Health Tolerance Research Articles

AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.

Respiratory and locomotor muscle blood flow measurements using near-infrared spectroscopy and indocyanine green dye in health and disease.

Measuring respiratory and locomotor muscle blood flow during exercise is pivotal for understanding the factors limiting exercise tolerance in health and disease. Traditional methods to measure muscle blood flow present limitations for exercise testing. This article reviews a method utilising near-infrared spectroscopy (NIRS) in combination with the light-absorbing tracer indocyanine green dye (ICG) to simultaneously assess respiratory and locomotor muscle blood flow during exercise in health and disease. NIRS provides high spatiotemporal resolution and can detect chromophore concentrations. Intravenously administered ICG binds to albumin and undergoes rapid metabolism, making it suitable for repeated measurements. NIRS-ICG allows calculation of local muscle blood flow based on the rate of ICG accumulation in the muscle over time. Studies presented in this review provide evidence of the technical and clinical validity of the NIRS-ICG method in quantifying respiratory and locomotor muscle blood flow. Over the past decade, use of this method during exercise has provided insights into respiratory and locomotor muscle blood flow competition theory and the effect of ergogenic aids and pharmacological agents on local muscle blood flow distribution in COPD. Originally, arterial blood sampling was required via a photodensitometer, though the method has subsequently been adapted to provide a local muscle blood flow index using venous cannulation. In summary, the significance of the NIRS-ICG method is that it provides a minimally invasive tool to simultaneously assess respiratory and locomotor muscle blood flow at rest and during exercise in health and disease to better appreciate the impact of ergogenic aids or pharmacological treatments.

Type 1 regulatory T cell-mediated tolerance in health and disease.

Type 1 regulatory T (Tr1) cells, in addition to other regulatory cells, contribute to immunological tolerance to prevent autoimmunity and excessive inflammation. Tr1 cells arise in the periphery upon antigen stimulation in the presence of tolerogenic antigen presenting cells and secrete large amounts of the immunosuppressive cytokine IL-10. The protective role of Tr1 cells in autoimmune diseases and inflammatory bowel disease has been well established, and this led to the exploration of this population as a potential cell therapy. On the other hand, the role of Tr1 cells in infectious disease is not well characterized, thus raising concern that these tolerogenic cells may cause general immune suppression which would prevent pathogen clearance. In this review, we summarize current literature surrounding Tr1-mediated tolerance and its role in health and disease settings including autoimmunity, inflammatory bowel disease, and infectious diseases.

Effect of Blood Flow on Hemoglobin and Myoglobin Oxygenation in Contracting Muscle Using Near-Infrared Spectroscopy.

Insufficient O2 delivery to, and uptake by skeletal muscle can produce mobility limitations for patients with chronic diseases. Near-infrared spectroscopy (NIRS) can be used to noninvasively quantify the balance between skeletal muscle O2 delivery and utilization during contraction. However, it is not clear how the oxygenated or deoxygenated NIRS signal should be used to assess muscle O2 changes. This issue is related to the fact that the contributions of hemoglobin (Hb) and myoglobin (Mb) cannot be distinguished. This conundrum can be resolved by quantitative analysis of experimental data by computer simulations with a mechanistic, mathematical model. Model simulations distinguish dynamic responses of the oxygenated (HbO2, MbO2) and deoxygenated (HHb, HMb) contributions to the NIRS signal components (HbMbO2, HHbMb). Simulations of muscle O2 uptake and NIRS kinetics correspond closely to published experimental data (Hernández et al.,J Appl Physiol 108: 1169-1176, 2010). Simulated muscle O2 uptake and oxygenation kinetics with different blood flows indicate (1) faster O2 delivery is responsible for slower muscle oxygenation kinetics; (2) Hb and Mb contributions to the HbMbO2 are similar (40-60%); and (3) Hb and Mb contributions to the HHbMb are significantly different, 80% and 20%, respectively. The effect of slow blood flow kinetics on oxygenated Hb and Mb contributions is minimal. However, the effect on the imbalance between O2 delivery and utilization rates causes significant overshoots and undershoots of deoxygenated Hb and Mb contributions. Model analysis in combination with NIRS measurements and information on hemodynamic and microvascular distribution can help to determine the use of NIRS signal in evaluating the factors limiting exercise tolerance in health and disease states.

