Circulating Glucose Concentrations Research Articles

Hyperglycemic Comas in Children: New Insights into Pathophysiology and Management

The hyperglycemic comas in pediatric patients, ketoacidosis (DKA), occurring with both type 1 and type 2 diabetes, and hyperglycemic hyperosmolar state (HHS), which occurs almost exclusively with type 2 diabetes, account for most of the diabetes related morbidity and mortality in childhood. DKA is defined as acidosis measured as venous pH 11 mmol/L. This is typically associated with glucosuria, ketonuria, and ketonemia. Near normal circulating glucose concentrations may occur rarely in DKA with partial treatment or with pregnancy [1]. HHS was formerly referred to as hyperglycemic hyperosmolar nonketotic state, but the nomenclature was changed to recognize the frequent presence of mild ketosis. Indeed, diabetic comas can be viewed as a continuum from DKA with normal osmolality to HHS without ketosis [2]. The emergence of type 2 diabetes in childhood, accounting for as much as 50% of newly-diagnosed diabetes in the 10–19 year age group, depending on socioeconomic and ethnic composition of the population, has resulted in an appreciation of HHS as no longer a condition seen rarely outside of elderly populations [3,4]. The criteria for HHS include plasma glucose concentration >33.3 mmol/L, serum bicarbonate concentration >15 mmol/L, no or small ketonuria, absent to small ketonemia, effective serum osmolality greater than 320 mOsm/kg, and stupor or coma [2].

Measurement of Circulating Glucose Concentrations: The Time Is Now for Consistency among Methods and Types of Samples

Diabetes mellitus was first described in the Egyptian papyrus of Ebers in 1552 BC by people who noted the attraction of insects to the “sweet urine” of those who produced abnormal amounts and later by tasters of urine who could fashion a diagnosis by recognizing the “sweet taste”. The name “diabetes”, initially used in the 1st century AD, comes from the Greek word meaning “to pass through”. “Mellitus”, a Latin word meaning “sweet as honey”, was added in the 18th century. The first chemical tests to measure sugar in urine were developed in the early 19th century. Early in the last century, whole-blood colorimetric analyses became available to clinicians, despite complexities in the preparation and analysis of samples. The term “blood glucose” remains a prominent feature to describe the state of glycemia in patients with diabetes, whether as a fasting value, during a glucose tolerance test, or in monitoring glucose values to determine the insulin dose. Measurements of glucose in venous whole blood, capillary whole blood, or plasma still define diabetes mellitus by WHO criteria (1), with the American Diabetes Association (ADA) referring only to concentrations in plasma (2). Modern applications of glucose assays practically diverge in the diagnosis vs monitoring of treatment(s) of diabetes. Thus, diagnosis is best made in a certified laboratory with the measurement of glucose in plasma after a fast of at least 8 h (3). The benefits of relating closely monitored glucose concentrations to treatment decisions have become feasible and practical with the availability of small devices capable of measuring with precision and accuracy glucose from …

Future alternative therapies in a quest to halt aberrations in diabetes mellitus

Under normal physiological conditions, euglycaemia is maintained principally by the homeostatic balance of insulin and glucagon which are secreted from the pancreas. In both type 1 and type 2 diabetes mellitus there is a substantial and chronic increase in the circulating glucose concentration. This elevation in glucose levels is accompanied by a plethora of other biochemical disturbances, including disruption of carbohydrate, fat and protein metabolism. Clinical manifestations of diabetes, which arise from the metabolic disturbances vary between individuals but are often a serious threat to quality and length of life. Pancreas transplantation (Tx) and islet modifications are methods used to restore endogenous insulin secretion in insulin-dependent diabetic patients. In order for this to be achieved successfully, however, some of the problems such as hyperglycemia states (>150 mg/dl), which may harm pancreatic graft beta cells, immunorejection, the effects of immunosuppression, for example, must be overcome. Considering these problems, therefore, it seems logical that the replacement of the islet tissue itself, either by transplanting a vascularised pancreatic allograft or by transplanting modified pancreatic islet cells, provides a better alternative therapeutic approach than simply replacing insulin that has been lost. This review will show the recent development in the use of pancreatic islets and their modification in a quest to halt the aberrations seen in diabetes mellitus.

