Changes In Plasma Glucose Concentrations Research Articles

Cytosolic and Mitochondrial Malic Enzyme Isoforms Differentially Control Insulin Secretion

In islet beta-cells and INS-1 cells both the high activity of malic enzyme and the correlation of insulin secretion rates with pyruvate carboxylase (PC) flux suggest that a pyruvate-malate cycle is functionally relevant to insulin secretion. Expression of the malic enzyme isoforms in INS-1 cells and rat islets was measured, and small interfering RNA was used to selectively reduce isoform mRNA expression in INS-1 cells to evaluate its impact on insulin secretion. The cytosolic NADP(+)-specific isoform (ME1) was the most abundant, with the mitochondrial isoforms NAD(+)-preferred (ME2) expressed at approximately 50%, and the NADP(+)-specific (ME3) at approximately 10% compared with ME1. Selective reduction (89 +/- 2%) of cytosolic ME1 mRNA expression and enzyme activity significantly reduced glucose (15 mM:41 +/- 6%, p < 0.01) and amino acid (4 mM glutamine +/- 10 mM leucine: 39 +/- 6%, p < 0.01)-stimulated insulin secretion. Selective small interfering RNA reduction (51 +/- 6%) of mitochondrial ME2 mRNA expression did not impact glucose-induced insulin secretion, but decreased amino acid-stimulated insulin secretion by 25 +/- 4% (p < 0.01). Modeling of the metabolism of [U-(13)C]glucose by its isotopic distribution in glutamate indicates a second pool of pyruvate distinct from glycolytically derived pyruvate in INS-1 cells. ME1 knockdown decreased flux of both pools of pyruvate through PC. In contrast, ME2 knockdown affected only PC flux of the pyruvate derived from glutamate metabolism. These results suggest a physiological basis for two metabolically and functionally distinct pyruvate cycles. The cycling of pyruvate by ME1 generates cytosolic NADPH, whereas mitochondrial ME2 responds to elevated amino acids and serves to supply sufficient pyruvate for increased Krebs cycle flux when glucose is limiting.

Protection by cAMP and cGMP phosphodiesterase inhibitors of diazinon-induced hyperglycemia and oxidative/nitrosative stress in rat Langerhans islets cells: Molecular evidence for involvement of non-cholinergic mechanisms

The objective of this study was to study the effects of acute administration of diazinon alone or in combination with two phosphodiesterase (PDE) inhibitors with selectivity to cAMP and cGMP (theophylline and sildenafil, respectively) on oxidative/nitrosative stress biomarkers, including nitric oxide (NO), lipid peroxides (TBARS), total antioxidant power (TAP), and concentration of tumor necrosis factor (TNF-α) in isolated Langerhans islets, plasma glucose and insulin levels, and the activity of plasma cholinesterase (ChE). Examination by different doses of diazinon (15, 30, and 60 mg/kg) in single administration lead us to choose diazinon (30 mg/kg) in combination therapies. Theophylline and sildenafil were used at doses of 25 and 5 mg/kg, respectively. In all diazinon-treated groups, plasma ChE activity and plasma insulin level were significantly decreased and plasma glucose concentration and Langerhans islets TNF-α, TBARS, and NO levels were significantly increased in comparison to controls. The TAP did not change in comparison to control. In combination therapy, both theophylline and sildenafil restored diazinon-induced changes in plasma glucose concentration, Langerhans islets TNF-α, NO, and TBARS concentrations but Langerhans islets TAP, plasma insulin, and ChE levels. It is concluded that diazinon stimulates oxidative/nitrosative stress in Langerhans islets that results in hyperglycemia due to insufficiency of insulin. Altered glucagons/insulin ratio, activated hepatic glucose production/release, and insulin resistance are possible mechanisms. The protective effects of cAMP and cGMP PDE inhibitors in restoration of diazinon-induced oxidative/nitrosative stress and hyperglycemia stress back to their antioxidant potentials that seem to be independent of ChE inhibition.

