Biomedical subjects

Robert S Sherwin

Publications and source records attributed to Robert S Sherwin.

At least 19 recordsLinked to original sources

PubMed2007

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.

Acoustic Stimulation↗

PubMed2006

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Animals↗

PubMed2006

Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia-induced hormonal counterregulation.

Recurrent episodes of hypoglycemia impair sympathoadrenal counterregulatory responses (CRRs) to a subsequent episode of hypoglycemia. For individuals with type 1 diabetes, this markedly increases (by 25-fold) the risk of severe hypoglycemia and is a major limitation to optimal insulin therapy. The mechanisms through which this maladaptive response occurs remain unknown. The corticotrophin-releasing factor (CRF) family of neuropeptides and their receptors (CRFR1 and CRFR2) play a critical role in regulating the neuroendocrine stress response. Here we show in the Sprague-Dawley rat that direct in vivo application to the ventromedial hypothalamus (VMH), a key glucose-sensing region, of urocortin I (UCN I), an endogenous CRFR2 agonist, suppressed (approximately 55-60%), whereas CRF, a predominantly CRFR1 agonist, amplified (approximately 50-70%) CRR to hypoglycemia. UCN I was shown to directly alter the glucose sensitivity of VMH glucose-sensing neurons in whole-cell current clamp recordings in brain slices. Interestingly, the suppressive effect of UCN I-mediated CRFR2 activation persisted for at least 24 hours after in vivo VMH microinjection. Our data suggest that regulation of the CRR is largely determined by the interaction between CRFR2-mediated suppression and CRFR1-mediated activation in the VMH.

Animals↗

PubMed2006

Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation.

Defective counterregulatory responses (CRRs) to hypoglycemia are associated with a marked increase in the risk of severe hypoglycemia. The mechanisms leading to the development of defective CRRs remain largely unknown, although they are associated with antecedent hypoglycemia. Activation of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) amplifies the counterregulatory increase in glucose production during acute hypoglycemia. To examine whether activation of AMPK in the VMH restores defective CRR, controlled hypoglycemia ( approximately 2.8 mmol/l) was induced in a group of 24 Sprague-Dawley rats, all of which had undergone a 3-day model of recurrent hypoglycemia before the clamp study. Before the acute study, rats were microinjected to the VMH with either 5-aminoimidazole-4-carboxamide (AICAR; n=12), to activate AMPK, or saline (n=12). In a subset of rats, an infusion of H(3)-glucose was additionally started to calculate glucose turnover. Stimulation of AMPK within the VMH was found to amplify hormonal CRR and increase endogenous glucose production. In addition, analysis of tissue from both whole hypothalamus and VMH showed that recurrent hypoglycemia induces an increase in the gene expression of AMPK alpha(1) and alpha(2). These findings suggest that the development of novel drugs designed to selectively activate AMPK in the VMH offer a future therapeutic potential for individuals with type 1 diabetes who have defective CRRs to hypoglycemia.

AMP-Activated Protein Kinases↗

PubMed2006

Blockade of GABA(A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia.

Hypoglycemia provokes a multifaceted counterregulatory response involving the sympathoadrenal system, stimulation of glucagon secretion, and the hypothalamo-pituitary-adrenal axis that is commonly impaired in diabetes. We examined whether modulation of inhibitory input from gamma-aminobutyric acid (GABA) in the ventromedial hypothalamus (VMH), a major glucose-sensing region within the brain, plays a role in affecting counterregulatory responses to hypoglycemia. Normal Sprague-Dawley rats had carotid artery and jugular vein catheters chronically implanted, as well as bilateral steel microinjection guide cannulas inserted down to the level of the VMH. Seven to 10 days following surgery, the rats were microinjected with artificial extracellular fluid, the GABA(A) receptor agonist muscimol (1 nmol/side), or the GABA(A) receptor antagonist bicuculline methiodide (12.5 pmol/side) before being subjected to a hyperinsulinemic-hypoglycemic (2.5 mmol/l) glucose clamp for 90 min. Following VMH administration of bicuculline methiodide, glucose infusion rates were significantly suppressed, whereas muscimol raised glucose infusion rates significantly compared with controls. Glucagon and epinephrine responses were elevated with the antagonist and suppressed with the agonist compared with controls. Corticosterone responses, however, were unaffected by either administration of the agonist or antagonist into the VMH. These data demonstrate that modulation of the GABAergic system in the VMH alters both glucagon and sympathoadrenal, but not corticosterone, responses to hypoglycemia. Our findings are consistent with the hypothesis that GABAergic inhibitory tone within the VMH can modulate glucose counterregulatory responses.

