Decline In Serum Glucose Research Articles

Bone marrow stem cell-derived β-cells: New issue for diabetes cell therapy

This investigation aimed to establish the promising role of insulin-producing cells (IPCs) growing from bone marrow-mesenchymal stem cells (BM-MSCs) in relieving hyperglycemia induced in rats. BM-MSCs were differentiated into IPCs using three different protocols. The efficiency of BM-MSCs differentiation into IPCs in vitro was confirmed by detecting IPCs specific gene expression (Foxa-2, PDX-1 and Ngn-3) and insulin release assay. The in vivo study design included 3 groups of male Wistar rats; negative control group, diabetic group and IPCs-transfused group (5 ×106 cells of the most functional IPCs/rat). One month after IPCs infusion, serum glucose, insulin, c-peptide and visfatin levels as well as pancreatic glucagon level were quantified. Gene expression analysis of pancreatic Foxa-2 and Sox-17, IGF-1 and FGF-10 was done. Additionally, histological investigation of pancreatic tissue sections was performed. Our data clarified that, the most functional IPCs are those generated from BM-MSCs using differentiation protocol 3 as indicated by the significant up-regulation of Foxa-2, PDX-1 and Ngn-3 gene expression levels. These findings were further emphasized by releasing of a significant amount of insulin in response to glucose load. The transplantation of the IPCs in diabetic rats elicited significant decline in serum glucose, visfatin and pancreatic glucagon levels along with significant rise in serum insulin and c-peptide levels. Moreover, it triggered significant up-regulation in the expression levels of pancreatic Foxa-2, Sox-17, IGF-1 and FGF-10 genes versus the untreated diabetic counterpart. The histopathological examination of pancreatic tissue almost assisted the biochemical and molecular genetic analyses. These results disclose that the cell therapy holds potential to develop a new cure for DM based on the capability of BM-MSCs to generate β-cell phenotype using specific protocol.

Effects of Dietary Doum Palm Fruit Powder on Growth, Antioxidant Capacity, Immune Response, and Disease Resistance of African Catfish, Clarias gariepinus (B.)

Simple SummaryIn aquaculture, medicinal plants and their by-products can be effectively used as natural immune-stimulants, growth promoters, anti-stress agents, and antimicrobials. However, very few studies have been conducted to evaluate the possible use of doum palm fruit powder (DPFP) in diets for African catfish. In this study, four experimental diets with four levels of DPFP (0, 5, 10, and 15 g kg−1 diet) in African catfish were evaluated. The findings suggested that DPFP is a good dietary supplement in the aquaculture, which can positively influence fish growth, intestinal histomorphology, hepatic antioxidant activity phagocytic percent and index, lysozyme activity, nitric oxide (NO) production, and disease resistance against A. hydrophila challenge.Application of herbal immune-stimulants for modulation of fish growth and immune response has received great interest during the past decades. With several pharmacological properties, Doum palm, Hyphaene thebaica (Mart.) is known to be a beneficial medicinal plant. The objective of this study was to investigate the effects of the dietary addition of doum palm fruit powder (DPFP) on growth performance, non-specific immune response, and antioxidant parameters of African catfish, Clarias gariepinus (B.). A total of 120 fish (average initial weight 60.50 ± 0.04 g) were randomly allocated to four groups (three replicates/group, 10 fish/aquarium); a basal diet without DPFP supplementation was used as a control, and three other diets were prepared by supplementing 5, 10, or 15 g kg−1 DPFP for a ten-week feeding period. Following ten weeks of feeding, the fish were challenged with Aeromonas hydrophila (as an immune challenge test), and mortalities were recorded. In comparison to the control diet, dietary DPFP significantly improved growth parameters, including final body weight, body weight gain (WG), specific growth rate (SGR), feed conversion ratio (FCR), and protein efficiency ratio (PER), along with an increase in the content of dry matter of the whole body, in a concentration-dependent manner. Moreover, the heights of intestinal villi, numbers of goblet cells, and intraepithelial lymphocytes (IEL) exhibited marked escalation in all parts of the intestine by increasing the level of DPFP, except for numbers of IEL in the proximal part. The decline in serum glucose, cholesterol, and triglyceride levels was prominent in DPFP10 and DPFP15 groups respective to the DPFP0 group. Furthermore, DPFP boosted the hepatic level of catalase (CAT) in the fish, in a dose-dependent manner; meanwhile, the activity of superoxide dismutase (SOD) and reduced glutathione (GSH) content were also augmented in DPFP10 and DPFP15 groups respective to the DPFP0 group. Dietary DPFP (DPFP15 followed by DPFP10 then DPFP5) led to a pronounced enhancement in the innate immune response (phagocytic percent and index, lysozyme activity, nitric oxide (NO) production, and sialoglycans, namely α 2,3-sialyltransferase and α 2,6-sialyltransferase content); however, the myeloperoxidase (MPO) activity was reduced. Significantly higher relative percentage survival (RPS, 88.56%) of the fish, following the A. hydrophila challenge, was observed for the DPFP15 group. We can suggest that DPFP can beneficially influence fish growth, intestinal histomorphology, hepatic levels of catalase (CAT), superoxide dismutase (SOD) activity and glutathione (GSH) content, immune response, and disease resistance against A. hydrophila challenge.