Isosteviol reduces plasma glucose levels in the intravenous glucose tolerance test in Zucker diabetic fatty rats

The aim of this study was to test the effect of isosteviol on blood glucose and insulin levels during the intravenous glucose tolerance test (IVGTT) in Wistar and Zucker diabetic fatty (ZDF) rats. ZDF rats were divided into a control and three isosteviol treatment (1, 5 and 10 mg/kg) groups. Wistar rats were divided into a control group and an isosteviol treatment group (10 mg/kg). The rats were fasted for 12 h prior to infusion of isosteviol and glucose (1.0 g/kg). Blood samples were taken at 0, 5, 15, 30, 60, 90 and 120 min after the injection of glucose. Glucose concentrations were determined by the glucose oxidase method, and plasma insulin was analysed by radioimmunoassay. The area under the curve (AUC) of the net change in plasma glucose concentration was used to compare the isosteviol treatment and control groups. In ZDF rats, isosteviol at 5 and 10 mg/kg caused a significant (p < 0.05) reduction in the AUC of glucose during the IVGTT. However, isosteviol did not increase plasma insulin concentrations in ZDF rats. In Wistar rats, isosteviol did not significantly affect plasma glucose or insulin levels during the IVGTT. Isosteviol exerts an antihyperglycaemic effect during IVGTT in ZDF rats but not in Wistar rats. Isosteviol has no significant effect on plasma insulin concentrations. The glucose-lowering effect of isosteviol may be due to changes in the sensitivity of peripheral tissues to insulin.

MicroRNAs: A new class of regulatory genes affecting metabolism

MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression by binding to target mRNAs, which leads to reduced protein synthesis and sometimes decreased steady-state mRNA levels. Although hundreds of miRNAs have been identified, much less is known about their biological function. Several studies have provided evidence that miRNAs affect pathways that are fundamental for metabolic control in higher organisms such as adipocyte and skeletal muscle differentiation. Furthermore, some miRNAs have been implicated in lipid, amino acid, and glucose homeostasis. These studies open the possibility that miRNAs may contribute to common metabolic diseases and point to novel therapeutic opportunities based on targeting of miRNAs.

2-Deoxy-2-[F-18]fluoro-d-glucose-Positron Emission Tomography Sensitivity to Serum Glucose: A Survey and Diagnostic Applications

The positron emission tomography (PET) clinical utility of the sensitivity (gamma) of uptake (Q) to a change in plasma glucose concentration (C) is investigated. Gamma is obtained from data as [ln(Q (2)/Q (1))] / [ln(C(2)/C(1))], using previously published intrapatient studies varying C within a single patient and some interpatient ones. It can be theoretically related to the half-saturation constant in the Michaelis-Menten quantification of competitive uptake. One of its uses is making uptake corrections for desired vs. actual C using Q(2) = Q(1) (C(2)/C(1))(gamma). Intrapatient studies proved to be preferable to interpatient ones, and a 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET survey with analyses for gamma yielded the following result: usually the gamma values of tumors and brain tissues were near -1, whereas those of other noncerebral tissues were near 0. Regarding correcting uptakes for C, instead of a universally assumed and applied gamma = -1, corrections should be for a single tissue using its known gamma. An advantageous use of gamma is predicting how C affects image contrast, including where glucose loading is sometimes preferable to fasting. A potentially useful quantifier of uptake sensitivity to plasma glucose has been defined and values obtained. Correcting uptakes to some standard C requires special care. gamma can help PET clinicians select fasting or loading to achieve glucose levels for optimum contrast.