The Effect of Carotid Chemoreceptor Inhibition on Exercise Tolerance in Chronic Heart Failure.

PurposeChronic heart failure (CHF) is characterized by heightened sympathetic nervous activity, carotid chemoreceptor (CC) sensitivity, marked exercise intolerance and an exaggerated ventilatory response to exercise. The purpose of this study was to determine the effect of CC inhibition on exercise cardiovascular and ventilatory function, and exercise tolerance in health and CHF.MethodsTwelve clinically stable, optimally treated patients with CHF (mean ejection fraction: 43 ± 2.5%) and 12 age- and sex-matched healthy controls were recruited. Participants completed two time-to-symptom-limitation (TLIM) constant load cycling exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 μg⋅kg–1⋅min–1; order randomized). Ventilation was measured using expired gas data and operating lung volume data were determined during exercise by inspiratory capacity maneuvers. Cardiac output was estimated using impedance cardiography, and vascular conductance was calculated as cardiac output/mean arterial pressure.ResultsThere was no change in TLIM in either group with dopamine (CHF: saline 13.1 ± 2.4 vs. dopamine 13.5 ± 1.6 min, p = 0.78; Control: saline 10.3 ± 1.2 vs. dopamine 11.5 ± 1.3 min, p = 0.16). In CHF patients, dopamine increased cardiac output (p = 0.03), vascular conductance (p = 0.01) and oxygen delivery (p = 0.04) at TLIM, while ventilatory parameters were unaffected (p = 0.76). In controls, dopamine improved vascular conductance at TLIM (p = 0.03), but no other effects were observed.ConclusionOur findings suggest that the CC contributes to cardiovascular regulation during full-body exercise in patients with CHF, however, CC inhibition does not improve exercise tolerance.

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.

The Respiratory Compensation Point and the Deoxygenation Break Point Are Not Valid Surrogates for Critical Power and Maximum Lactate Steady State.

The Respiratory Compensation Point and the Deoxygenation Break Point Are Not Valid Surrogates for Critical Power and Maximum Lactate Steady State.

The Respiratory Compensation Point and the Deoxygenation Break Point Are Valid Surrogates for Critical Power and Maximum Lactate Steady State.

The Respiratory Compensation Point and the Deoxygenation Break Point Are Valid Surrogates for Critical Power and Maximum Lactate Steady State.

Open-circuit respirometry: real-time, laboratory-based systems.

This review explores the conceptual and technological factors integral to the development of laboratory-based, automated real-time open-circuit mixing-chamber and breath-by-breath (B × B) gas-exchange systems, together with considerations of assumptions and limitations. Advances in sensor technology, signal analysis, and digital computation led to the emergence of these technologies in the mid-20th century, at a time when investigators were beginning to recognise the interpretational advantages of nonsteady-state physiological-system interrogation in understanding the aetiology of exercise (in)tolerance in health, sport, and disease. Key milestones include the 'Auchincloss' description of an off-line system to estimate alveolar O2 uptake B × B during exercise. This was followed by the first descriptions of real-time automated O2 uptake and CO2 output B × B measurement by Beaver and colleagues and by Linnarsson and Lindborg, and mixing-chamber measurement by Wilmore and colleagues. Challenges to both approaches soon emerged: e.g., the influence of mixing-chamber washout kinetics on mixed-expired gas concentration determination, and B × B alignment of gas-concentration signals with respired flow. The challenging algorithmic and technical refinements required for gas-exchange estimation at the alveolar level have also been extensively explored. In conclusion, while the technology (both hardware and software) underpinning real-time automated gas-exchange measurement has progressively advanced, there are still concerns regarding accuracy especially under the challenging conditions of changing metabolic rate.

B Cell Tolerance in Health and Disease

B lymphocyte receptors are generated randomly during the bone marrow developmental phase of B cells. Hence, the B cell repertoire consists of both self and foreign antigen specificities necessitating specific tolerance mechanisms to eliminate self-reactive B cells. This review summarizes the major mechanisms of B cell tolerance, which include clonal deletion, anergy and receptor editing. In the bone marrow presentation of antigen in membrane bound form is more effective than soluble form and the role of dendritic cells in this process is discussed. Toll like receptor derived signals affect activation of B cells by certain ligands such as nucleic acids and have been shown to play crucial roles in the development of autoimmunity in several animal models. In the periphery availability of BAFF, a B cell survival factor plays a critical role in the survival of self-reactive B cells. Antibodies against BAFF have been found to be effective therapeutic agents in lupus like autoimmune diseases. Recent developments are targeting anergy to control the growth of chronic lymphocytic leukemia cells.