Persistent Exposure to Environmental Levels of Microcystin-LR Disturbs Cortisol Production via Hypothalamic-Pituitary-Interrenal (HPI) Axis and Subsequently Liver Glucose Metabolism in Adult Male Zebrafish (Danio rerio).

There is growing evidence that microcystin-LR (MC-LR) is a new endocrine disruptor, whereas the impacts of persistent exposure to MC-LR on the hypothalamic-pituitary-interrenal (HPI) axis and health hazards thereafter have not been investigated. In this work, adult male zebrafish (Danio rerio) were immersed into MC-LR solutions at concentrations of 0, 1, 5 and 25 μg/L for 30 d, respectively. The results showed that persistent MC-LR exposure caused an extensive upregulation of HPI-axis genes but an inhibition of brain nuclear receptors (gr and mr), which finally increased serum cortisol levels. Furthermore, the decreased expression of hepatic gr might partly be responsible for the strong inhibition on the expression of downstream genes involved in glucose metabolic enzymes, including gluconeogenesis-related genes (pepck, fbp1a, g6pca), glycogenolysis-related gene (pyg), glycolysis-related genes (gk, pfk1b, pk) and glycogenesis-related gene (gys2). These findings are in accordance with the decline in serum glucose, indicating that long-term MC-LR exposure caused a lower production of glucose relative to glucose lysis. Our above results firstly establish the link between persistent MC-LR exposure and impaired glucose metabolism, suggesting that long-term MC-LR-mediated stress might threaten fish’s health.

The protective effect of Satureja bachtiarica hydroalcoholic extract on streptozotocin‐induced diabetes through modulating glucose transporter 2 and 4 expression and inhibiting oxidative stress

Context: Oxidative stress plays an important role in development of diabetes mellitus. Satureja bachtiarica Bunge (Lamiaceae) is a rich source of bioactive compounds with antioxidant properties.Objective: This study investigates the antidiabetic effect of hydroalcoholic extract of aerial parts of S. bachtiarica.Methods and materials: Male Wistar rats were randomly divided into six groups (n = 8) including control (normal saline), diabetic [Streptozotocin (STZ)], intervention (STZ plus hydroalcoholic extract of S. bachtiarica at doses of 75, 150 and 250 mg/kg/d) and positive control (STZ plus captopril 50 mg/kg/d) groups. A single intraperitoneal (IP) injection of STZ (60 mg/kg) was used to induce diabetes and IP therapy with drugs was performed for four weeks.Results: In diabetic rats, serum total antioxidant capacity (TAC) decreased significantly, but glucose, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and malondialdehyde (MDA) increased significantly as compared to the control (p < 0.05). Treatment with extract (250 mg/kg) caused a significant decline in serum glucose, GGT, ALT, AST and MDA as well as a significant increase in serum TAC (p < 0.05). During the intervention period, diabetic rats showed significant weight loss, but extract (250 mg/kg) treated rats did not show any weight loss. Extract (250 mg/kg) up-regulated GLUT2 expression and down-regulated GLUT4 expression in the liver (p < 0.05). S. bachtiarica extract at all dosage levels prevented STZ-induced histological damage of liver, kidney and pancreas.Discussion and conclusions: S. bachtiarica extract exhibits antidiabetic effects through modulation of oxidative stress and expression of GLUT2 and GLUT4.