Serum adiponectin concentrations during a 72-hour fast in over- and normal-weight humans

Adiponectin is currently considered an important link between obesity and insulin resistance, since circulating levels of this insulin sensitizing hormone have consistently been found to be reduced in obese subjects. However, until now it is not known how the secretion of adiponectin is regulated in response to acute metabolic changes. Here, we assessed the influence of complete fasting for 72 h on serum adiponectin levels. Between group comparison of repeated measurements. In total, 18 normal-weight (mean+/-s.e.m. BMI: 22.2+/-0.4 kg/m(2); age: 39.2+/-4.4 y) and nine over-weight (BMI: 33.2+/-1.8 kg/m(2); age: 36.9+/-4.5 y) subjects. Serum adiponectin levels were measured every 4 h during a 72-h fasting period. Additionally, concentrations of plasma glucose and serum insulin and leptin were assessed at the beginning and in the end of the fasting experiment. Insulin resistance was estimated using the homeostasis model assessment (HOMA). While concentrations of glucose, insulin, and leptin decreased across the fasting period by 31.0, 33.1 and 60.0%, respectively (all P<0.005), adiponectin levels remained unchanged (P=0.817). Overall, over-weight subjects exhibited slightly lower adiponectin levels than normal-weight subjects (P=0.092), but there was no difference in the time course of adiponectin levels during fasting between these two groups (P=0.970). Although, averaged adiponectin levels before and after fasting did not systematically differ, individual changes in adiponectin levels across fasting displayed a slight but significant inverse correlation with changes in plasma glucose concentration (r=-0.42, P=0.03). The data show that serum adiponectin concentrations remain remarkably stable during 72 h of fasting in normal- and over-weight subjects. Thus, adiponectin appears to reflect primarily long-term changes in body weight with little evidence for a dependence on short-term regulatory influences.

Acute Insulin‐induced Hypoglycaemia does not alter IGF‐1 and LH Release in Cyclic Mares

Lactation in the mare is associated with changes in the release of metabolic as well as reproductive hormones. Plasma glucose concentration is constantly reduced in lactating compared with non-lactating mares. Several metabolic signals have been proposed to link nutrition and somatic metabolism with reproductive function. The following experiment was performed to study the effect of acute hypoglycaemia on the release of insulin-like growth factor-1 (IGF-1) and luteinizing hormone (LH) in cyclic mares. Different doses of insulin (0.1 and 0.2 IU/kg body weight) were given to induce a decrease in plasma glucose concentration, as existent in lactating mares. All horses treated with insulin developed a hypoglycaemia over a time period of nearly 10 h. The IGF-1 and LH were analysed before and after insulin administration. At no point of time, a significant difference between the two insulin treatments and the control treatment was observed. Therefore, the hypoglycaemic horse is apparently able to provide the brain with sufficient glucose. Short-term hypoglycaemia does not affect the hypothalamo-pituitary-ovarian axis, and concentrations of IGF-1 and LH remained stable during insulin-induced hypoglycaemia. An acute change in plasma glucose concentration is thus not or at least not the only metabolic signal that links nutrition and somatic metabolism with reproductive function in the horse mare.

Provocation of Kainic Acid Receptor mRNA Changes in the Rat Paraventricular Nucleus by Insulin‐Induced Hypoglycaemia

Hypoglycaemia induced by insulin injection is a powerful stimulus to the hypothalamic-pituitary-adrenal (HPA) axis and drives the secretion of corticotropin-releasing hormone and vasopressin from the neurones in the paraventricular nucleus (PVN), as well as the downstream hormones, adrenocorticotropic hormone and corticosterone. In some brain regions, hypoglycaemia also provokes increases in extracellular fluid concentrations of glutamate. Regulation of glutamatergic mechanisms could be involved in the control of the HPA axis during hypoglycaemic stress and one potential site of regulation might be at the receptors for glutamate, which are expressed in the PVN. Insulin (2.0 IU/kg, i.p.) or saline was administered to adult male Sprague-Dawley rats and the animals were sacrificed 30 min, 180 min and 24 h after injection. The amount of several kainic acid-preferring glutamate receptor mRNAs (i.e. KA2, GluR5 and GluR6) were assessed in the PVN by in situ hybridisation histochemistry. Injection of insulin induced a rapid fall in plasma glucose concentrations, which was mirrored by an increase in plasma corticosterone concentrations. KA2 and GluR5 mRNAs are highly expressed within the rat PVN, and responded to hypoglycaemia with robust increases in expression that endured beyond the period of hypoglycaemia itself. However, GluR6 mRNA is expressed in the areas adjacent to the PVN and hypoglycaemic stress failed to alter expression of this mRNA. These experiments suggest that kainic acid-preferring glutamate receptors are responsive to changes in plasma glucose concentrations and may participate in the activation of the PVN neurones during hypoglycaemic stress.

