Direct laser acceleration: A model for the electron injection from the walls of a cylindrical guiding structure.

We use analytical methods and particle-in-cell simulation to investigate the origin of electrons accelerated by the process of direct laser acceleration driven by high-power laser pulses in preformed narrow cylindrical plasma channels. The simulation shows that the majority of accelerated electrons are originally located along the interface between the channel wall and the channel interior. The analytical model based on the electron hydrodynamics illustrates the underlying physical mechanism of the release of electrons from the channel wall when irradiated by an intense laser, the subsequent electron dynamics, and the corresponding evolution of the channel density profile. The quantitative predictions of the total charge of released electrons and the average electron density inside the channel are validated by comparison with the simulation results.

Direct Laser Acceleration in Underdense Plasmas with Multi-PW Lasers: A Path to High-Charge, GeV-Class Electron Bunches.

The direct laser acceleration (DLA) of electrons in underdense plasmas can provide hundreds of nC of electrons accelerated to near-GeV energies using currently available lasers. Here we demonstrate the key role of electron transverse displacement in the acceleration and use it to analytically predict the expected maximum electron energies. The energy scaling is shown to be in agreement with full-scale quasi-3D particle-in-cell simulations of a laser pulse propagating through a preformed guiding channel and can be directly used for optimizing DLA in near-future laser facilities. The strategy towards optimizing DLA through matched laser focusing is presented for a wide range of plasma densities paired with current and near-future laser technology. Electron energies in excess of 10 GeV are accessible for lasers at I∼10^{21} W/cm^{2}.

Collisionless shock acceleration in the corona of an inertial confinement fusion pellet with possible application to ion fast ignition.

Two-dimensional particle-in-cell simulations are used to explore collisionless shock acceleration in the corona plasma surrounding the compressed core of an inertial confinement fusion pellet. We show that an intense laser pulse interacting with the long scale-length plasma corona is able to launch a collisionless shock around the critical density. The nonlinear wave travels up-ramp through the plasma reflecting and accelerating the background ions. Our results suggest that protons with characteristics suitable for ion fast ignition may be achieved in this way. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Collimated protons accelerated from an overdense gas jet irradiated by a 1 µm wavelength high-intensity short-pulse laser.

We have investigated proton acceleration in the forward direction from a near-critical density hydrogen gas jet target irradiated by a high intensity (1018 W/cm2), short-pulse (5 ps) laser with wavelength of 1.054 µm. We observed the signature of the Collisionless Shock Acceleration mechanism, namely quasi-monoenergetic proton beams with small divergence in addition to the more commonly observed electron-sheath driven proton acceleration. The proton energies we obtained were modest (~MeV), but prospects for improvement are offered through further tailoring the gas jet density profile. Also, we observed that this mechanism is very robust in producing those beams and thus can be considered as a future candidate in laser-driven ion sources driven by the upcoming next generation of multi-PW near-infrared lasers.

Seeded QED cascades in counterpropagating laser pulses.

The growth rates of seeded QED cascades in counterpropagating lasers are calculated with first-principles two- and three-dimensional QED-PIC (particle-in-cell) simulations. The dependence of the growth rate on the laser polarization and intensity is compared with analytical models that support the findings of the simulations. The models provide insight regarding the qualitative trend of the cascade growth when the intensity of the laser field is varied. A discussion about the cascade's threshold is included, based on the analytical and numerical results. These results show that relativistic pair plasmas and efficient conversion from laser photons to γ rays can be observed with the typical intensities planned to operate on future ultraintense laser facilities such as ELI or Vulcan.

All-optical radiation reaction at 10²¹ W/cm².

Using full-scale 3D particle-in-cell simulations we show that the radiation reaction dominated regime can be reached in an all-optical configuration through the collision of a ~1 GeV laser wakefield accelerated electron bunch with a counterpropagating laser pulse. In this configuration the radiation reaction significantly reduces the energy of the particle bunch, thus providing clear experimental signatures for the process with currently available lasers. We also show that the transition between the classical and quantum radiation reaction could be investigated in the same configuration with laser intensities of 10²³ W/cm².

Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats.