First lactation ovarian function in dairy heifers in relation to prepubertal metabolic profiles.

The aim of this study was to determine whether any differences in the GH-IGF-I axis in juvenile calves were predictive of fertility problems as adult cows. Endogenous metabolic hormone profiles before and after feeding and the response to a GH-releasing factor (GRF) challenge were measured in prepubertal (6 month) dairy calves. These metabolic parameters were subsequently related to physical characteristics at puberty and to ovarian function during the first lactation. Milk progesterone analysis was used to categorize the animals into those with normal progesterone profiles following calving (n=17) and those that developed delayed ovulation (DOV1, n=9) or persistent corpus luteum (PCL1, n=6) profiles. There were associations between prepubertal GH parameters, glucose and non-esterified fatty acid (NEFA) concentrations and the body condition score at which the animals attained puberty. The calves which subsequently developed DOV1 profiles as cows tended to have a higher GH pulse amplitude during fasting than normal profile animals, they did not show the anticipated decrease in circulating glucose concentrations following a post-prandial rise in insulin and they also had the lowest IGF-I concentrations. The calves that later developed PCL1 had a significantly larger GH pulse amplitude and pulse area than normal profile animals in the fed period and had the highest IGF-I concentrations. There were no differences in prepubertal insulin or NEFA concentrations or in the GH response to a GRF challenge between the different progesterone profile categories. Plasma IGF-I concentrations in prepubertal animals were positively correlated with their post-calving concentrations, whereas glucose concentrations had a negative correlation between these time-periods. These results suggested that the different juvenile endocrine profiles of the DOV1 cows may predispose them to a higher rate of tIssue mobilization during lactation and a consequent reduction in fertility, while altered GH and IGF-I levels in PCL1 cows may later contribute to the maintenance of the persistent corpus luteum. Therefore metabolic differences in prepubertal calves were later reflected by altered reproductive function during the first lactation.

N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress.

Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 +/- 1.7 vs. HG 32.4 +/- 1.9 mg. kg-1. min-1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 +/- 3.5 mg. kg-1. min-1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.

Detrimental effect of protracted hyperglycaemia on beta-cell neogenesis in a mouse murine model of diabetes.

Previous studies have shown that new beta cells differentiate from intra-islet precursors in pancreatic islets of mice in which diabetes is induced by injecting a high dose of the beta-cell toxin streptozotocin. Moreover, the re-establishment of euglycaemia by insulin therapy 1 day after streptozotocin treatment improved the process of regeneration. We sought to assess whether a 1-week delay in the restoration of euglycaemia would affect beta-cell regeneration. Adult CD-1 mice were injected with 200 mg/kg of streptozotocin. One group of mice remained hyperglycaemic throughout the experiment while a second group became normoglycaemic following the administration of insulin therapy 1 week after the injection of streptozotocin. Pancreata removed at different times after treatment were processed for visualization ofbeta precursor-cell markers and insulin by confocal microscopy. New beta cells appeared in islets of streptozotocin-treated mice after restoration of normoglycaemia. Like islets of streptozotocin mice in which blood glucose concentrations were rapidly restored, islets of mice that became normoglycaemic 1 week after streptozotocin treatment also had two potential insulin precursor cell types. Protracted hyperglycaemia however, had several harmful effects on insulin cell neogenesis, such as a reduction in the number of euglycaemic mice with successful beta-cell regeneration and a decrease in the number and survival of the newly differentiated insulin-containing cells. These results indicate that islets gradually lose their regenerative potential when they are exposed to high circulating glucose concentrations for an extended period of time.

Muscle glucose uptake does not increase when only local arterial glucose concentration is increased.