β-Naphthoflavone disrupts cortisol production and liver glucocorticoid responsiveness in rainbow trout

We investigated the impact of aryl hydrocarbon receptor (AhR) activation on cortisol production in rainbow trout ( Oncorhynchus mykiss) using β-naphthoflavone (BNF) and α-naphthoflavone (ANF) as agonist and antagonist of AhR, respectively. Fish were given a single intraperitoneal injection of either corn oil alone or corn oil containing ANF (50 mg/kg body mass), BNF (50 mg/kg) or a combination of both (ANF/BNF; 50 mg/kg each) and sampled at 2- and 6-day post-injection. Higher CYP1A protein expression in the liver and mRNA abundance in the head kidney confirmed AhR activation with BNF, but ANF did not abolish this response. BNF treatment did not significantly affect mRNA abundance of key steroidogenic enzymes (StAR protein, P450 side chain cleavage and 11β-hydroxylase) in the head kidney of trout. However, BNF depressed the in vitro ACTH- or 8-br-cAMP-mediated cortisol production and this effect was also not modified by ANF. Plasma cortisol levels were significantly higher with BNF in the present study and this BNF-mediated cortisol response was completely abolished with ANF suggesting a role for AhR and/or CYP1A in the regulation of plasma cortisol concentration. However, despite elevated plasma cortisol levels, there was no significant effect of BNF on liver glucocorticoid receptor (GR) protein expression suggesting a lack of liver responsiveness to cortisol stimulation. Also, this was reflected in the absence of any change in plasma glucose concentration in the BNF group at 2 days, and a significant drop at 6 days compared to other treatments. Altogether, our results suggest that AhR activation disrupts interrenal corticosteroidogenesis and target tissue responsiveness to glucocorticoid stimulation in rainbow trout.

Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants.

Many extremely preterm infants develop hyperglycemia in the first week of life during continuous glucose infusion. The objective of this study was to determine whether defective insulin secretion or resistance to insulin was the primary factor involved in transient hyperglycemia of extremely preterm infants. A prospective comparative study was conducted in appropriate-for-gestational-age preterm infants <30 weeks of gestational age with the aim specifically to evaluate the serum levels of proinsulin, insulin, and C-peptide secreted during transient hyperglycemia by specific immunoassays. Three groups of infants were investigated hyperglycemic (n = 15) and normoglycemic preterm neonates (n = 12) and normal, term neonates (n = 21). In addition, the changes in beta-cell peptide levels were analyzed during and after intravenous insulin infusion in the hyperglycemic group. Data were analyzed using analysis of variance and analysis of variance for repeated measures. At inclusion, insulin and C-peptide levels did not differ in hyperglycemic subjects and in preterm controls. Proinsulin concentration was significantly higher in the hyperglycemic group (36.5 +/- 3.9 vs 23.2 +/- 0.9 pmol/L). Compared with term neonates, proinsulin and C-peptide levels were higher in normoglycemic preterm infants (23.2 +/- 0.9 vs 18.9 +/- 2.71 pmol/L and 1.67 +/- 0.3 vs 0.62 +/- 0.12 nmol/L, respectively). During and after insulin infusion in hyperglycemic neonates, plasma glucose concentration fell and proinsulin and C-peptide levels were lowered (18.4 +/- 7.6 and 20.7 +/- 4.5 pmol/L, respectively). These data suggest that 1) preterm neonates are sensitive to changes in plasma glucose concentration, but proinsulin processing to insulin is partially defective in hyperglycemic preterm neonates; 2) hyperglycemic neonates are relatively resistant to insulin because higher insulin levels are needed to achieve euglycemia in this group compared with normoglycemic neonates. These results also show that insulin infusion is beneficial in extremely preterm infants with transient hyperglycemia.