OBJECTIVES: Adult neurogenesis in dentate gyrus (DG) is an evolutionarily preserved trait in most mammals examined thus far. Neuronal proliferation and subsequent integration of new neurons into the hippocampal circuit are regulated processes that can have profound effects on an animal's behaviour. A streptozotocin model of type I diabetes, characterized by low insulin and high plasma glucose levels, affects not only body's overall metabolism but also brain activity. MATERIALS AND METHODS: Neurogenesis was measured within the DG of the hippocampus using immunohistochemical markers Ki67, Doublecortin, Calbindin (CaBP) and bromodeoxyuridine (BrdU). RESULTS: Cell proliferation, measured with the endogenous marker Ki67, was reduced by 45%, and cell survival, measured with BrdU, was reduced by 64% of the control. Combined effects on proliferation and survival produced dramatically lower neuronal production. Among the surviving cells only 33% matured normally as judged by the co-labelling of BrdU and CaBP. CONCLUSION: Such a reduction lowered the number of surviving cells with neuronal phenotype by over 80% of the control values and this is expected to cause a significant functional impairment of learning and memory in diabetic animals. These results may shed light on causes of diabetic neuropathology and provide an explanation for the memory deficiencies seen in some diabetic patients.

Estudio prospectivo del tratamiento de los pseudoaneurismas de la arteria femoral con inyección de trombina guiada por ultrasonido: hacia una terapia menos invasiva / A prospective study of the treatment of pseudoaneurysms in the femoral artery with ultrasound-guided thrombin injections: towards a less invasive therapy

Introducción. Los procedimientos endovasculares en los que se cateteriza la arteria femoral pueden complicarsecon la formación de pseudoaneurismas. Recientemente se ha utilizado una técnica menos mórbida que utiliza inyecciónde trombina guiada por ultrasonido (ITGU) en el saco aneurismático. Objetivo. Evaluar de manera prospectivala efectividad de la ITGU como tratamiento de los pseudoaneurismas iatrogénicos de la arteria femoral. Pacientes y métodos.Se realizaron 3.734 cateterizaciones de la arteria femoral. Treinta y dos pacientes desarrollaron 33 pseudoaneurismasde la arteria femoral (0,88%) de menos de 8 cm; este grupo de pacientes se sometió a ITGU y fue seguido de maneraprospectiva. Resultados. La incidencia inicial de éxito fue del 100%. Treinta y un casos (93,9%) permanecierontrombosados de manera exitosa con una sola inyección, controlados hasta el día 30. Dos pseudoaneurismas recurrieronlos días 1 y 8 después del procedimiento (6,1%). Mas de la mitad de los pacientes fueron pacientes hospitalizados(53,1%). Al 88,2% de los pacientes se les dio de alta en el primer o segundo día. Diez de los últimos 11 casos necesitaronmenos de 800 UI y casi la mitad de los pseudoaneurismas (49%) se trombosaron con éxito utilizando menos de 600 UI.No se demostró una relación estadísticamente significativa entre la aparición del pseudoaneurisma y el tamaño del introductoro entre el tamaño del pseudoaneurisma y la efectividad de la trombosis. Conclusión. La ITGU es un tratamientoefectivo. Es menos doloroso y se puede realizar de manera ambulatoria; asimismo, la terapia anticoagulante no contraindicasu uso ni disminuye su efectividad. Se utilizan cantidades mínimas de trombina, lo que disminuye la incidenciade complicaciones

Introduction. Catheterizations and endovascular procedures in which the femoral artery is cannulated aresometimes complicated by iatrogenic pseudoaneurysms. A less uncomfortable technique involving the ultrasound scanguidedinjection of thrombin (UGTI) has been used more recently. Aim. To prospectively evaluate the effectiveness ofUGTI as a treatment of iatrogenic femoral pseudoaneurysms. Patients and methods. 3,734 femoral artery catheterizationswere performed, and from those, 32 consecutive patients with 33 femoral pseudoaneurysm (0.88%) of less than 8 cmwere prospectively enrolled for UGTI. Results. The initial success rate was 100%. Thirty-one cases (93.9%) remainedsuccessfully thrombosed with a single injection at day 30. Recurrence of two pseudoaneurysms (6.1%) was sent at day 1and day 8. More than half of the patients were on an inpatient basis (53.1%) . Hospital stay was 1 to 9 days, with 88.2%of the patients released on day or 2. Ten of the last 11 cases needed less than 800 IU, and nearly half of the pseudoaneurysms(49%) were successfully thrombosed with less than 600 IU. No statistical significance was found betweenoccurrence of the pseudoaneurysm and sheat size or between the size of the pseudoaneurysm and successful thrombosis.Conclusion. UGTI is an effective treatment. Not only is it minimally painful, but it can be done as an outpatientprocedure and anticoagulation therapy does not hinder the success. Minimal thrombin seems necessary to successfullytreat pseudoaneurysms that may further limit procedure-related complications

Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis.