Averrhoa bilimbi fruits attenuate hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats

Hyperglycemia-mediated oxidative stress plays a major role in the development of diabetic complications. Averrhoa bilimbi Linn. (Oxalidaceae) is a medicinal plant with fruits reported to possess antidiabetic activity. This study evaluated the beneficial effects of the ethyl acetate fraction of A. bilimbi fruit (ABAEE) on the antioxidant/oxidant status in diabetes mellitus. Diabetic rats were treated orally with the ethyl acetate fraction of A. bilimbi fruits at a dose of 25 mg/kg body weight for 60 days. Serum glucose, glycated hemoglobin, plasma insulin, hepatic toxicity markers, antioxidant enzymes, lipid peroxidation products, and liver histopathology were assayed checked after 60 days of extract treatment. Diabetic rats administered ABAEE showed a significant decline in serum glucose, glycated hemoglobin, and also significantly increases the level of plasma insulin, as well as a notable attenuation in thiobarbituric acid-reactive substances, conjugated dienes, and hydroperoxides. ABAEE also modulated hepatic antioxidant potential by significantly increasing the activities of catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and reducing glutathione content. The results associated with ABAEE were more significant than those observed following treatment with the standard drug metformin. Histopathological observations showed that ABAEE effectively rescued hepatocytes from oxidative damage without affecting cellular function and structural integrity. High-performance liquid chromatography analysis of ABAEE indicated the presence of phenolic compound, quercetin, indicating that the antidiabetic effect of the extract might be related to quercetin. These results demonstrated the potential beneficial effect of ABAEE on streptozotocin-induced diabetes in rats.

Adolescents with clinical type 1 diabetes display reduced red blood cell glucose transporter isoform 1 (GLUT1)

Type 1 diabetic (T1D) adolescent children on insulin therapy suffer episodes of both hyper- and hypoglycemic episodes. Glucose transporter isoform GLUT1 expressed in blood-brain barrier (BBB) and red blood cells (RBC) compensates for perturbed circulating glucose toward protecting the supply to brain and RBCs. We hypothesized that RBC-GLUT1 concentration, as a surrogate for BBB-GLUT1, is altered in T1D children. To test this hypothesis, we measured RBC-GLUT1 by enzyme-linked immunosorbent assay (ELISA) in T1D children (n = 72; mean age 15.3 ± 0.2 yr) and control children (CON; n = 11; mean age 15.6 ± 0.9 yr) after 12 h of euglycemia and during a hyperinsulinemic-hypoglycemic clamp with a nadir blood glucose of ~3.3 mmol/L for 90 min (clamp I) or ~3 mmol/L for 45 min (clamp II). Reduced baseline RBC-GLUT1 was observed in T1D (2.4 ± 0.17 ng/ng membrane protein); vs. CON (4.2 ± 0.61 ng/ng protein) (p < 0.0001). Additionally, baseline RBC-GLUT1 in T1D negatively correlated with hemoglobin A1c (HbA1c) (R = -0.23, p < 0.05) but not in CON (R = 0.06, p < 0.9). Acute decline in serum glucose to 3.3 mmol/L (90 min) or 3 mmol/L (45 min) did not change baseline RBC-GLUT1 in T1D or CON children. We conclude that reduced RBC-GLUT1 encountered in T1D, with no ability to compensate by increasing during acute hypoglycemia over the durations examined, may demonstrate a vulnerability of impaired RBC glucose transport (serving as a surrogate for BBB), especially in those with the worst control. We speculate that this may contribute to the perturbed cognition seen in T1D adolescents.

Glucose Metabolism and Diet Predict Changes in Adiposity and Fat Distribution in Weight‐reduced Women

Among obesity-prone individuals, metabolic state may interact with diet in determining body composition. We tested the hypotheses that, among 103 weight-reduced women over 1 year, (i) insulin sensitivity would be positively associated with change in %fat; (ii) this association would be modulated by dietary glycemic load (GL); and (iii) changes in fat distribution would be related to indexes of glucose metabolism. Insulin sensitivity, glucose effectiveness, fasting and postchallenge insulin and glucose, and glucose tolerance were assessed during intravenous glucose tolerance test (IVGTT). Changes in %fat and fat distribution were examined using dual-energy X-ray absorptiometry and computed tomography. Dietary GL was assessed on 67 women using food records. On average, women showed a +5.3 +/- 3.0% change in %fat over 1 year, with the magnitude of this change being greater in relatively insulin sensitive women (+6.0 +/- 0.4%, mean +/- s.e.m.) than in relatively insulin resistant women (+4.4 +/- 0.4 kg; P < 0.05). Women who were relatively insulin sensitive and who consumed a higher GL diet showed a +6.8 +/- 0.7% change in %fat, which was greater than those who were less insulin sensitive, regardless of diet (P < 0.05), but did not differ from women who were relatively insulin sensitive and who consumed a lower GL diet (P = 0.105). Changes in intra-abdominal and deep subcutaneous abdominal fat were inversely associated with the postchallenge decline in serum glucose. In conclusion, greater insulin sensitivity may predispose to adiposity among weight reduced women, an effect that may be ameliorated by a lower GL diet. The potential association between indexes of glucose disposal and changes in fat distribution warrants further study.