Improvement of Insulin Absorption from Intratracheally Administrated Dry Powder Prepared by Supercritical Carbon Dioxide Process

The purpose of this study was to improve insulin absorption from dry powder after administration in lung without an absorption enhancer. The dry powders, with mannitol as a carrier, were prepared with or without an absorption enhancer (citric acid) by supercritical carbon dioxide (SCF) and spray drying (SD) processes. Insulin powder was precipitated from dimethyl sulfoxide and aqueous solutions by dispersing the insulin solutions from parallel and V‐type nozzles, respectively, into supercritical carbon dioxide, which is an antisolvent for insulin. In vitro aerosol performance was evaluated with a cascade impactor. Insulin powder containing citric acid prepared by the SCF method (MIC SCF) showed improved inhalation performance compared with insulin powder prepared by the SD process, although the particle size of the former powder was larger than that in powders prepared by SD. Insulin absorption was estimated from the change in plasma glucose level. The blood glucose level after administration of the insulin powder without citric acid prepared by the SCF process (MI SCF) decreased rapidly, and a significant difference was observed for areas under the curve of change in plasma glucose concentration versus time (AUCs) between MI SCF and the insulin powder without citric acid prepared by the SD process (MI SD). These results suggest that the SCF technique would be useful to prepare dry powders suitable for inhalation. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2475–2486, 2003

Acute incapacitating hyperopia during hypoglycemic treatment

Patients with diabetes mellitus can develop various ocular complications such as cataract, retinopathy, optic neuropathy, uveitis, and keratopathy etc. In addition, transient refractive error occurs during the course of diabetes mellitus and is associated with treatment induced changes in the plasma glucose concentration [1, 2]. The association of myopia with hyperglycaemia and hyperopia with hypoglycaemia have been reported in diabetic patients [3]. There are studies which show that an abrupt reduction in plasma glucose in diabetic patients with marked hyperglycaemia, induce transient hyperopia [1, 2, 4]. It has been seen that the degree of hyperopia is highly dependent on the magnitude of the change in plasma glucose concentration [2]. Patients may get alarmed and may request for change of glasses but fresh prescription should be given only when the refraction stabilises, otherwise, the glasses thus prescribed will soon become inadequate. A case is presented where a lady developed acute incapacitating hyperopia during hypoglycemic treatment. It is quite unusual to come across such high degree of induced transient hyperopia in clinical practice. The pattern of development and gradual decay of the transient hyperopia is described with review of relevant literature.

Biological Variation of Glycohemoglobin

Glycohemoglobin (GHb) is a measure of long-term mean glycemia that predicts risks for the development and/or progression of diabetic complications in patients with type 1 and type 2 diabetes (1)(2). Several reports have suggested, however, that although the within-subject variation in GHb unrelated to glycemia is minimal, there is substantial between-subject variation in GHb, e.g., “low glycators” and “high glycators” (3)(4)(5). These reports have suggested that because of this large between-subject variation, GHb may not be useful for diabetes screening or diagnosis and that when GHb is used for routine management of patients with diabetes, different patients may require very different GHb target values to achieve the same overall glycemic status. We therefore examined the biological variation of GHb and fasting plasma glucose (FPG) in nondiabetic individuals. Individuals without diabetes (n = 48) participated in a study of an artificial sweetener that has no effect on GHb or plasma glucose concentrations [Submission to Food and Drug Administration. McNeil Specialty Products Company food additive petition 7A3987 (Sucralose), 1987–1997]. Because the study was designed to detect minimal changes in plasma glucose concentrations, all participants were men to avoid the effects of cyclic hormonal changes on insulin (and therefore, plasma glucose) concentrations. At the prestudy screening, all individuals were healthy on the basis of a medical history, physical examination, and electrocardiography results; results of hematology and blood chemistry studies, urine examination, and measures of blood …

Glycemic response during exercise after administration of insulin lispro compared with that after administration of regular human insulin