Patients and animals with poorly controlled or uncontrolled diabetes present with diurnal hypersecretion of glucocorticoids and altered regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. Although some of these changes are reversed with insulin replacement therapy, neuroendocrine function is not always restored to normal, even with rigorous glycemic control. In addition, stress responsiveness is also impaired in diabetes and this has important implications in the way patients with diabetes cope with many stress challenges, including the metabolic challenge of insulin-induced hypoglycemia. HPA dysregulation in diabetes appears to involve complex interactions between impaired glucocorticoid negative feedback sensitivity and factors such as hypoinsulinemia, hyperglycemia and/or hypoleptinemia, that may increase central drive of the axis. This review examines some of the evidence indicating hyperactivation of the HPA axis in patients with diabetes. Using the streptozotocin-diabetic rat as a model of type-1 diabetes, we will focus on elucidating some of the mechanisms underlying HPA dysregulation in diabetes. Hyperactivation of the HPA axis in diabetes is associated with increased expression of hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal mineralocorticoid receptor (MR) mRNA. Although insulin replacement restores ACTH and corticosterone levels to normal, likely through glucocorticoid-mediated suppression of ACTH secretion, CRH and MR mRNA expression remain elevated. A better understanding of these mechanisms may be important in developing new treatment modalities for patients with diabetes mellitus.

Mechanisms of impaired hypothalamic-pituitary-adrenal (HPA) function in diabetes: reduced counterregulatory responsiveness to hypoglycaemia.

In summary, our data suggest that in uncontrolled diabetes, increased HPA activity is caused by increased central drive at or above the level of the PVN. Insulin treatment only restores HPA activity at and below the pituitary level, presumably by GC-mediated suppression of ACTH secretion. We hypothesize that the defective HPA response to hypoglycaemia is at least in part due to a lack of a decrease in MR mRNA in response to hypoglycaemia, and diminished sensitivity of the pituitary and adrenal gland to stimulation. Interestingly, insulin treatment restores the HPA response, but not the defective epinephrine response. Therefore, defective epinephrine responses are not linked to defective HPA responses. Similarly, antecedent hypoglycaemia specifically impairs epinephrine responses, but not HPA responses to hypoglycaemia. These studies have revealed some of the mechanisms of impaired HPA function in diabetes and its impaired responsiveness to hypoglycaemia. Further investigations are essential for understanding poor counterregulation in insulin-treated diabetes and may lead to new strategies for preventing hypoglycaemia.

Impact of endovascular repair for abdominal aortic aneurysms in octogenarians.

A total of 50 consecutive patients (86% male; median age, 82 years) underwent endovascular repair of abdominal aortic aneurysms (AAAs) ranging from 4.0 to 9.0 cm (median, 5.2 cm). Efficacy of aneurysm exclusion was assessed by angiography, duplex scan, and/or contrast-enhanced computed tomography (CT). Acute technical success was 82%. Access failed in one patient, and immediate conversion to open operation was required in two patients. Improper deployment of the endoluminal graft (ELG) across the renal arteries occurred in one patient. The median operation time, estimated blood loss, packed red blood cells received, contrast volume, and length of intensive care and hospital stay were 128 min, 200 mL, 0.1 unit, 297 mL, 0.9 days, and 3 days, respectively. ELG limb thrombosis was seen in one patient. There were 4 (8%) early endoleaks, and 2 endoleaks were discovered in other patients at 3 and 6 months. Local/vascular and remote/systemic postoperative complications were seen in 13 (26%) and 9 (18%) patients, respectively. At a median follow-up of 11 months (range 2 to 36 months), clinical success was 78%. The aneurysm sac diameter (n = 49) decreased from a preoperative median of 5.2 to 4.7 cm (p = 0.0001). Technical success was high, and results at 11 months were satisfactory. Long-term outcomes require further study.

Molecular regulation of the hypothalamo-pituitary-adrenal axis in streptozotocin-induced diabetes: effects of insulin treatment.

Increased hypothalamo-pituitary-adrenocortical (HPA) activity in diabetes is likely important in the development of some pathologies associated with the disorder. We hypothesized that central regulation of HPA activity differs among normal, streptozotocin (STZ)-diabetic, and insulin-treated diabetic rats. Blood glucose, ACTH, and corticosterone were elevated, 8 d after inducing diabetes. Insulin treatment normalized these parameters. Plasma norepinephrine was similar in all groups, but epinephrine was lower in STZ-diabetic and higher in insulin-treated rats vs. normals. Increased ACTH with diabetes corresponded with increased hypothalamic CRH mRNA, but no change in pituitary POMC mRNA. With insulin-treatment, CRH mRNA remained elevated, and POMC mRNA was unaltered. Hippocampal MR mRNA expression was dramatically increased with diabetes and, moreover, was not normalized by insulin. No differences in GR mRNA were detected between normal and STZ-diabetic rats. However, insulin treatment increased GR mRNA levels in the paraventricular nucleus and pituitary. We postulate that, in STZ-diabetes: 1) increased HPA activity is caused by increased central drive at and/or above the level of the paraventricular nucleus and is associated with decreased epinephrine; and 2) normalized pituitary-adrenal activity with insulin may be caused by the compensatory increase in GR mRNA allowing glucocorticoid-mediated suppression of ACTH secretion despite the residual increase in central HPA activity. Thus, insulin apparently restored HPA activity at and below the pituitary but, surprisingly, not above it.