Published models of mammalian whole-body glucose metabolism generally assume that glucose uptake is proportional to circulating glucose concentration at constant insulin concentration. One widely used model labels the increased whole-body glucose uptake seen with increased venous glucose concentration as "glucose effectiveness." In 1956 and 1957, we found on average no change in forearm glucose uptake when we doubled, or more than doubled, local forearm arterial glucose concentration by close arterial infusion so that pancreatic arterial glucose concentration did not change. These experiments are being reported in extenso for the first time. Since that time, two other groups have found in glucose/insulin clamp experiments that whole-body glucose uptake was not proportional to hyperglycemic concentrations, although uptake did increase. It was hypothesized that perhaps some organs and tissues do increase uptake proportionally and other tissues not at all. Our results show that skeletal muscle is a tissue in which glucose uptake, at constant insulin, is not changed acutely by hyperglycemia; there is no forearm glucose effectiveness. We suppose that this constancy occurs because there are so few GLUTs on the sarcolemma surface in the basal state and that they are saturated even at euglycemia. We also report earlier experiments from 1954 to 1955 in which comparable hyperglycemia was reached by a large oral dose of glucose, with a 10-fold increase in glucose uptake. The arterial glucose time curve during hyperglycemia was 20-30 mg/dl higher than the forearm venous curve.

Skeletal muscle magnesium content is correlated with plasma glucose concentration in patients with essential hypertension treated with lisinopril or bendrofluazide

The association between change in glucose metabolism and change in skeletal muscle magnesium (Mg) concentration induced by antihypertensive treatment was evaluated in 37 patients with essential hypertension randomly treated with either lisinopril or bendrofluazide. Before and after 6 months of treatment, skeletal muscle biopsies were performed, glucose tolerance was determined by oral (OGTT) and intravenous glucose tolerance tests (IVGTT), and insulin sensitivity was assessed by the hyperinsulinemic euglycemic clamp technique. An inverse relationship was found between the treatment-induced change in fasting plasma glucose concentration and change in skeletal muscle Mg concentration (r = −0.39, P < .05). However, there was no significant correlation between skeletal muscle Mg content and either insulin sensitivity measured by the hyperinsulinemic euglycemic clamp test or glucose tolerance evaluated by IVGTT and OGTT. In conclusion, an increased circulating glucose concentration was correlated with a decreased Mg concentration in skeletal muscle during antihypertensive treatment. However, the Mg concentration in skeletal muscle did not significantly predict the insulin sensitivity or glucose tolerance.

Antihypertensive and metabolic effects of whole Maitake mushroom powder and its fractions in two rat strains.

Maitake mushroom has been reported to favorably influence hypertension and diabetes mellitus. The purpose of this study was to compare the effects of whole Maitake mushroom powder and two extracts designated as ether soluble (ES) and water soluble (WS) on Zucker fatty rats (ZFR), a model of insulin resistance, and on spontaneously hypertensive rats (SHR), a model of genetic hypertension. In the initial study, we followed four groups of eight ZFR and SHR receiving special diets: a baseline diet (BD), BD + whole Maitake mushroom powder (20% w/w), BD + fraction ES (0.10% w/w), and BD + WS (0.22% w/w). Different effects of these dietary regimens on the 2 rat strains were found. At 35 days, only consumption of the ES diet significantly decreased systolic BP (SBP) in SHR (average 197 vs. 176 mm Hg, p < 0.001), while in ZFR only the groups consuming the whole Maitake and WS diets showed significantly decreased SBP (138 vs. 120-125 mm Hg, p < 0.001). A challenge test with losartan (an angiotensin II receptor blocker) indicates that angiotensin II does not play a major role in SBP regulation of ZFR, but does in SHR where consumption of ES relative to other groups significantly lowered activity of this system. In SHR, glucose, cholesterol, circulating insulin and HbA1C were virtually similar among all dietary groups; but whole Maitake (-22%), ES (-120%) and WS (-80%) diets were associated with decreased triglycerides, and the ES diet with lowered serum creatinine (-29%). In ZFR, circulating insulin and HbA1C were significantly decreased in the whole Maitake powder and ES groups, and tended to be lower in the WS group compared to control. In the ensuing studies, we gavaged ZFR once daily with water (control), 44 mg fraction WS, or 44 mg fraction WS plus 100 microg niacin-bound chromium (NBC). Oral gavage of WS clearly lowered SBP and circulating glucose concentrations, more so with the addition of chromium. We conclude that the examined forms of Maitake mushroom have antihypertensive and antidiabetic potential which differ among rat strains. The ES fraction may decrease SBP in SHR via alteration in the renin-angiotensin system.

Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis.

Numerous peripheral signals contribute to the regulation of food intake and energy homeostasis. Mechano- and chemoreceptors signaling the presence and energy density of food in the gastrointestinal (GI) tract contribute to satiety in the immediate postprandial period. Changes in circulating glucose concentrations appear to elicit meal initiation and termination by regulating activity of specific hypothalamic neurons that respond to glucose. Other nutrients (e.g., amino acids and fatty acids) and GI peptide hormones, most notably cholecystokinin, are also involved in short-term regulation of food intake. However, the energy density of food and short-term hormonal signals by themselves are insufficient to produce sustained changes in energy balance and body adiposity. Rather, these signals interact with long-term regulators (i.e., insulin, leptin, and possibly the orexigenic gastric peptide, ghrelin) to maintain energy homeostasis. Insulin and leptin are transported into the brain where they modulate expression of hypothalamic neuropeptides known to regulate feeding behavior and body weight. Circulating insulin and leptin concentrations are proportional to body fat content; however, their secretion and circulating levels are also influenced by recent energy intake and dietary macronutrient content. Insulin and leptin concentrations decrease during fasting and energy-restricted diets, independent of body fat changes, ensuring that feeding is triggered before body energy stores become depleted. Dietary fat and fructose do not stimulate insulin secretion and leptin production. Therefore, attenuated production of insulin and leptin could lead to increased energy intake and contribute to weight gain and obesity during long-term consumption of diets high in fat and/or fructose. Transcription of the leptin gene and leptin secretion are regulated by insulin-mediated increases of glucose utilization and appear to require aerobic metabolism of glucose beyond pyruvate. Other adipocyte-derived hormones and proteins that regulate adipocyte metabolism, including acylation stimulating protein, adiponectin, diacylglycerol acyltransferase, and perilipin, are likely to have significant roles in energy homeostasis.

Effects of intra-abomasal infusion of β-casomorphins on circulating concentrations of hyperglycaemic insulin and glucose in dairy cows

The effects of intra-abomasal infusion of a mixture of -casomorphins on circulating concentrations of insulin and glucose prestimulated by either abomasal (experiment 1) or intravenous (experiment 2) glucose were studied using non-lactating dairy cows. In both experiments, bolus infusion of 240 mg of a mixture of three β-casomorphins (β-casomorphin-4-amide, -5 and -7) was given via an abomasal infusion line. The β-casomorphins significantly lowered the responses of serum insulin to both abomasal and intravenous glucose infusions (P<0.05). However, the β-casomorphins did not significantly affect circulating glucose concentrations. The insulinopenic action of the β-casomorphins is consistent with the action of somatostatin-28 (SS-28) as judged from the effects of SS-28 on the insulin secretion when administered intravenously in experiment 1.

Afferent signals regulating food intake.

Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. beta-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

Human photopic response to circulating glucose.

Circulating glucose was manipulated in young human volunteers with clinically normal vision. Fasting achieved a concentration range of 45-91 mg/dl. And sugar loading produced a range of 79-108 mg/dl. Glucose increased in all subjects. A nonparametric ANOVA provided a p=0.0005 for the significance of the concentration differences between group glucose concentrations under the two conditions in the sample. Each volunteer participated in each condition of the repeated-measures design. Clinical tests were completed before electroretinograms were recorded under photopic and scotopic adaptation conditions. Measures were made from 12 eyes. Only photopic adaptation conditions with maximal stimuli produced significant results. Inter-individual differences were robust and constrained to reduced implicit times for b-wave peaks and 30 Hz flicker implicit times. Under the elevated glucose conditions. Other variables showed very strong trends. These results confirm and extend other human indications of photopic retinal sensitivity to variations within the normal range of circulating glucose concentrations.

The α1-adrenoceptor antagonist/5-hydroxy-tryptamine1A agonist urapidil improves glucose disposition in streptozotocin diabetic rats