To examine the glycemic response during exercise after administration of short-acting insulin lispro, we compared changes in plasma glucose concentrations during exercise performed by patients with diabetes after the administration of either insulin lispro or regular human insulin. Seven patients with diabetes (two with type 1 and five with type 2) participated in this study. Each of the insulin-depleted subjects received the same number of units of either insulin lispro or regular human insulin, delivered subcutaneously to the abdomen. The next day, each subject received a similar injection of the solution not previously administered. After each injection, the subjects were fed a standard meal of approximately 9 kcal/kg body weight. One hour after eating the test meal, the subjects performed 30 min of cycle ergometer exercise at 50% maximal oxygen uptake. Plasma glucose, insulin, glucagon, growth hormone (GH), and catecholamine concentrations were then measured at specific intervals. Insulin concentrations were higher and peaked earlier after administration of insulin lispro than after administration of regular human insulin. The length of time, needed to reach minimum plasma glucose concentration after exercise was begun, was significantly shorter after administration of insulin lispro, and the percentage of plasma glucose decrease induced by exercise relative to the peak concentration was significantly greater. No differences were found in the concentration changes of counterregulatory hormones between the insulin lispro data and the regular human insulin data. Compared with regular human insulin, insulin lispro induces a more rapid and greater decrease in plasma glucose concentration during exercise because of its faster absorption.

The influence of plasma glucose upon pulsatile ocular blood flow in subjects with type II diabetes mellitus.

This study investigated the influence of plasma glucose upon pulsatile ocular blood flow in subjects with Type II (non-insulin-dependent) diabetes mellitus. A total of 19 subjects with Type II diabetes and 8 normal control subjects undertook a meal tolerance test after an overnight fast. The pulsatile ocular blood flow, using the Ocular Blood Flow Tonometer, and plasma glucose concentrations were taken at times 0 min, 90 min and 240 min. Blood pressure and glycated haemoglobin concentrations, in the subjects with diabetes, were also measured at time 0 min. Pulsatile ocular blood flow and plasma glucose were also measured at times 0 and 90 min in 5 subjects with Type II diabetes mellitus who remained fasting. It was found that the subjects with diabetes who undertook the meal tolerance test showed a significant increase in both plasma glucose concentrations and pulsatile ocular blood flow from time 0-90 min, followed by a decrease from 90 min to the end of the session at 240 min. (p < 0.001 in each case). Regression analysis showed a significant correlation between the change in pulsatile ocular blood flow and the change in plasma glucose concentration (r = 0.671,p = 0.001). Control subjects showed no significant change in either plasma glucose or pulsatile ocular blood flow during the meal tolerance test. Subjects with diabetes mellitus who remained fasting also showed no significant change in pulsatile ocular blood flow or plasma glucose concentrations. No correlation was found between glycated haemoglobin concentrations or blood pressure and pulsatile ocular blood flow. Pulsatile ocular blood flow is influenced by changes in plasma glucose concentrations in Type II diabetes mellitus, indicating that uncontrolled hyperglycaemia might result in a higher pulsatile ocular blood flow than might otherwise be expected.

Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans

A polymorphism in FABP2 that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. In vitro, the threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala54). We tested whether this polymorphism affected metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indians, half homozygous for the Thr54 form of IFABP and half homozygous for the Ala54 form, were studied. The groups were matched for sex, age, and body mass index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, and insulin responses were measured after a mixed meal (35% of daily energy requirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were approximately 15% higher after the mixed meal and peaked earlier and were approximately 20% higher at 7 h in response to the high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygotes, but glucose and triglyceride responses were not different.The results of this study suggest that the Thr54 form of IFABP is associated with higher and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentrations may contribute to insulin resistance and hyperinsulinemia in individuals with this allele.

Interstitial glucose concentration and glycemia: implications for continuous subcutaneous glucose monitoring.