T Cells at the Site of Autoimmune Inflammation Show Increased Potential for Trogocytosis

CD4+ T cells acquire membrane fragments from antigen-presenting-cells via a process termed trogocytosis. Identifying which CD4+ T cells undergo trogocytosis in co-culture with Ag-loaded APC can enrich for antigen-reactive T cells without knowledge of their fine specificity or cytokine-production profiles. We sought to assess the suitability of this method to identify disease relevant effector and regulatory T cells during autoimmune inflammation. Trogocytosis efficiently identified MBP-reactive T cells in vitro and ex-vivo following immunization. However, Foxp3+ regulatory T cells constitutively displayed a higher rate of trogocytosis than their Foxp3- counterparts which limits the potential of trogocytosis to identify antigen-reactive Treg cells. During inflammation a locally elevated rate of trogocytosis (seen in both effector and regulatory T cells isolated from the inflamed CNS) precludes the use of trogocytosis as a measure of antigenic reactivity among cells taken from inflammatory sites. Our results indicate trogocytosis detection can enrich for Ag-reactive conventional T cells in the periphery but is limited in its ability to identify Ag-reactive Treg or T effector cells at sites of inflammation. Increased trogocytosis potential at inflammatory sites also draws into the question the biological significance of this phenomenon during inflammation, in Treg mediated suppression and for the maintenance of tolerance in health and disease.

Disrupted Toll-Like Receptor Signalling Of Intestinal Epithelium In Intestinal Graft-Versus-Host Disease

BackgroundThe intestine is preferentially damaged in acute graft-versus-graft disease (aGVHD). Patients with intestinal GVHD are usually associated with drug-resistant diarrhea and microflora disturbance. Recent studies suggest that toll-like receptor (TLR) signaling can protect the intestinal epithelial barrier and confer commensal tolerance in health. But less is known about how functional versus dysfunctional TLR pathway opposes or favours the intestinal GVHD. MethodsIn the current study, BALB/c mice were transplanted whole spleen and T cell deleted (TCD) bone marrow cells from C57BL/6 mice as GVHD group, and transplanted TCD bone marrow cells as control group. The jejunum, ileum, colon and rectum epithelium were harvested and total RNA of the intestinal epithelium were extracted in two groups. The mRNA expression of classical TLR pathway TLRx/MYD88/IRAK4 signaling molecules (TLR2, TLR4, MYD88, IRAK4 and Tollip) and cytokines (IFN-γ, TNF-α and TGF-β) were detected by RT-PCR. ResultsThe intestine of aGVHD recipients showed severe mucosal edema and erythema with histologic changes of apoptotic epithelial cells and crypt cell dropout, while the intestine of recipients in the control group did not show any intestinal GVHD evidence. TLR2 expression was markedly down-regulated and little TLR4 expression was observed in GVHD intestinal epithelium in comparison to control group. MYD88 and IRAK4 expression were lower in the entire intestinal epithelium of GVHD group but only significant in colon and rectum epithelium between the two groups. Tollip, a TLR signaling inhibitor by interfering IRAK, was found much higher in the GVHD group. For cytokines, both of IFN-γ and TNF-α expression were markedly up-regulated from proximal to distal intestine in GVHD group as compared to control group. There was no difference in TGF-β expression between the two groups. ConclusionsWe propose TLR signaling in the intestinal epithelium, especially in colon and rectum, presents disruption in intestinal graft-versus-host disease. IFN-γ and TNF-α might contribute to accelerate TLR pathway alteration. Disclosures:Liu:It was supported by 863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017).: Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding. Wu:It was supported by 863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017).: Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding. Zhao:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017).: Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding. Wu:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Zhang:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Fan:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Fan:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Yin:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Zheng:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Yi:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Liu:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding.