O-31 Introduction: Urapidil (U) is an established drug in the treatment of hypertension. Serotonin1A-(5-HT1A) agonists impair glucose metabolism [1]. We investigated, possible adverse metabolic effects of U due to its 5-HT1A agonistic properties in streptozotocin diabetic rats. Methods: Male Wistar Kyoto Rats were made diabetic by streptozotocin i.p. and randomized (n = 6) to four treatment groups (U3: U 3 mg kg−1 (2×/day) PO, U10: U 10 mg kg−1 2×/day PO, U30: U30 mg kg−1 2×/day PO, insulin 2 IU kg−1 2×/day s.c.). Results: 7 days' treatment with U 10 mg kg−1 and U 30 mg kg−1 2×/day decreased mean blood glucose values significantly (U10: 281 ± 20 mg dL−1, P = 0.024; U30: 285 ± 15 mg dL−1, P = 0.04) in comparison to diabetic control (376 ± 15 mg dL−1). Insulin treatment normalized blood glucose levels (Fig. 1).FigureConclusion: Urapidil, even in high doses, has no disadvantage on circulating glucose concentration in experimental diabetes mellitus despite its 5-HT1A agonistic properties. Possibly the α1-antagonistic properties counteract the 5-HT1A receptor-mediated negative metabolic effects [2].

Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Glucose, memory, and aging

Circulating glucose concentrations regulate many brain functions, including learning and memory. Much of the evidence for this view comes from experiments assessing stress-related release of epinephrine with subsequent increases in blood glucose concentrations. One application of this work has been to investigate whether age-related memory impairments result from dysfunctions in the neuroendocrine regulation of the brain processes responsible for memory. Like humans, aged rodents exhibit some memory impairments that can be reversed by administration of epinephrine or glucose. In elderly humans, ingestion of glucose enhances some cognitive functions, with effects best documented thus far on tests of verbal contextual and noncontextual information. Glucose also effectively enhances cognition in persons with Alzheimer disease or Down syndrome. Although earlier evidence suggested that glucose does not enhance cognitive function in healthy young adults, more recent findings suggest that glucose is effective in this population, provided the tests are sufficiently difficult. In college students, glucose consumption significantly enhanced memory of material in a paragraph. Glucose also appeared to enhance attentional processes in these students. Neither face and word recognition nor working memory was influenced by treatment with glucose. The neurobiological mechanisms by which glucose acts are under current investigation. Initial evidence suggests that glucose or a metabolite may activate release of the neurotransmitter acetylcholine in rats when they are engaged in learning. Consequently, the issue of nutrition and cognition becomes increasingly important in light of evidence that circulating glucose concentrations have substantial effects on brain and cognitive functions.

Fasting and cognition in well- and undernourished schoolchildren: a review of three experimental studies

This paper reviews three experiments on the effects of an overnight and morning fast on attention and memory processes among 9-11-y-old children. Two of the experiments focused on middle-class, well-nourished boys and girls in the United States: the third involved boys from low-income families with and without nutritional risk in Huaraz, Peru. All experiments used the same crossover design and followed similar experimental procedures to control the subjects' intakes and motor activity during the study period. The children were admitted to a research center on two different evenings, approximately 7 d apart. After arrival the children ate dinner, played table games or watched television, and went to bed. They were awakened at 0730 and, by design, were either served breakfast (approximately 2301 kJ) or not. At 1100 they took psychologic tests that assessed recall from working memory and competence in discriminating visual stimuli. At 1200 the children were discharged. The consequences of the overnight and morning fast, particularly among the children who were nutritionally at risk, included slower stimulus discrimination, increased errors, and slower memory recall. We propose that these alterations result from a state of metabolic stress in which homeostatic mechanisms work to maintain circulating glucose concentrations.

Regulation of insulin-like growth factor I (IGF-I) bioactivity in vivo: further characterization of an IGF-I-enhancing antibody.