Animals↗

PubMed2006

Antecedent hypercortisolemia is not primarily responsible for generating hypoglycemia-associated autonomic failure.

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 +/- 53 vs. 337 +/- 57 pg/ml, P = 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 +/- 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 +/- 28 vs. 192 +/- 28 pg/ml, P = NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemia-induced hypercortisolemia is not primarily responsible for the generation of HAAF.

Adolescent↗

PubMed2006

Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia.

Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months, recurrent hypoglycemia improved euglycemic task performance (76 +/- 4 vs. 64 +/- 3% for controls) and reversed the task-associated dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic (45 +/- 4 vs. 55 +/- 2%). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance (62%) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals, whereas control animals' performance deteriorated to chance (44%) by 8 months. At 12 months, hippocampal slice physiology was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved gamma-aminobutyric acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological components.

Animals↗

PubMed2005

Modulation of memory with septal injections of morphine and glucose: effects on extracellular glucose levels in the hippocampus.

The concentration of glucose in the extracellular fluid (ECF) of the hippocampus decreases substantially during memory testing on a hippocampus-dependent memory task. Administration of exogenous glucose, which enhances task performance, prevents this decrease, suggesting a relationship between hippocampal glucose availability and memory performance. In the present experiment, spontaneous alternation performance and task-related changes in hippocampal ECF glucose were assessed in rats after intraseptal administration of morphine, which impairs memory on a spontaneous alternation task, and after co-administration of intraseptal glucose, which attenuates that impairment. Consistent with previous findings, spontaneous alternation testing resulted in a decrease in hippocampal ECF glucose levels in control rats. However, rats that received intraseptal morphine prior to testing showed memory impairments and an absence of the task-related decrease in hippocampal ECF glucose levels. Intraseptal co-administration of glucose with morphine attenuated the memory impairment, and ECF glucose levels in the hippocampus decreased in a manner comparable to that seen in control rats. These data suggest that fluctuations in hippocampal ECF glucose levels may be a marker of mnemonic processing and support the view that decreases in extracellular glucose during memory testing reflect increased glucose demand during memory processing.

Analgesics, Opioid↗

PubMed2005

Extracellular metabolites in the cortex and hippocampus of epileptic patients.

Interictal brain energy metabolism and glutamate-glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero-flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate-glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies.

Adolescent↗

PubMed2005

The prevention of type 2 diabetes mellitus.

With a worldwide pandemic of type 2 diabetes upon us, it is imperative that effective and practical preventive strategies be developed for this disease which, once established, carries with it excess morbidity and mortality. This article reviews recently published data on the prevention of type 2 diabetes and compares the demonstrated effectiveness of each strategy, including lifestyle modification and several pharmacologic agents. Although much new information is available, many translational questions remain that chiefly concern the generalizability and applicability of these programs to clinical practice. Recent diabetes prevention guidelines are discussed, and a practical framework for their implementation is presented.

Adult↗

PubMed2005

Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats.

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic beta-cell, ATP-sensitive K+ channels (K ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K ATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (approximately 2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU x kg(-1) x min(-1)) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation.

Animals↗

PubMed2004

The normal glucose tolerance continuum in obese youth: evidence for impairment in beta-cell function independent of insulin resistance.

Normal glucose tolerance is expressed over a wide range of glucose concentrations. Whether there is a continuum of risk for developing type 2 diabetes mellitus even when the 2-h plasma glucose is still within this normal range is uncertain. Oral glucose tolerance tests were performed in 407 obese normal glucose tolerance youth (4-20 yr) to examine the relationship between variations in 2-h plasma glucose levels and beta-cell responsiveness. Individuals were grouped by 2-h plasma glucose levels as follows: 1) less than 100 mg/dl, 2) 100-119 mg/dl, and 3) 120-139 mg/dl. Subsequent analysis stratified each 2-h plasma level by insulin sensitivity index. Increased 2-h glucose level was associated with a progressive increase in glucose between 0 and 30 min (P < 0.05). The Delta (0-30 min) insulin did not vary significantly across levels, thus resulting in a decreased insulinogenic index (P < 0.02). This pattern was observed at every level of insulin sensitivity (P < 0.02). These data translated to an unfavorable (leftward) shift in the insulin feedback system for increasing 2-h glucose level (P < 0.005). Increased 2-h plasma glucose within the range of normal glucose tolerance in obese youth is associated with a specific impairment of beta-cell responsiveness distinct from the deterioration of insulin sensitivity.

Adolescent↗

PubMed2004

Obesity and the metabolic syndrome in children and adolescents.