Effects of antecedent hypoglycemia, hyperinsulinemia, and excess corticosterone on hypoglycemic counterregulation.

This study aimed to differentiate the effects of repeated antecedent hypoglycemia, antecedent marked hyperinsulinemia, and antecedent increases in corticosterone on counterregulation to subsequent hypoglycemia in normal rats. Specifically, we examined whether exposure to hyperinsulinemia or elevated corticosterone per se could impair subsequent counterregulation. Four groups of male Sprague-Dawley rats were used: 1) normal controls (N) had 4 days of sham antecedent treatment; 2) an antecedent hypoglycemia group (AH) had 7 episodes of hyperinsulinemic hypoglycemia over 4 days; 3) an antecedent hyperinsulinemia group (AE) had 7 episodes of hyperinsulinemic euglycemia; and 4) an antecedent corticosterone group (AC) had 7 episodes of intravenous corticosterone to simulate the hypoglycemic corticosterone levels in AH rats. On day 5, hyperinsulinemic euglycemic-hypoglycemic clamps were performed. Epinephrine responses to hypoglycemia were impaired (P < 0.05 vs. N) after antecedent hypoglycemia and hyperinsulinemia. This correlated with diminished (P < 0.05 vs. N) absolute glucose production responses in AH rats and diminished incremental glucose production responses in AE rats. Paradoxically, norepinephrine responses were increased (P < 0.05 vs. N) after antecedent hypoglycemia. Glucagon and corticosterone responses were unaffected by antecedent hypoglycemia and hyperinsulinemia. In AC rats, incremental but not absolute glucose production responses were decreased (P < 0.05 vs. N). However, neuroendocrine counterregulation was unaltered. We conclude that both antecedent hypoglycemia and hyperinsulinemia impair epinephrine and glucose production responses to subsequent hypoglycemia, suggesting that severe recurrent hyperinsulinemia may contribute to the development of hypoglycemia-associated autonomic failure.

Norepinephrine infusion during moderate-intensity exercise increases glucose production and uptake.

A role for the increase in circulating norepinephrine (NE) during intense exercise [IE; > or = 80% maximum O(2) uptake (VO(2max))] in the marked increment in glucose rate of production (Ra) during IE is hypothesized. Seven fit male subjects (27 +/- 2 yr old; body mass index, 23 +/- 1 kg/m(2); VO(2max), 63 +/- 5 mL/kg.min) underwent 40 min of postabsorptive moderate-intensity (53% VO(2max)) cycle ergometer exercise (126 +/- 14 W), once without [control (CON)] and once with NE infusion (0.1 microg/kg.min) from 30-40 min (NE). With infusion, plasma NE reached 15.9 +/- 1.0 nM (8-fold rest, 2-fold CON). Ra doubled to 4.40 +/- 0.44 in CON, but rose to 7.55 +/- 0.68 mg/kg.min with NE infusion (P = 0.003). Ra correlated strongly (r(2) = 0.92, P < 0.02) with plasma NE during and immediately after infusion. With NE infusion, peak glucose uptake [rate of disappearance (Rd), 6.57 +/- 0.59 vs. 4.53 +/- 0.55 mg/kg.min, P < 0.02] and glucose metabolic clearance rate (P < 0.05) were higher than in CON. Glycemia rose minimally during the NE infusion but did not differ between groups at any time during exercise. Glucagon-to-insulin ratio increased minimally, and epinephrine increased approximately 2.5- to 3-fold at peak but did not differ between groups. Thus, NE infusion during moderate exercise led to increments in Ra and Rd in fit individuals, supporting a possible contributory role for the increase of plasma NE in IE. NE effects on Rd and metabolic clearance rate during exercise may differ from its effects at rest.

The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism.

Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n = 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n = 7) and healthy control subjects (n = 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite approximately 35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization during the euglycemic-hyperinsulinemic clamp was approximately 40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an approximately 50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no elevation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.