We have previously demonstrated the ability of a polyclonal antibody raised against human insulin-like growth factor I (IGF-I) to potentiate, rather than inhibit, the growth-promoting activity of IGF-I. The anti-IGF-I Ig had a modest affinity for IGF-I, protected IGF-I from degradation, and reduced the IGF-I clearance rate while allowing efficient transfer of peptide from the circulation, leading to the suggestion that the antiserum might be behaving in an analogous manner to enhancing IGF-binding proteins (IGFBPs). The purpose of these studies was to investigate further the characteristics of this antiserum as a means of assessing the importance of IGF-I associated with circulating high mol wt IGFBPs to serve as a bioavailable reservoir of IGF-I peptide. 1) Epitope scanning using sequential and overlapping peptides spanning the entire length of IGF-I revealed one major linear region of anti-IGF-I Ig binding to IGF-I comprising the C-terminal region of the C-domain and the N-terminal region of the A-domain (Arg36-Ile43), a region not associated with receptor or IGFBP binding. 2) The fact that the antibody could potentiate IGF-I whether administered as a preincubated complex or separately indicated that complex formation could occur in the presence of IGFBPs in vivo. 3) The ability of the antibody to attenuate the acute hypoglycemic actions of IGF-I and LR3IGF-I was assessed by pretreating dwarf rats with either anti-IGF-I Ig or nonimmune Ig; 1 h after s.c. administration of peptide, plasma glucose levels decreased by about 4 mM (P < 0.001) in rats pretreated with nonimmune Ig. The duration of hypoglycemia was more prolonged in the LR3IGF-I-treated rats (P < 0.01). Neither IGF-I or LR3IGF-I induced any decrease in circulating glucose concentrations in the rats pretreated with the anti-IGF-I Ig, suggesting that the antibody gave protection against inappropriate acute IGF-induced hypoglycemia. 4) The potentiating effects of the anti-IGF-I Ig on the anabolic actions of IGF-I and LR3IGF-I were compared in dwarf mice. The anti-IGF-I Ig potentiated the increase in whole body weight gain induced by IGF-I by over 3-fold (P < 0.001), but did not change the anabolic action of LR3IGF-I despite its ability to double circulating levels of both IGF peptides. It is, therefore, possible that part of the mechanism of action of the anti-IGF-I Ig involves transfer of IGF-I to smaller mol wt binding proteins. These data confirm the potential of IGFBP-associated IGF-I to act as a reservoir of peptide and to regulate IGF-I activity in vivo.

Regulation of Insulin-Like Growth Factor I (IGF-I) Bioactivity in Vivo: Further Characterization of an IGF-I-Enhancing Antibody

We have previously demonstrated the ability of a polyclonal antibody raised against human insulin-like growth factor I (IGF-I) to potentiate, rather than inhibit, the growth-promoting activity of IGF-I. The anti-IGF-I Ig had a modest affinity for IGF-I, protected IGF-I from degradation, and reduced the IGF-I clearance rate while allowing efficient transfer of peptide from the circulation, leading to the suggestion that the antiserum might be behaving in an analogous manner to enhancing IGF-binding proteins (IGFBPs). The purpose of these studies was to investigate further the characteristics of this antiserum as a means of assessing the importance of IGF-I associated with circulating high mol wt IGFBPs to serve as a bioavailable reservoir of IGF-I peptide. 1) Epitope scanning using sequential and overlapping peptides spanning the entire length of IGF-I revealed one major linear region of anti-IGF-I Ig binding to IGF-I comprising the C-terminal region of the C-domain and the N-terminal region of the A-domain (Arg36-Ile43), a region not associated with receptor or IGFBP binding. 2) The fact that the antibody could potentiate IGF-I whether administered as a preincubated complex or separately indicated that complex formation could occur in the presence of IGFBPs in vivo. 3) The ability of the antibody to attenuate the acute hypoglycemic actions of IGF-I and LR3IGF-I was assessed by pretreating dwarf rats with either anti-IGF-I Ig or nonimmune Ig; 1 h after sc administration of peptide, plasma glucose levels decreased by about 4 mm (P < 0.001) in rats pretreated with nonimmune Ig. The duration of hypoglycemia was more prolonged in the LR3IGF-I-treated rats (P < 0.01). Neither IGF-I or LR3IGF-I induced any decrease in circulating glucose concentrations in the rats pretreated with the anti-IGF-I Ig, suggesting that the antibody gave protection against inappropriate acute IGF-induced hypoglycemia. 4) The potentiating effects of the anti-IGF-I Ig on the anabolic actions of IGF-I and LR3IGF-I were compared in dwarf mice. The anti-IGF-I Ig potentiated the increase in whole body weight gain induced by IGF-I by over 3-fold (P < 0.001), but did not change the anabolic action of LR3IGF-I despite its ability to double circulating levels of both IGF peptides. It is, therefore, possible that part of the mechanism of action of the anti-IGF-I Ig involves transfer of IGF-I to smaller mol wt binding proteins. These data confirm the potential of IGFBP-associated IGF-I to act as a reservoir of peptide and to regulate IGF-I activity in vivo.

Autoregulation of hepatic glucose production.

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.