Extreme hyperglycemia with ketoacidosis and hyperkalemia in a patient on chronic hemodialysis

A patient on hemodialysis for end-stage renal disease secondary to diabetic nephropathy was admitted in a coma with Kussmaul breathing and hypertension (232/124 mmHg). She had extreme hyperglycemia (1884 mg/dL), acidosis (total CO(2) 4 mmol/L), hyperkalemia (7.2 mmol/L) with electrocardiographic abnormalities, and hypertonicity (330.7 mOsm/kg). Initial treatment with insulin drip resulted in a decrease in serum potassium to 5.3 mmol/L, but no significant change in mental status or other laboratory parameters. Hemodialysis of 1.75 hours resulted in rapid decline in serum glucose and tonicity and rapid improvement of the acidosis, but no change in mental status, which began to improve slowly after the hemodialysis was stopped, but with ongoing treatment with continuous insulin infusion. The rate of decline in tonicity during hemodialysis (14.5 mOsm/kg/h) was high, raising concerns about neurological complications. In this case, extreme hyperglycemia with ketoacidosis, hyperkalemia, and coma developing in a hemodialysis patient responded to insulin infusion. Monitoring of the clinical status and the pertinent laboratory values is required to assess the need for other therapeutic measures including volume and potassium replacement and emergency dialysis. The indications for and risks of emergency dialysis in this setting are not clearly defined.

Serum Glucose Changes During Insulin Therapy in Pediatric Patients With Diabetic Ketoacidosis

There are limited data on which to base insulin dosing schemes for diabetic ketoacidosis (DKA). The goal of therapy is to avoid excessive decreases in serum glucose (greater than 100 mg/dL/h) because of the risks of rapid changes in serum osmolarity and the potential risk of cerebral edema. We retrospectively reviewed the therapy of DKA in pediatric patients admitted to our Pediatric Intensive Care Unit over the past 10 years. There were 35 patients who received IV bolus insulin therapy (0.08 to 1.6 units/kg, 0.24 +/- 0.27 units/kg). The serum-glucose decrease was less than or equal to 100 mg/dL in 10 patients, 101 to 200 mg/dL in 13 patients, 201 to 300 mg/dL in 8 patients, 301 to 400 mg/dL in 2 patients, and more than 500 mg/dL in 2 patients. In patients who received 0.05 to 0.1 units/kg of insulin as a bolus dose, the decrease in serum glucose was greater than 100 mg/dL in 5 of 11 patients. An insulin infusion was administered to 91 patients. During the 243 hours of insulin infusion therapy, the decline in serum glucose was 0 to 100 mg/dL during 162 hours, 101 to 200 mg/dL during 49 hours, 201 to 300 mg/dL during 8 hours, and more than 300 mg/dL during 3 hours. Of the 193 hours of 0.05 to 0.1 units/kg/h insulin administration, there were 47 hours (24%) during which the serum-glucose decrease was greater than 100 mg/dL. Of the 21 hours of insulin administration at less than 0.05 units/kg/h, there was 1 hour (4.8%) where the serum-glucose decrease was greater than 100 mg/dL (P = 0.05 vs. insulin infusion at 0.05 to 0.1 units/kg/h). Commonly used insulin dosing regimens of a bolus of 0.1 units/kg followed by an infusion of 0.05 to 0.1 units/kg/h frequently resulted in a decrease in serum glucose of greater than 100 mg/dL/h. Prospective trials are needed to more accurately define appropriate insulin dosing regimens for pediatric patients with DKA.

