45 results on '"Halter, J."'
Search Results
2. Association of Host Factors With Antibody Response to Seasonal Influenza Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Patients.
- Author
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Linnik J, Syedbasha M, Kaltenbach HM, Vogt D, Hollenstein Y, Kaufmann L, Cantoni N, Ruosch-Girsberger S, Müller AMS, Schanz U, Pabst T, Stüssi G, Weisser M, Halter J, Stelling J, and Egli A
- Subjects
- Antibodies, Viral, Antibody Formation, Cohort Studies, Humans, Influenza A Virus, H3N2 Subtype, Seasons, Vaccination, Hematopoietic Stem Cell Transplantation, Influenza A Virus, H1N1 Subtype, Influenza Vaccines adverse effects, Influenza, Human prevention & control
- Abstract
Background: Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood., Methods: We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison., Results: Both regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding., Conclusions: HSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups., Clinical Trials Registration: NCT03467074., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)
- Published
- 2022
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3. Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis.
- Author
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Stuehler C, Kuenzli E, Jaeger VK, Baettig V, Ferracin F, Rajacic Z, Kaiser D, Bernardini C, Forrer P, Weisser M, Elzi L, Battegay M, Halter J, Passweg J, and Khanna N
- Subjects
- Adrenal Cortex Hormones adverse effects, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes physiology, Cell Proliferation, Graft vs Host Disease prevention & control, Humans, Immunocompromised Host, Killer Cells, Natural, Reactive Oxygen Species, Aspergillus immunology, Hematopoietic Stem Cell Transplantation, Immunity, Cellular physiology, Invasive Pulmonary Aspergillosis immunology
- Abstract
Background: Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA., Methods: Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors., Results: Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome., Conclusions: This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therapy., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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4. ABO blood group-incompatible living donor kidney transplantation: a prospective, single-centre analysis including serial protocol biopsies.
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Oettl T, Halter J, Bachmann A, Guerke L, Infanti L, Oertli D, Mihatsch M, Gratwohl A, Steiger J, and Dickenmann M
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- Adult, Aged, Female, Graft Survival, Histocompatibility Testing, Humans, Immunosorbent Techniques, Isoantibodies isolation & purification, Kidney Failure, Chronic immunology, Kidney Failure, Chronic physiopathology, Kidney Failure, Chronic surgery, Kidney Transplantation methods, Kidney Transplantation pathology, Kidney Transplantation physiology, Male, Middle Aged, Prospective Studies, Switzerland, ABO Blood-Group System, Kidney Transplantation immunology, Living Donors
- Abstract
Background: ABO incompatible kidney transplantation using antigen-specific immunoadsorption is increasingly performed but data on outcome, complications and protocol biopsies are still scarce. The present prospective single-centre study was aimed at these issues., Methods: This was a prospective single-centre cohort study of 10 successive ABO incompatible living donor kidney transplantations at the University Hospital Basel from September 2005 to October 2007. The following parameters were closely monitored during the whole follow-up: graft function, albuminuria, blood group antibody titres, CD19+ cell count, total IgG and IgG subclasses, CMV antigenaemia, decoy cells in the urine, EBV and polyoma BK virus PCR in the blood. Protocol biopsies were performed on Days 0 and 7 after 3, 6, 12 and 18 months., Results: Patient and graft survival is 100% after a median follow-up of 489 days (range 183-916 days). Median serum creatinine is 137 micromol/l (range 70-215 micromol/l), and median urine albumin-creatinine ratio (UACR) is 3.1 mg/ mmol (range 0.6-7.8 mg/mmol) at the time of the last follow-up. All patients had sustained diminished CD19+ cell count and/or total IgG concentrations. Neither CMV antigenaemia nor EBV replication in the blood was observed. Seven patients had positive polyoma BK virus replication in the blood but none developed polyoma virus-associated nephropathy (PVAN). Protocol biopsies revealed rejection Banff IIa in three patients on Day 7, and in one patient after 3 and 6 months. Banff Ia rejection was found in five patients. All rejection episodes resolved. Mild signs of chronic antibody-mediated rejection were observed in five patients., Conclusions: ABO-incompatible kidney transplantation seems to be successful and safe. Modifications of the current protocol may be possible and may further reduce potential side effects and costs.
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- 2009
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5. Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature.
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Khanna N, Widmer AF, Decker M, Steffen I, Halter J, Heim D, Weisser M, Gratwohl A, Fluckiger U, and Hirsch HH
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- Adult, Cell Culture Techniques, Female, Hematologic Diseases immunology, Hematologic Diseases therapy, Hematopoietic Stem Cell Transplantation methods, Humans, Immunocompromised Host, Immunoglobulins, Intravenous immunology, Immunoglobulins, Intravenous therapeutic use, Male, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections therapy, