoglycemia (blood glucose 60 mg/dl) and insulin-induced moderate hypoglycemia (blood glucose 35 mg/dl) on brain cell membrane function and energy metabolism during hypoxia-ischemia in newborn piglets. Sixty-three ventilated piglets were divided into six groups; normoglycemic control (NC, n=8), fasting-induced mildly hypoglycemic control (FC, n=10), insulin-induced moderately hypoglycemic control (IC, n=10), normoglycemic/hypoxic-ischemic (NH, n=11), fasting-induced mildly hypoglycemic/hypoxic-ischemic (FH, n=12) and insulin-induced moderately hypoglycemic/hypoxic-ischemic (IH, n=12) group. Cerebral hypoxia-ischemia was induced by occlusion of bilateral common carotid arteries and simultaneous breathing with 8% oxygen for 30 min. The brain lactate level was elevated in NH group and this change was attenuated in FH and IH groups. The extent of cerebral lactic acidosis during hypoxic-ischemic insult showed significant positive correlation with blood glucose level (r=0.55, p<0.001). Cerebral Na+, K+-ATPase activity and concentrations of high-energy phosphate compounds were reduced in NH group and these changes were not ameliorated in FH or IH group. Cortical levels of conjugated dienes, measured as an index of lipid peroxidation of brain cell membrane, were significantly elevated in NH, FH and IH groups compared with NC, FC and IC groups and these increases were more profound in FH and IH with respect to NH. Blood glucose concentration showed significant inverse correlation with levels of conjugated dienes (r=-0.35, p<0.05). These findings suggest that, unlike in adults, mild or moderate hypoglycemia, regardless of methods of induction such as fasting or insulin-induced, during cerebral hypoxia-ischemia is not beneficial and may even be harmful in neonates.     

Neuropathy in diabetic BB/Wor rats treated with insulin implants

To elucidate the pathophysiology of diabetic neuropathy many workers have examined nerve specimens from diabetic rats. While most workers found that animals with high blood glucose levels develop neuropathy, some researchers report that the peripheral nerves are normal in hyperglycaemic rats. Hypoglycaemia may also cause neuropathy. Some workers suggest that neuropathy is linked to fluctuations of the blood glucose level. In the present study we examine plantar nerves of diabetic BB/ Wor rats maintained on an eu-/hyperglycaemic or an eu-/ hypoglycaemic regime with insulin implants. Treatment with implants worked well. Light microscopic examination of nerve fibres in non-diabetic control rats and in eu-/ hyperglycaemic diabetic rats showed a normal picture. Preparations from eu-/hypoglycemic rats showed irregular myelin sheaths and signs of Wallerian degeneration. The lengths and diameters of the largest internodes were significantly subnormal. We conclude, that periodic moderate hypoglycaemia, but not periodic moderate hyperglycaemia, elicits neuropathy in diabetic BB/Wor rats treated with insulin implants. Received: 5 December 1997 / Revised, accepted: 3 February 1998     

MK801 decreases glutamate release and oxidative metabolism during hypoglycemic coma in piglets.

Hypoglycemic coma increases extracellular excitatory amino acids, which mediate hypoglycemic neuronal degeneration. Cerebral oxygen consumption increases during hypoglycemic coma in piglets. We tested the hypothesis that the NMDA-receptor antagonist dizocilpine (MK801) attenuates the increase in cerebral oxygen consumption during hypoglycemia. We measured EEG, cerebral blood flow (CBF), cerebral oxygen consumption (CMRO(2)) and cortical microdialysate levels of glutamate, aspartate and glycine in pentobarbital-anesthetized piglets during 60 min of insulin-induced hypoglycemic coma. NMDA-receptor distribution was measured by autoradiography. MK801 (0.75 mg/kg i.v.) was given within 5 min after onset of isoelectric EEG. Saline- and MK801-treated normoglycemic control animals were also studied. Brain temperature was maintained at 38.5+/-0.5 degrees C. MK801 prevented the 5--10-fold increase in glutamate and aspartate occurring in saline-treated hypoglycemic animals, and attenuated the increase in CMRO(2). Increases in CBF of 200--400% during hypoglycemic coma were not affected by MK801. MK801 did not alter CBF, CMRO(2) or microdialysate amino acid levels in normoglycemic control animals. Parietal cortex corresponding to microdialysis sites was highly enriched in NMDA receptors, and the density and distribution overall of NMDA receptor binding sites were comparable to that reported in other species. We conclude that NMDA receptor activation plays a central role in hypoglycemia-induced glutamate release, and contributes to increased cerebral oxygen consumption. Neuroprotective effects of MK801 during hypoglycemia in piglets may involve inhibitory effects on glutamate release and oxidative metabolism.     

The lumped constant of the deoxyglucose method in hypoglycemia: effects of moderate hypoglycemia on local cerebral glucose utilization in the rat

The applicability of the [14C]deoxyglucose method for measuring local cerebral glucose utilization (lCMRglc) has been extended for use in hypoglycemia by determination of the values of the lumped constant to be used in rats with plasma glucose concentrations ranging from approximately 2 to 6 mM. Lumped constant values were higher in hypoglycemia and declined from a value of 1.2 at the lowest arterial plasma glucose level (1.9 mM) to about 0.48 in normoglycemia. The distribution of glucose, and therefore also of the lumped constant, was found to remain relatively uniform throughout the brain at the lowest plasma glucose levels studied. lCMRglc in moderate, insulin-induced hypoglycemia (mean arterial plasma glucose concentration +/- SD of 2.4 +/- 0.3 mM) was determined with the appropriate lumped constant corresponding to the animal's plasma glucose concentration and compared with the results obtained in six normoglycemic rats. The weighted average rate of glucose utilization for the brain as a whole was significantly depressed by 14% in the hypoglycemic animals, i.e., 61 mumols/100 g/min in hypoglycemia compared to 71 mumols/100 g/min in the normoglycemic controls (p less than 0.05). lCMRglc was lower in 47 of 49 structures examined but statistically significantly below the rate in normoglycemic rats in only six structures (p less than 0.05) by multiple comparison statistics. Regions within the brainstem were most prominently affected. The greatest reductions, statistically significant or not, occurred in structures in which glucose utilization is normally high, suggesting that glucose delivery and transport to the tissue became rate-limiting first in those structures with the greatest metabolic demands for glucose.     

Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozoticin induced diabetic rats

Intensive glycemic control during diabetes is associated with an increased incidence of hypoglycemia, which is the major barrier in blood glucose homeostasis during diabetes therapy. The CNS neurotransmitters play an important role in the regulation of glucose homeostasis. In the present study, we showed the effects of hypoglycemia in diabetic and non- diabetic rats on motor functions and alterations of GABA receptor and CREB expression in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. Scatchard analysis of [³H]GABA binding in the cerebellum of diabetic hypoglycemic and control hypoglycemic rats showed significant (P < 0.01) decrease in B_max and K_d compared to diabetic and control rats. Real-time PCR amplification of GABA receptor subunit GABA_Aα1 and GAD showed significant (P < 0.001) down-regulation in the cerebellum of hypoglycemic rats compared to diabetic and control rats. Confocal imaging study confirmed the decreased GABA receptors in hypoglycemic rats. CREB mRNA expression was down-regulated during recurrent hypoglycemia. Both diabetic and non-diabetic hypoglycemic rats showed impaired performance in grid walk test compared to diabetic and control. Impaired GABA receptor and CREB expression along with motor function deficit were more prominent in hypoglycemic rats than hyperglycemic which showed that hypoglycemia is causing more neuronal damage at molecular level. These molecular changes observed during hypo/hyperglycemia contribute to motor and learning deficits which has clinical significance in diabetes treatment.     

Hypoglycemia reduces the blood-oxygenation level dependent signal in primary auditory and visual cortex: a functional magnetic resonance imaging study

Studies of the effects of hypoglycemia on the brain using neurocognitive testing have suggested that mainly complex functions subserved by secondary and tertiary cortex are affected by mild to moderate hypoglycemia and that intensively treated patients with Type I diabetes mellitus (T1DM) may have altered sensitivity to the central nervous system effects of hypoglycemia. Functional magnetic resonance imaging provides a sensitive, regionally-specific probe of possible neurophysiologic changes related to hypoglycemia in the brain. Eleven intensively-treated T1DM patients and 11 matched non-diabetic controls took part in a 2-day protocol in which functional magnetic resonance imaging (MRI) was used to measure changes in the patterns of brain activation produced by simple auditory and visual stimuli in different conditions. On one day, participants were euglycemic the entire time. On the other day, an initial 50-min euglycemic period was followed by a 50-min hypoglycemic period. Results indicated that hypoglycemia reduced the amplitude of the blood-oxygenation level dependent response in primary auditory and visual cortex to simple auditory and visual stimuli. The latency and duration of the transient hemodynamic response function were not affected. Responses to hypoglycemia were similar in diabetic and non-diabetic participants. These results suggest that mild to moderate hypoglycemia may alter the balance of blood flow and oxygen extraction when glucose levels are lowered. Intensively-treated T1DM, with its attendant frequent hypoglycemic episodes, did not seem to alter hypoglycemic responses in primary visual and auditory cortex.     

Extracellular pH in the rat brain during hypoglycemic coma and recovery

It has previously been shown that hypoglycemic coma is accompanied by marked energy failure and by loss of cellular ionic homeostasis. The general proposal is that shortage of carbohydrate substrate prevents lactic acid formation and thereby acidosis during hypoglycemic coma. The objective of the present study was to explore whether rapid downhill ion fluxes, known to occur during coma, are accompanied by changes in extra- and/or intracellular pH (pHe and/or pHi), and how these relate to the de- and repolarization of cellular membranes. Cortical pHe was recorded by microelectrodes in insulin-injected rats subjected to 30 min of hypoglycemic coma, with cellular membrane depolarization. Some rats were allowed up to 180 min of recovery after glucose infusion and membrane repolarization. Arterial blood gases and physiological parameters were monitored to maintain normotension, normoxia, normocapnia, and normal plasma pH. Following depolarization during hypoglycemia, a prompt, rapidly reversible alkaline pHe shift of about 0.1 units was observed in 37/43 rats. Immediately thereafter, all rats showed an acid pH shift of about 0.2 units. This shift developed during the first minute, and pHe remained at that level until repolarization was induced. Following repolarization, there was an additional, rapid, further lowering of pHe by about 0.05 units, followed by a more prolonged decrease in pHe that was maximal at 90 min of recovery (delta pHe of approximately -0.4 units). The pHe then slowly normalized but was still decreased (-0.18 pH units) after 180 min when the experiment was terminated. The calculated pHi showed no major alterations during hypoglycemic coma or after membrane repolarization following glucose administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of insulin-induced hypoglycemia on blood-brain barrier permeability

The effects of hypoglycemia on cerebrovascular permeability to the Evans blue-albumin complex were studied in rats injected with 50 IU/kg, i.v. crystalline zinc insulin. One group of hypoglycemic animals was warmed to keep their body temperatures close to 37 degrees C, and the rats in the other group were allowed to become hypothermic by hypoglycemia. The arterial blood pressures of the hypoglycemic rats were continuously monitored during the coma and a significant rise in pressure was observed in most animals at the end of the coma. When glucose was administered i.v. to five animals of each group, this elevated pressure returned to normal values within 0.5 min and the animals slowly recovered normal behavior. At termination of the coma, most brains in the hypothermic hypoglycemic group showed an intensive and extensive staining by Evans blue; whereas only two brains in the normothermic hypoglycemic group showed any noticeable extravasation of Evans blue-albumin. Arterial PO2, PCO2, and pH were determined and no significant difference was found between values from animals in hypoglycemic coma and the controls. Four animals were surface-cooled and were used to examine the effects of hypothermia on blood-brain barrier permeability. These brains did not show any macroscopically evident Evans blue-albumin extravasation. The results indicated that prolonged, severe hypoglycemia with hypothermia caused a profound blood-brain barrier dysfunction whereas normothermic hypoglycemia resulted in few cases of any noticeable increase in blood-brain barrier permeability.     

Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia

The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 7.1 +/- 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes after glucose-induced recovery, the PDHC activity had decreased by 33% compared to control levels, and remained significantly depressed after 3 h of recovery. This decrease in activity was not due to a decrease in the total PDHC activity. At 24 h of recovery, PDHC activity had returned to control levels. We conclude that the activation of PDHC during hypoglycemic coma is probably the result of an increased PDH phosphatase activity following depolarization and calcium influx, and allosteric inhibition of PDH kinase due to increased ADP/ATP ratio. The depression of PDHC activity following hypoglycemic coma is probably due to an increased phosphorylation of the enzyme, as a consequence of an imbalance between PDH phosphatase and kinase activities. Since some reduction of the ATP/ADP ratio persisted and since the lactate/pyruvate ratio had normalized by 3 h of recovery, the depression of PDHC most likely reflects a decrease in PDH phosphatase activity, probably due to a decrease in intramitochondrial Ca2+.     

Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats

The cerebral metabolic responses to perinatal hypoglycemia and anoxia were studied in newborn rats given regular insulin (30 units per kilogram of body weight). Animals were observed for up to 2 hours with no apparent ill effects in spite of blood glucose concentrations of 0.75 mmol per liter. When exposed to 100% nitrogen at 37°C, hypoglycemic animal survived only one-tenth as long as littermate controls with normal blood glucose levels (4.7 mmol/L). Pretreatment of hypoglycemic rats with glucose (10 mmol/kg) 10 and 30 minutes prior to nitrogen exposure nearly completely reversed the anoxic vulnerability. Hypoglycemia led to progressive reductions in crebral glycogen and glucose; however, only glucose reverted to normal levels 20 minutes after systemic glucose administration. The glycolytic intermediates glucose 6-phosphate and lactate were also lower during hypoglycemia. Brain glucose levels below 0.1 mmol per kilogram were associated with a disrupted cerebral energy state, reflected by declines in phosphocreatine (33%) and adenosine triphosphate (ATP) (10%). Cerebral energy utilization (metabolic rate) was minimally reduced (?7.2%) by hypoglycemia and returned to the control value (2.36 mmol ～ P/kg/min) with glucose treatment. The cerebral energy reserves ATP, adenosine diphosphate, and phosphocreatine delined more rapidly and to a lower level in hypoglycemic rats subjected to 2 1/2 minutes of anoxia than in normoglycemic animals rendered similarly hypoxic. The findings suggest that decreased anoxic resistance of hypoglycemic newborn rats is not primarily a function of reduced brain glycogen or altered cerebral metabolic rate. The presence of endogenous cerebral glucose stores combined with continued circulating glucose (cerebrovascular perfusion) appear to be critical factors for maintaining perinatal hypoxic survival.     

Effects of fasting and insulin-induced hypoglycemia on brain cell membrane function and energy metabolism during hypoxia–ischemia in newborn piglets

This study was done to determine the effects of 12 h fasting-induced mild hypoglycemia (blood glucose 60 mg/dl) and insulin-induced moderate hypoglycemia (blood glucose 35 mg/dl) on brain cell membrane function and energy metabolism during hypoxia–ischemia in newborn piglets. Sixty-three ventilated piglets were divided into six groups; normoglycemic control (NC, n=8), fasting-induced mildly hypoglycemic control (FC, n=10), insulin-induced moderately hypoglycemic control (IC, n=10), normoglycemic/hypoxic–ischemic (NH, n=11), fasting-induced mildly hypoglycemic/hypoxic–ischemic (FH, n=12) and insulin-induced moderately hypoglycemic/hypoxic–ischemic (IH, n=12) group. Cerebral hypoxia–ischemia was induced by occlusion of bilateral common carotid arteries and simultaneous breathing with 8% oxygen for 30 min. The brain lactate level was elevated in NH group and this change was attenuated in FH and IH groups. The extent of cerebral lactic acidosis during hypoxic–ischemic insult showed significant positive correlation with blood glucose level (r=0.55, p<0.001). Cerebral Na⁺, K⁺-ATPase activity and concentrations of high-energy phosphate compounds were reduced in NH group and these changes were not ameliorated in FH or IH group. Cortical levels of conjugated dienes, measured as an index of lipid peroxidation of brain cell membrane, were significantly elevated in NH, FH and IH groups compared with NC, FC and IC groups and these increases were more profound in FH and IH with respect to NH. Blood glucose concentration showed significant inverse correlation with levels of conjugated dienes (r=−0.35, p<0.05). These findings suggest that, unlike in adults, mild or moderate hypoglycemia, regardless of methods of induction such as fasting or insulin-induced, during cerebral hypoxia–ischemia is not beneficial and may even be harmful in neonates.     

Hypoglycemic encephalopathy with extensive lesions in the cerebral white matter

Here we report an autopsy case of hypoglycemic encephalopathy with prolonged coma. Laboratory data obtained when the patient lapsed into a coma showed that she had a low level of serum glucose (27 mg/dL). Although the level of glucose returned to within the normal range rapidly after glucose infusion, the patient remained in a coma for 22 months. It was presumed that the state of hypoglycemia persisted for about 4 h. There was no evidence of hypotension or hypoxia. Magnetic resonance imaging was performed 3 h after glucose administration; diffusion‐weighted images revealed hyperintensity in the cerebral white matter and in the boundary zone between the middle and posterior cerebral arteries. Post‐mortem examination revealed superficial laminar necrosis throughout the cerebral cortex. Neuronal necrosis was also found in the hippocampus and dentate gyrus, although the CA3 region appeared normal. In addition to these lesions, which are consistent with hypoglycemia‐induced brain damage, the cerebral white matter exhibited severe loss of myelin and axons with reactive astrocytosis and macrophage infiltration. Old infarcts were also present in the bilateral occipital lobes. Since the cerebral blood flow is reported to be decreased during severe hypoglycemia, the present findings suggest that white matter lesions and boundary‐zone infarctions may develop primarily in uncomplicated hypoglycemia.     

Disruption of Mitochondrial Homeostasis by Phytanic Acid in Cerebellum of Young Rats

Phytanic acid (Phyt) brain concentrations are highly increased in Refsum disease, a peroxisomal disorder clinically characterized by neurological features, cardiac abnormalities, and retinitis pigmentosa. Considering that the pathogenesis of cerebellar ataxia, a common finding in this disease, is still unknown, in the present work we investigated the in vitro effects of Phyt at concentrations similar to those found in affected patients on important parameters of mitochondrial homeostasis in cerebellum from young rats. The respiratory parameters states 3 and 4 and respiratory control ratio (RCR) determined by oxygen consumption, membrane potential (?Ψm), NAD(P)H pool content, and swelling were evaluated in mitochondrial preparations from this cerebral structure. Phyt markedly increased state 4 respiration, whereas state 3 respiration, the RCR, the mitochondrial matrix NAD(P)H content, and ?Ψm were decreased by this fatty acid, being the latter effect partially prevented by N-acetylcysteine. These data indicate that Phyt behaves as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor disrupting mitochondrial homeostasis in cerebellum. It is proposed that these pathomechanisms may contribute at least in part to the cerebellar alterations found in Refsum disease.     