BACKGROUND: The prevalence and magnitude of childhood obesity are increasing dramatically. We examined the effect of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to insulin resistance and to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial cohort of children and adolescents. METHODS: We administered a standard glucose-tolerance test to 439 obese, 31 overweight, and 20 nonobese children and adolescents. Baseline measurements included blood pressure and plasma lipid, C-reactive protein, and adiponectin levels. Levels of triglycerides, high-density lipoprotein cholesterol, and blood pressure were adjusted for age and sex. Because the body-mass index varies according to age, we standardized the value for age and sex with the use of conversion to a z score. RESULTS: The prevalence of the metabolic syndrome increased with the severity of obesity and reached 50 percent in severely obese youngsters. Each half-unit increase in the body-mass index, converted to a z score, was associated with an increase in the risk of the metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95 percent confidence interval, 1.16 to 2.08), as was each unit of increase in insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95 percent confidence interval, 1.07 to 1.18 for each additional unit of insulin resistance). The prevalence of the metabolic syndrome increased significantly with increasing insulin resistance (P for trend, <0.001) after adjustment for race or ethnic group and the degree of obesity. C-reactive protein levels increased and adiponectin levels decreased with increasing obesity. CONCLUSIONS: The prevalence of the metabolic syndrome is high among obese children and adolescents, and it increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters.

Adiponectin↗

PubMed2004

From artificial cerebro-spinal fluid (aCSF) to artificial extracellular fluid (aECF): microdialysis perfusate composition effects on in vivo brain ECF glucose measurements.

Microdialysis (mD) is the predominant technique for measurements of brain chemistry, especially when such measurements are made in awake animals. Relatively little attention has been paid, however, to the potential effect on such measurements of variation in the perfusate solution used. Here, we report that small variations in the ionic composition of microdialysis perfusate produced four-fold differences (0.53-2.18 mM) in the results obtained when measuring brain extracellular fluid (ECF) glucose. These changes may be linked to concomitant alterations of local neural activity caused by the perfusate composition. In addition to perfusate composition, probe type also proved to have a significant impact on microdialysis measurements. Further, we report the first direct microdialysis measurements of brain ECF ionic composition, showing significant differences from that of the cerebro-spinal fluid (CSF). Modifying the ionic composition of microdialysis perfusate based on these measurements resulted in a measured hippocampal ECF glucose level of 1.26 +/- .04 mM. Increased understanding of the impact of differences in the perfusate solutions used by different laboratories may provide a basis for reconciliation of apparently disparate microdialysis results within the literature.

Animals↗

PubMed2004

Experience with the continuous glucose monitoring system in a medical intensive care unit.

Strict glycemic control improves clinical outcomes in critically ill patients. However, practical tools for frequent monitoring of blood glucose (BG) levels in the intensive care unit (ICU) are limited. The Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) is currently approved for detecting glycemic excursions in outpatients with diabetes mellitus. The use of this device has never been carefully examined in the inpatient setting. This preliminary study was designed to investigate the accuracy of the CGMS in critically ill patients admitted to a medical ICU (MICU). Subjects at risk for hyperglycemia were recruited from among all patients admitted to our MICU. CGMS sensors were implanted for up to 72 h. Study subjects wore between one and five consecutive sensors. Four or more standard capillary BG readings were recorded per 24 h. All paired meter-sensor (M-S) readings were used both for CGMS calibration and for data analysis. Twenty-two MICU patients wore 41 CGMS sensors, yielding 546 M-S BG pairs. Overall, the Pearson correlation coefficient ( r ) was 0.88, with a mean M-S difference of 3.3 +/- 26.7 mg/dL (0.6 +/- 17.4%) and a mean absolute M-S difference of 19.7 +/- 18.3 mg/dL (12.8 +/- 11.9%). Clarke Error Grid analysis categorized 98.7% of the M-S pairs within "clinically acceptable" zones A and B. The CGMS is promising for potential use in critically ill patients. If validated in larger studies, the device could serve as a useful research tool for investigating the role of hyperglycemia (and strict glycemic control) in ICU patients. If further developed as a "real-time" glucose sensor, CGMS technology could ultimately prove clinically useful in the ICU, by decreasing nursing workload and/or by providing alarm signals for impending glycemic excursions.

APACHE↗

PubMed2004

Combined hyperinsulinemia and hyperglycemia, but not hyperinsulinemia alone, suppress human skeletal muscle lipolytic activity in vivo.