The changes in plasma glucose concentration and in interstitial glucose concentration, determined with a miniaturized subcutaneous glucose sensor, were investigated in anesthetized nondiabetic rats. Interstitial glucose was estimated through two different calibration procedures. First, after a glucose load, the magnitude of the increase in interstitial glucose, estimated through a one-point calibration procedure, was 70% of that in plasma glucose. We propose that this is due to the effect of endogenous insulin on peripheral glucose uptake. Second, during the spontaneous secondary decrease in plasma glucose after the glucose load, interstitial glucose decreased faster than plasma glucose, which may also be due to the effect of insulin on peripheral glucose uptake. Third, during insulin-induced hypoglycemia, the decrease in interstitial glucose was less marked than that of plasma glucose, suggesting that hypoglycemia suppressed transfer of glucose into the interstitial tissue; subsequently, interstitial glucose remained lower than plasma glucose during its return to basal value, suggesting that the stimulatory effect of insulin on peripheral glucose uptake was protracted. If these observations obtained in rats are relevant to human physiology, such discrepancies between plasma and interstitial glucose concentration may have major implications for the use of a subcutaneous glucose sensor in continuous blood glucose monitoring in diabetic patients.

Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.

Acute Ethanol Effects on Focal Cerebral Ischemia in Fasted Rats

The effects of acute ethanol intoxication were investigated in a rat model of unilateral middle cerebral artery occlusion. Groups of 5 to 8 male Sprague-Dawley rats were subjected to 4 hr of left middle cerebral artery occlusion. All groups were deprived of food overnight and were pretreated intraperitoneally with 5% dextrose solution (10 ml/kg), 20% ethyl alcohol in 5% dextrose solution (2 g/kg), or 30% ethyl alcohol in a 5% dextrose solution (3 g/kg) 1 hr before middle cerebral artery occlusion. Regional cerebral blood flow during ipsilateral occlusion was approximately 9.1 to 10% of baseline in all groups. The mean % brain water content in control, 2 g/kg ethanol-treated groups, and 3 g/kg ethanol-treated groups were: in the ischemic core--81.6, 81.2, and 82.4; intermediate zone--80.5, 80.6, and 81.7; and outer zone--79.7, 79.7, and 80.8, respectively. Brain Na+ and K+ content in the three groups was related to water content, but much greater with ethanol pretreatment. The water content of the intermediate zones in the 3 g/kg ethanol-treated animals was significantly greater than in the control (p < 0.01 and 0.001) and the 2 g/kg ethanol-treated groups. One-way analysis of variance indicated a significant dose-effect relationship in which the lower dose of ethanol tended to reduce ischemic core water content, and the larger dose increased ischemic core water, compared with the control. None of the overnight fasted groups had any significant hyperglycemia. The group given 3 g/kg i.p. ethanol 1 hr before had exacerbated edema formation with a mean whole blood level of ethanol of approximately 230 mg/dl. The neurotoxic effects of high concentrations of ethanol were unrelated to any change in plasma glucose concentrations.

Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects.

We have studied the effect of prolonged hyperinsulinemia and hyperglycemia on serum leptin levels in young nonobese males during 72-h euglycemic-hyperinsulinemic and hyperglycemic ( approximately 8.5 and 12.6 mM) clamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An increase of approximately 800 pM increased serum leptin by approximately 70% over 72 h. Changes in plasma glucose concentrations (from approximately 5.0 to approximately 12.6 mM) or changes in plasma FFA concentrations (from < 100 to > 1,000 microM) had no effect on serum leptin. Serum leptin concentrations changed with circadian rhythmicity. The cycle length was approximately 24 h, and the cycle amplitude (peak to trough) was approximately 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates needed to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 (from 11.4+/-0.2 to 9. 8+/-0.2 mg/kg min, P< 0.05) when mean 24-h leptin levels reached a peak. In summary, we found (a) that 72 h of hyperinsulinemia increased serum leptin levels dose-dependently; (b) that hyperglycemia or high plasma FFA levels did not affect leptin release; (c) that leptin was released with circadian rhythmicity, and (d) that 24-h leptin cycles correlated inversely with 24-h cycles of insulin sensitivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.