Hypotension as a complication of hypoglycemia leads to enhanced energy failure but no increase in neuronal necrosis

The hypothesis that arterial hypotension aggravates hypoglycemic brain damage was tested. Thirty minutes of insulin induced hypoglycemia with a flat EEG ("isoelectricity") was compared in seven series of rats. In three series of animals, the energy state of the cerebral cortex was determined at blood pressures of 140, 100 and 80 mm Hg respectively. Hypotension during hypoglycemia exacerbated cortical energy failure. In the fourth to sixth series, blood pressure was adjusted during isoelectricity to 160, 100 and 60 mm Hg, respectively. A seventh series had induced hypotension to 60 mm Hg only in the recovery period. Quantitation of neuronal death was performed in the fourth to seventh series of rats by direct visual counting of acidophilic neurons in sub-serially sectioned brains after one week survival. Although the first three series demonstrated enhanced deterioration of the cerebral energy state with lower blood pressures during hypoglycemia, the fourth to seventh series showed no augmentation of quantitated hypoglycemic neuronal necrosis. The distinct distribution of hypoglycemic brain damage, suggesting a fluid-borne toxin, was present at normal and reduced blood pressures, with no tendency toward an ischemic pattern of pathology. In spite of previously demonstrated reductions of cerebral blood flow to ischemic levels in regions with pronounced loss of autoregulation, no regional exacerbation of neuronal necrosis was seen in these brain areas. It is concluded that hypoglycemic brain damage is distinct from ischemic brain damage, and that the two insults are not additive. Furthermore, moderate hypotension to 60 mm Hg does not aggravate the damage in spite of an enhanced energy failure.     

Clinical restitution following cerebral ischemia in hypo-, normo- and hyperglycemic rats

Rats with different levels of blood glucose concentration were exposed to 10 min of complete brain ischemia achieved by compression of neck vessels by a pneumatic cuff. All normoglycemic rats survived the ischemic period and made the best clinical recovery. Hyperglycemic rats died within 12 h. Seizure activity was observed in all animals in this group. Three of eight hypoglycemic rats died between 3 and 16 days. The clinical recovery was less complete than in the control group. Thus, recovery from cerebral ischemia depends upon preischemic blood glucose concentration. Hyper- and hypoglycemia hamper the clinical recovery after transient cerebral ischemia.     

Regional differences in vascular autoregulation in the rat brain in severe insulin-induced hypoglycemia

The present experiments were undertaken to determine if loss of vascular autoregulation during severe hypoglycemia shows regional differences that could help to explain the localization of hypoglycemic cell damage. Artificially ventilated rats (70% N2O) were subjected to a 30-min insulin-induced hypoglycemic coma (with cessation of EEG activity), with mean arterial blood pressure being maintained at 140, 120, 100, and 80 mm Hg. After 30 min of hypoglycemia, local cerebral blood flow (CBF) in 25 brain structures was measured autoradiographically with a [14C]iodoantipyrine technique. Since local CBF values did not differ between the 120 and the 100 mm Hg groups, the animals of these groups were pooled (110 mm Hg group). The results showed that at a blood pressure of 140 mm Hg, CBF was increased in 22 of 25 structures analyzed, the maximal values approximating 300% of control. At 110 mm Hg, cerebral cortical structures had CBF values that were either decreased, normal, or slightly increased; however, many subcortical structures (and cerebellum) showed markedly increased flow rates. Although a lowering of blood pressure to 80 mm Hg usually further reduced flow rates, some of these latter structures also had well-maintained CBF values at that pressure. Thus, there were large interstructural variations of local CBF at any of the pressures examined. Analysis of the pressure-flow relationship showed loss of autoregulation in some structures, whereas others had remarkably well-preserved CBF values at low pressures. The results indicate that during severe hypoglycemia, even relatively moderate arterial hypotension may add a circulatory insult to the primary one, and they strongly suggest that any such insult affects some brain structures more than others.     