Low-dose IGF-I has no selective advantage over insulin in regulating glucose metabolism in hyperglycemic depancreatized dogs.

At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 microg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 microg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67.8 microg/kg, i.e. 29.1 microg/kg bolus plus 0.215 microg/kg( )per min infusion; n=5) or insulin 49.5 mU/kg (9 mU/kg bolus plus 0.45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54+/-3 and 56+/-2% s.e. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5.2+/-0.2, insulin 5.5+/-0.3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and beta-hydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 1 diabetes mellitus.

Effect of JTT-501 on net hepatic glucose balance and peripheral glucose uptake in alloxan-induced diabetic dogs.

JTT-501, a new insulin sensitizer, improves peripheral glucose uptake in insulin-resistant animals such as KK-Ay mice and Zucker fatty rats. However, the effect of JTT-501 on hepatic glucose metabolism has not been addressed. To investigate this effect, experiments were performed on 6 alloxan-diabetic dogs. Three experiments were conducted for each dog: the treatment experiment, which followed a 10-day oral treatment with JTT-501 30 mg x kg(-1) x d(-1), and 2 control experiments 2 weeks before and 2 weeks after the treatment experiment. A hyperinsulinemic-hyperglycemic clamp was performed with the tracer dilution method (intraportal insulin infusion rate, 18 pmol x kg(-1) x min(-1)). Arterial hyperglycemia (approximately 10 mmol/L) was maintained by adjusting the peripheral glucose infusion rate. After a 45-minute basal period (period I), portal glucose infusion (22.2 micromol x kg(-1)min(-1)) was administered for 120 minutes (period II). This was followed by a 90-minutes recovery period (period III). JTT-501 increased insulin-stimulated glucose utilization (P < .05) and enhanced insulin-mediated suppression of glucose production (P < .05) in periods I and III. Net hepatic glucose balance (NHGB) determined by the arterial-venous (A-V) difference method was increased by JTT-501 in period II (P < .01). We conclude that JTT-501 enhances both hepatic and peripheral insulin sensitivity and therefore may have important therapeutic effects in type 2 diabetes.

Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs.

Stress-induced hyperglycemia can lead to significant deterioration in glycemic control in individuals with diabetes. Previously, we have shown in normal dogs that, after intracerebroventricular (ICV) administration of carbachol (a model of moderate stress), increases in both the metabolic clearance rate (MCR) of glucose and endogenous glucose production (GP) occur. However, in hyperglycemic diabetic dogs subjected to the same stress, the MCR of glucose does not increase and glycemia therefore markedly deteriorates because of stimulation of GP. Our aims were to determine the following: 1) whether insulin-induced acute normalization of glycemia, with or without beta-blockade, would correct glucose clearance and prevent the hyperglycemic effect of stress, and 2) whether hyperinsulinemia per se could correct these abnormalities. Stress was induced by ICV carbachol in 27 experiments in five alloxan-administered diabetic dogs subjected to the following protocols in random order: 1) basal insulin infusion (BI) to restore normoglycemia; 2) basal insulin infusion with beta-blockade (BI+block); 3) normoglycemic-hyperinsulinemic clamp with threefold elevation of insulin above basal (3x BI); and 4) normoglycemic-hyperinsulinemic clamp with fivefold elevation of insulin above basal (5 x BI). The BI+block protocol fully prevented stress-induced hyperglycemia, both by increasing MCR (deltaMCR at peak: 0.72 +/- 0.25 ml x kg(-1) x min(-1) vs. no change in BI, P < 0.05) and by diminishing the stress-induced increment in GP observed in BI (deltaGP at peak: 3.72 +/- 0.09 micromol x kg(-1) x min(-1) for BI+block vs. 14.10 +/- 0.31 micromol x kg(-1) x min(-1) for BI, P < 0.0001). In contrast, 3x BI and 5x BI treatments with normoglycemic-hyperinsulinemic clamps proportionately increased basal MCR at baseline, but paradoxically were not associated with an increase in MCR in response to stress, which induced a twofold increase in GP. Thus, in alloxan-administered diabetic dogs, stress increased GP but not MCR, despite normalization of glycemia with basal or high insulin. In contrast, beta-adrenergic blockade almost completely restored the metabolic response to stress to normal and prevented marked hyperglycemia, both by limiting the rise in GP and by increasing glucose MCR. We conclude that acute normalization of glycemia with basal insulin or hyperinsulinemia does not prevent hyperglycemic effects of stress unless accompanied by beta-blockade, and we speculate that short-term beta-blockade may be a useful treatment modality under some stress conditions in patients with diabetes.