Influence of Ramadan-type fasting on enzymes of carbohydrate metabolism and brush border membrane in small intestine and liver of rat used as a model

During Ramadan, Muslims the world over abstain from food and water from dawn to sunset for a month. We hypothesised that this unique model of prolonged intermittent fasting would result in specific intestinal and liver metabolic adaptations and hence alter metabolic activities. The effect of Ramadan-type fasting was studied on enzymes of carbohydrate metabolism and the brush border membrane of intestine and liver from rat used as a model. Rats were fasted (12 h) and then refed (12 h) daily for 30 d, as practised by Muslims during Ramadan. Ramadan-type fasting caused a significant decline in serum glucose, cholesterol and lactate dehydrogenase activity, whereas inorganic phosphate increased but blood urea N was not changed. Fasting resulted in increased activities of intestinal lactate (+34%), isocitrate (+63%), succinate (+83%) and malate (+106%) dehydrogenases, fructose 1,6-bisphosphatase (+17%) and glucose-6-phosphatase (+22%). Liver lactate dehydrogenase, malate dehydrogenase, glucose-6-phosphatase and fructose 1,6-bisphosphatase activities were also enhanced. However, the activities of glucose-6-phosphate dehydrogenase and malic enzyme fell significantly in the intestine but increased in liver. Although the activities of alkaline phosphatase, gamma-glutamyl transpeptidase and sucrase decreased in mucosal homogenates and brush border membrane, those of liver alkaline phosphatase, gamma-glutamyl transpeptidase and leucine aminopeptidase significantly increased. These changes were due to a respective decrease and increase of the maximal velocities of the enzyme reactions. Ramadan-type fasting caused similar effects whether the rats fasted with a daytime or night-time feeding schedule. The present results show a tremendous adaptation capacity of both liver and intestinal metabolic activities with Ramadan-type fasting in rats used as a model for Ramadan fasting in people.

A Prospective Study of the “Two-Bag System” in Diabetic Ketoacidosis Management

The "two-bag'' system, an adaptation of the euglycemic clamp technique, consists of simultaneous administration of 2 intravenous (IV) fluid bags of differing dextrose concentrations. Individualized therapy is dictated by adjustment of the infusion rate of each bag. We sought to assess the benefits of the two-bag system in the initial acute emergency department management of children in diabetic ketoacidosis (DKA). Thirty-three children presenting to an urban pediatric emergency department in DKA were randomized into 2 groups: patients managed with the two-bag system and patients managed with the traditional "one-bag'' system. Other aspects of the management were standardized. Outcome measures included rate of decline in serum glucose, rate of bicarbonate correction, time on IV insulin therapy, and response time for IV fluid changes. Study period was defined as time on IV insulin therapy. There were no differences between the 2 groups in demographic parameters, initial baseline metabolic parameters, or total time on IV insulin therapy. There were no differences between the groups in average rates of serum glucose decline: two-bag 33.1 mg/dL/hr (s.e. 5.57, 95% CI 22.2, 44), one-bag 30.2 mg/dL/hr (s.e. 5.72, 95% CI 19, 41.4); average rate of serum bicarbonate correction: two-bag 1.19 mEq/L/hr, one-bag 1.27 mEq/L/hr; or the average number of IV fluid bags used: two-bag 4.1 bags, one-bag 3.2 bags. However, there was a difference between the groups in regard to elapsed total time to make changes in the IV fluids: two-bag 1 minute, one-bag 42 minutes, (p < 0.001). The "two-bag'' system enables a faster response time in making IV fluid therapy changes. This efficiency makes this system ideal for use in the emergency department.

Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine

The effects of food restriction on energy metabolism have been under investigation for more than a century. Data obtained are conflicting and research has failed to provide conclusive results. The objective of this study was to test the hypothesis that in lean subjects under normal living conditions, short-term starvation leads to an increase in serum concentrations of catecholamines and thus to an increase in resting energy expenditure. Resting energy expenditure, measured by indirect calorimetry, and hormone and substrate concentrations were measured in 11 healthy, lean subjects on days 1, 2, 3, and 4 of an 84-h starvation period. Resting energy expenditure increased significantly from 3.97 +/- 0.9 kJ/min on day 1 to 4.53 +/- 0.9 kJ/min on day 3 (P < 0.05). The increase in resting energy expenditure was associated with an increase in the norepinephrine concentration from 1716. +/- 574 pmol/L on day 1 to 3728 +/- 1636 pmol/L on day 4 (P < 0.05). Serum glucose decreased from 4.9 +/- 0.5 to 3.5 +/- 0.5 mmol/L (P < 0.05), whereas insulin did not change significantly. Resting energy expenditure increases in early starvation, accompanied by an increase in plasma norepinephrine. This increase in norepinephrine seems to be due to a decline in serum glucose and may be the initial signal for metabolic changes in early starvation.