Effect of acute peppermint oil administration on gastric sensorimotor function and nutrient tolerance in health

Menthol reduces intestinal motility in animal studies, an effect that is probably mediated by transient receptor potential channels. Peppermint oil (PO), with menthol as a major constituent, is widely used as a spasmolytic agent in irritable bowel syndrome. In the current study, we investigated the effect of acute PO administration on intragastric pressure (IGP) profiles and gastric sensorimotor functions in health. Healthy volunteers underwent IGP measurement before and during continuous intragastric infusion of a nutrient drink (n = 13), and gastric barostat studies (n = 13). A single capsule of PO (182 mg) or placebo was administered during the studies in a randomized controlled crossover design. Throughout the studies, healthy volunteers scored 11 epigastric symptoms on a visual analogue scale (VAS); satiation was scored on a 6-point Likert scale during intragastric infusion. During fasting, IGP and motility index (MI) of the proximal stomach decreased significantly after PO administration compared with placebo (P < 0.0001 and <0.05, respectively). In contrast, during intragastric infusion of the nutrient drink, no significant differences were detected between PO and placebo in IGP profiles, MI, satiation scores, and epigastric symptoms. The maximum infused volume, gastric compliance or sensitivity to balloon distention did not differ between both treatment arms. However, reduced appetite scores were seen during fasting after PO treatment, as compared with placebo (P = 0.01). Postprandial VAS scores were similar between PO and placebo. Peppermint oil reduces IGP, proximal phasic contractility, and appetite, with negligible effects on gastric sensitivity, tone, accommodation, and nutrient tolerance in health.

Variation in Glucose Tolerance in Health and Disease : Especially Pre-diabetes and Early Type 2 Diabetes

Variation in Glucose Tolerance in Health and Disease : Especially Pre-diabetes and Early Type 2 Diabetes

W1816 Loss of TLR 2 and 4 on Ileal Plasmacytoid Dendritic Cells in Post-Operative Crohn's Disease Patients

Introduction Aberrant responses to bacterial flora are implicated in post-operative recurrence of Crohn9s disease (CD) after ileo-ceacal resection. Response to gut flora is conducted by dendritic cells (DC) which can induce a tolerogenic or active immune response. DC express Toll like receptors (TLR) which recognise bacterial products and are important in immune tolerance in health and highly expressed in IBD colonic tissue. Two subsets of DC are plasmacytoid (PDC) and myeloid cells (MDC). These DC show functional differences in their response to bacteria and are able to cross-talk. Expression of TLR on DC in the small intestine of post-operative CD patients is still largely unknown. We aimed to assess expression of TLR on DC from lamina propria mononuclear cells (LPMC) in post-operative CD patients as compared with normal controls. Methods Small intestine biopsies were obtained from 18 post-operative CD patients and 5 controls by colonoscopy. LPMC were collected using collagenase digestion, labelled with monoclonal antibodies to TLR2 and 4 and assessed by multicolour flow cytometry. Result A high percentage of DC from normal ileum expressed TLR2 and 4 with no significant differences in expression between PDC and MDC. However, expression of TLR 2 and 4 was significantly lower in PDC from post op CD patients compared with PDC in normal controls (mean 22.30% vs 60%, p=0.0003 and 38.55% vs 65.16%, p=0.02), respectively. Furthermore, PDC and MDC differed in expression of TLR2 and 4 in tissues from post-op CD patients; PDC expressed significantly less TLR2 and 4 compared with MDC (22.30% vs 38.11%, p=0.002 and 38.55% vs 50.89%, p=0.01), respectively. Conclusion Reduction of TLR2 and 4 expression in PDC compared with their counterparts in normal controls is likely to be the reason for the reduced expression of both TLRs on PDC compared with MDC in CD tissues. The lack of TLR2 and 4 expression on PDC maybe related to the disease activity as the normal controls did not show any statistical differences in expression of either TLR between the DC subsets. Other groups have suggested that functional differences exist between PDC and MDC in their activation by bacterial products and ability to produce innate and acquired inflammatory responses. In particular, blood PDC require the presence of MDC to respond to bacterial products to activate T cells rather than driving innate immunity. Our results indicate that PDC response to intestinal microflora may differ from that in MDC and provide initial background to the DC function and diversity in post-operative CD recurrence.

Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo

AMP-activated protein kinase (AMPK) has been postulated as a super-metabolic regulator, thought to exert numerous effects on skeletal muscle function, metabolism, and enzymatic signaling. Despite these assertions, little is known regarding the direct role(s) of AMPK in vivo, and results obtained in vitro or in situ are conflicting. Using a chronically catheterized mouse model (carotid artery and jugular vein), we show that AMPK regulates skeletal muscle metabolism in vivo at several levels, with the result that a deficit in AMPK activity markedly impairs exercise tolerance. Compared with wild-type littermates at the same relative exercise capacity, vascular glucose delivery and skeletal muscle glucose uptake were impaired; skeletal muscle ATP degradation was accelerated, and arterial lactate concentrations were increased in mice expressing a kinase-dead AMPKalpha2 subunit (alpha2-KD) in skeletal muscle. Nitric-oxide synthase (NOS) activity was significantly impaired at rest and in response to exercise in alpha2-KD mice; expression of neuronal NOS (NOSmicro) was also reduced. Moreover, complex I and IV activities of the electron transport chain were impaired 32 +/- 8 and 50 +/- 7%, respectively, in skeletal muscle of alpha2-KD mice (p < 0.05 versus wild type), indicative of impaired mitochondrial function. Thus, AMPK regulates neuronal NOSmicro expression, NOS activity, and mitochondrial function in skeletal muscle. In addition, these results clarify the role of AMPK in the control of muscle glucose uptake during exercise. Collectively, these findings demonstrate that AMPK is central to substrate metabolism in vivo, which has important implications for exercise tolerance in health and certain disease states characterized by impaired AMPK activation in skeletal muscle.

Improved Pulmonary Function Following Increased Fruit and Vegetable Consumption in Healthy Subjects

1802 The pulmonary system can limit exercise tolerance in many subjects in health and disease, yet is not believed to change through diet or exercise. Previous epidemiologic literature has shown that both fruit and vegetable (FV) consumption and serum antioxidant levels are related to pulmonary function in healthy individuals. PURPOSE: Determine if increased FV consumption will improve pulmonary function in healthy subjects. METHODS: Fifty-two non-smoking subjects (M = 30; F = 22) with no pulmonary disorders were recruited from an 8-week fitness promotion program (Walk Kansas). Subjects were randomly divided into a control group (C; n = 22; 35 ± 11yr) and an intervention group (FV; n = 30; 45 ± 13yr). Both groups performed resting pulmonary function tests (PFT) and an NIH FV screener before and after the program while the FV group also received weekly newsletters to encourage FV consumption. RESULTS: There was no difference (p>0.05) in PFT or # of servings/day of FV between groups pre-testing. However, FV group significantly improved FV consumption by 0.75 ± 0.81 servings/day following the intervention whereas no difference (p>0.05) occurred in C. While no relation existed between PFT and FV consumption pre-testing among all subjects, a significant relationship was observed in FV group between the change in FV consumption and the change in forced expiratory volume in one second (FEV1)(r = 0.44) and the change in forced expiratory flow from 25–75% of expiration (FEF25–75)(r = 0.54). There were no changes in FV consumption or any PFT measurements in C following the 8-week testing period. CONCLUSIONS: These results suggest that increasing FV consumption, presumably through increased antioxidants, leads to improved pulmonary function in healthy subjects which may improve exercise tolerance in health and in reduced pulmonary function associated with aging and disease. Support from American Lung Association

EFFECT OF GLUCOSE DOSE UPON INTRAVENOUS GLUCOSE TOLERANCE IN HEALTH AND IN DIABETES.

The effect of variations in glucose dose from 0.25 to 3.0 g/kg0.7 upon the results of the rapid intravenous glucose tolerance test has been studied in healthy subjects, and in mildly and severely diabetic subjects. In healthy subjects the blood glucose decay constant increased progressively as the glucose dose increased. In mildly diabetic subjects there was only a slight tendency for the decay constant to increase with progressive glucose loading. The severely diabetic subjects had low decay constants at all glucose dose levels. The dose-response relationships were such that, when the amount of glucose given approximated that usually used in the rapid intravenous glucose test (20–30 g), there was considerable overlap between the results from healthy and mildly diabetic subjects, but when greater amounts of glucose were given the results from the 2 groups became distinctly separated. The data therefore suggest that, when an adequate quantity of glucose is given, the rapid intravenous glucose tolerance tes...