Hypoglycemic brain injury: potentiation from respiratory depression and injury aggravation from hyperglycemic treatment overshoots.

Hypoglycemia can cause brain dysfunction, brain injury, and death. The present study seeks to broaden current information regarding mechanisms of hypoglycemic brain injury by investigating a novel etiology. The cat's high resistance to brain injury from hypoglycemia suggested that additional influences such as respiratory depression might play a facilitating role. Three groups of cats were exposed to fasting and insulin-induced hypoglycemia (HG; n = 6), euglycemic respiratory depression (RD; n = 5), and combined hypoglycemic respiratory depression (HG/RD; n = 10). The HG animals were maintained at <1.5 mmol (mean 1 mmol) serum glucose concentration for 2 to 6.6 hours. The respiratory depression was associated with PaO2 and PaCO2 values of approximately 50 mm Hg for 1 hour and of approximately 35 and approximately 75 mm Hg, respectively, for the second hour. Magnetic resonance diffusion-weighted imaging estimated brain energy state before, during, and after hypoglycemia. The hypoglycemic respiratory depression exposures were terminated either to euglycemia (n = 4) or to hyperglycemia (n = 6). Brain injury was assessed after 5 to 7 days of survival. Cats exposed to hypoglycemia alone maintained unchanged diffusion coefficients; that is, they lacked evidence of brain energy failure and all six remained brain-intact. Only 1 of 5 euglycemic RD but 10 of 10 HG/RD cats developed brain damage (HG and RD vs. HG/RD, P < 0.01). This difference in brain injury rates suggests injury potentiation by hypoglycemia and respiratory depression acting together. Three injury patterns emerged, including activation of microglia, selective neuronal necrosis, and laminar cortical necrosis. Widespread activation of microglia suggesting damage to neuronal cell processes affected all damaged brains. Selective neuronal necrosis affecting the cerebral cortex, hippocampus, and basal ganglia was observed in all but one case. Instances of laminar cortical necrosis were limited to cats exposed to hypoglycemic respiratory depression treated with hyperglycemia. Thus, treatment with hyperglycemia compared with euglycemia after hypoglycemic respiratory depression exposures significantly increased the brain injury scores (24 +/- 6 vs. 13 +/- 2 points; P < 0.05). This new experimental hypoglycemia model's contribution lies in recognizing additional factors that critically define the occurrence of hypoglycemic brain injury.     

Effects of hypoglycemia on functional magnetic resonance imaging response to median nerve stimulation in the rat brain.

The authors studied the effects of a standardized mild-moderate hypoglycemic stimulus (glucose clamp) on brain functional magnetic resonance imaging (fMRI) responses to median nerve stimulation in anesthetized rats. In the baseline period (plasma glucose 6.6 +/- 0.3 mmol/L), the MR signal changes induced by median nerve activation were determined within a fixed region of the somatosensory cortex from preinfusion activation maps. Subsequently, insulin and a variable glucose infusion were administered to decrease plasma glucose. The goal was to produce a stable hypoglycemic plateau (2.8 +/- 0.2 mmol/L) for 30 minutes. Thereafter, plasma glucose was restored to euglycemic levels (6.0 +/- 0.3 mmol/L). In the early phase of insulin infusion (15 to 30 minutes), before hypoglycemia was reached (4.7 +/- 0.3 mmol/L), the activation signal was unchanged. However, once the hypoglycemic plateau was achieved, the activation signal was significantly decreased to 57 +/- 6% of the preinfusion value. Control regions in the brain that were not activated showed no significant changes in MR signal intensity. Upon return to euglycemia, the activation signal change increased to within 10% of the original level. No significant activation changes were noted during euglycemic hyperinsulinemic clamp experiments. The authors concluded that fMRI can detect alterations in cerebral function because of insulin-induced hypoglycemia. The signal changes observed in fMRI activation experiments were sensitive to blood glucose levels and might reflect increases in brain metabolism that are limited by substrate deprivation during hypoglycemia.