Changing pattern of prevalence of insulin resistance in Psammomys obesus, a model of nutritionally induced type 2 diabetes

Psammomys obesus (a desert gerbil, nicknamed the "sand rat") with innate insulin resistance was transferred to a high-energy (HE) diet at a young (8 to 20 weeks) and older (38 to 45 weeks) age. The young Psammomys progressed to in vivo insulin resistance, followed by pronounced hyperglycemia and hyperinsulinemia, as described previously. Analysis of the time dependency of these changes in response to the HE diet showed that the increase in serum glucose preceded the increase in insulin and plateaued earlier, reverting to normal together with insulin in the older Psammomys. Implants releasing insulin 2 IU/24 h did not induce appreciable hypoglycemia, a decrease in free fatty acids (FFAs), or a suppression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity in young animals after 5 hours, despite a markedly increased circulating insulin. However, in the older Psammomys, the exogenous hyperinsulinemia produced a significant decline in serum glucose and FFA and a suppression of hepatic PEPCK activity. A euglycemic-hyperinsulinemic clamp confirmed that hepatic glucose production (HGP) was lower in older Psammomys versus the young and was almost completely abolished by insulin (from 5.6 +/- 0.6 to 0.2 +/- 0.1 mg x min(-1) x kg(-1) v 10.9 +/- 0.8 to 3.9 +/- 0.5 mg x min(-1) x kg(-1)). This indicates that HGP, rather than glucose underutilization, was the main contributor to the hyperglycemia and that the hepatic insulin resistance in Psammomys is attenuated with age. In relation to the human condition, these findings point out that while the type 2 diabetes prevalence in Western populations generally increases with age, the excessive nutritional intake in high-risk populations produces a pattern of diabetes prevalence that tapers off with age. As such, the nutritionally induced diabetes in Psammomys represents a similar model for a differing pattern of the age-related prevalence of diabetes.

Carbohydrate feedings and exercise performance: effect of initial muscle glycogen concentration

To determine whether the ergogenic benefits of carbohydrate (CHO) feedings are affected by preexercise muscle glycogen levels, eight cyclists performed four self-paced time trials on an isokinetic ergometer over a simulated distance of 70 km. Trials were performed under the following preexercise muscle glycogen and beverage conditions: 1) high glycogen (180.2 +/- 9.7 mmol/kg wet wt) with a CHO beverage (HG-CHO), 2) high glycogen (170.2 +/- 10.4 mmol/kg wet wt) with a non-CHO beverage (HG-NCHO), 3) low glycogen (99.8 +/- 6.0 mmol/kg wet wt) with a CHO beverage (LG-CHO), and 4) low glycogen (109.7 +/- 5.3 mmol/kg wet wt) with a non-CHO beverage (LG-NCHO). The CHO drink (ingested at the onset of exercise and every 10 km thereafter) provided 116 +/- 6 g CHO/trial and prevented the decline in serum glucose observed during both NCHO trials. Performance times ranged from 117.93 +/- 1.44 (HG-CHO) to 122.91 +/- 2.46 min (LG-NCHO). No intertrial differences (P > 0.05) were observed for O2 consumption (75% of maximal O2 consumption), power output (237 W), or self-selected pace (8.44 min/5 km) during the initial 71-79% of exercise. Over the final 14% of the time trial, power output and pace (231 W and 8.62 min/5 km) were similar for the HG-CHO, HG-NCHO, and LG-CHO conditions, but both variables were significantly lower during the LG-NCHO trial (198 W and 9.67 min/5 km, P < 0.05 vs. all other trials).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of serum glucose on glutamate decarboxylase activity in the ventromedial nucleus of rats