Effects of circulating insulin and glucose concentrations on skeletal muscle and adipose tissue lipolytic activity were investigated in 10 type 1 diabetes patients with no endogenous insulin secretion. Microdialysis measurements of interstitial glycerol and determination of fractional glycerol release were carried out during standardized combinations of relative hypoinsulinemia/moderate hyperglycemia (11 mmol/liter), hyperinsulinemia/ normoglycemia (5 mmol/liter), and hyperinsulinemia/moderate hyperglycemia, respectively. Local tissue blood flow rates were measured with the (133)Xe clearance technique. In response to the change from hypo- to hyperinsulinemia, the fractional release of glycerol decreased from 159.6 +/- 17.8 to 85.1 +/- 13.7 micromol/liter (P < 0.0001) in adipose tissue, whereas it remained unchanged in skeletal muscle (44.6 +/- 6.4 vs. 36.0 +/- 7.4 micromol/liter; not significant). When hyperinsulinemia was combined with hyperglycemia, fractional glycerol release was further reduced in adipose tissue (64.5 +/- 12.2 micromol/liter; P < 0.05), and in this situation it was also markedly decreased in skeletal muscle (18.1 +/- 4.8 micromol/liter; P < 0.0001). Skeletal muscle blood flow was unaltered over the respective study periods. Adipose tissue blood flow decreased by 50% in response to hyperinsulinemia (P < 0.0005), but no further change was seen when hyperinsulinemia was combined with hyperglycemia. It is concluded that in patients with type 1 diabetes, insulin does not exert an antilipolytic effect in skeletal muscle during normoglycemia. However, in response to combined hyperinsulinemia and hyperglycemia, the lipolytic activity in skeletal muscle is restrained in a similar way as in adipose tissue. This may be explained by a glucose-mediated potentiation of the antilipolytic effectiveness of insulin.

Adipose Tissue↗

PubMed2004

Hypothalamic ATP-sensitive K + channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses.

It has been postulated that specialized glucose-sensing neurons in the ventromedial hypothalamus (VMH) are able to detect falling blood glucose and trigger the release of counterregulatory hormones during hypoglycemia. The molecular mechanisms used by glucose-sensing neurons are uncertain but may involve cell surface ATP-sensitive K(+) channels (K(ATP) channels) analogous to those of the pancreatic beta-cell. We examined whether the delivery of sulfonylureas directly into the brain to close K(ATP) channels would modulate counterregulatory hormone responses to either brain glucopenia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically catheterized rats. The closure of brain K(ATP) channels by global intracerebroventricular perfusion of sulfonylurea (120 ng/min glibenclamide or 2.7 microg/min tolbutamide) suppressed counterregulatory (epinephrine and glucagon) responses to brain glucopenia and/or systemic hypoglycemia (2.8 mmol/l glucose clamp). Local VMH microinjection of a small dose of glibenclamide (0.1% of the intracerebroventricular dose) also suppressed hormonal responses to systemic hypoglycemia. We conclude that hypothalamic K(ATP) channel activity plays an important role in modulating the hormonal counterregulatory responses triggered by decreases in blood glucose. Our data suggest that closing of K(ATP) channels in the VMH (much like the beta-cell) impairs defense mechanisms against glucose deprivation and therefore could contribute to defects in glucose counterregulation.

Animals↗

PubMed2004

Effect of recurrent hypoglycemia on spatial cognition and cognitive metabolism in normal and diabetic rats.

The effects of recurrent hypoglycemia (RH) on cognition in human subjects remain controversial, perhaps in part due to difficulty in completely controlling previous hypoglycemic history. We used a model of RH in nondiabetic and diabetic rats to examine the effects of short-term (3 h daily for 3 days) RH on subsequent hippocampally dependent spatial memory, tested either at euglycemia or under acute hypoglycemia. Hippocampal metabolism was simultaneously measured using microdialysis. Antecedent RH improved task performance (79 +/- 2% alternation in nondiabetic RH animals vs. 63 +/- 3% in controls; P < 0.001) at euglycemia, accompanied by reversal of the task-associated dip (20 +/- 1% below baseline) in hippocampal extracellular fluid (ECF) glucose seen in control animals. RH rats also had a larger rise in hippocampal ECF glucose, after intraperitoneal glucose injection, than did controls. However, RH animals tested at acute hypoglycemia ( approximately 2.8 mmol/l) performed significantly worse than control animals. Results were similar in diabetic and nondiabetic rats. Our data suggest that RH causes improvement in subsequent cognitive performance at euglycemia, accompanied by alterations in cognitive metabolism. When glucose availability is limited, complex cognitive functioning seems to be adversely effected in RH animals, perhaps to better maintain and preserve basic brain functions.

Animals↗