Changes in the activity of glutamate decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid synthesis, in response to insulin-induced hypoglycemia were measured in several brain areas involved in glucoregulation. A 20% increase in GAD activity in the ventromedial nucleus (VMN) of rats was measured 30 min after injections of insulin. The increase was significantly correlated with the decrease in serum glucose (r = -0.74) and increased food intake (r = 0.44). The increase in VMN GAD activity was linear between 5 and 30 min after insulin injection and coincided with the decline in serum glucose. Pretreatment with a gastric preload of a 50% glucose solution attenuated the decline in serum glucose, the increase in food intake, and the increase in GAD activity. Inhibition of protein synthesis by puromycin did not block the decrease in glucose, but neither the increase in GAD activity in the VMN nor the increase in food intake in response to insulin was observed. The increase in VMN GAD activity also was present 6 h after insulin injection if rats were denied access to food. No consistent changes in GAD activity were measured in any brain area other than the VMN. The results of these trials suggest that the increase in VMN GAD activity is associated with the decrease in serum glucose and may be involved in the increased feeding associated with insulin administration.

Glucose-dependent changes in α2-noradrenergic receptors in hypothalamic nuclei

Evidence indicates that hypothalamic norepinephrine (NE), acting via α 2-noradrenergic receptors, and also circulating glucose both have an important role in the control of normal feeding behavior in rats. In this report, we studied the relationship between glucose and the α 2-noradrenergic system, by manipulating blood glucose levels and analyzing changes in the binding of [ 3H]p-aminoclonidine ([ 3H]PAC) to α 2-noradrenergic receptors in discrete hypothalamic areas. Brief periods (1–3 hr) of food deprivation, at the onset of the dark cycle, produced a significant decline in serum glucose levels and a simultaneous decrease in α 2-receptor binding sites, specifically in the hypothalamic paraventricular nucleus (PVN) as opposed to other hypothalamic areas. Restoration of circulating glucose levels, by refeeding for 0.5 hr after 2.5 hr food deprivation or by administration of glucose to 1 hr food-deprived rats, prevented this decline in serum glucose, as well as the reduction in PVN α 2-noradrenergic receptor density. In each of these experiments, a strong positive correlation between circulating glucose levels and PVN α 2-noradrenergic receptor sites was obtained. These findings suggest that blood glucose has direct impact upon α 2-noradrenergic receptor activity in the PVN and may affect feeding behavior, in part, through this neurochemical system.

The effect of lithium on glucose- and tolbutamide-induced insulin release and glucose tolerance in the intact rat.

The effects of lithium on stimulus-induced insulin release and glucose tolerance were examined in intact, unanesthetized, and unrestrained rats with indwelling intravascular catheters. In the first study, a 150-mg iv glucose pulse was administered at 30 min after rapid iv injection of lithium carbonate (1 meq/kg) or vehicle. After the glucose pulse, mean serum glucose levels throughout the observation period were significantly greater in the lithium-treated rats than in the vehicle-treated (control) rats. Similarly, a mean glucose disappearance rate of 2.8 +/- 0.2%/min in the lithium-treated rats was significantly less (P < 0.02) than the mean glucose disappearance rate of 3.4 +/- 0.2%/min observed in the control rats. In response to glucose pulse, acute insulin release was significantly inhibited in the lithium-treated rats compared with that observed in the control rats. In the second study, a 10-mg tolbutamide pulse was administered 30 min after a rapid iv injection of lithium carbonate or vehicle. Acute insulin release in response to tolbutamide pulse was markedly inhibited in the lithium-treated rats compared with that observed in the control rats. In lithium-treated rats, the decline in serum glucose between 10-45 min after the tolbutamide pulse was significantly less than that observed in the control rats. Therefore, in the intact rat, lithium inhibits glucose- and tolbutamide-induced insulin release, which, in turn, causes glucose intolerance and prevents tolbutamide-induced hypoglycemia.

Diurnal variations in the action of insulin on muscle glycogen synthesis.

SUMMARY The effect of a single dose of insulin i.u./kg, i.p.) injected every 4 h during a 24-h period was studied in normal mice. The glycogen content of the diaphragm muscle and serum glucose levels were determined every 15 min throughout a period of 60 min after the hormone injection. Although insulin always produced an increase in glycogen and a decline in serum glucose, neither the sequential changes observed during the 60 min after injection nor the magnitude of these changes were constant throughout the 24 h of the day. The two circadian variations in the action of insulin (on glycogen and glucose) did not display any well-defined relationship, i.e. the most marked decline in glucose was not followed by a correspondingly marked increase in glycogen. These observations suggest that the results obtained from the administration of a single dose of insulin at an arbitrary time of day might be misleading. The circadian variations found could represent another component of the complex homeostatic mechanisms in which insulin is involved.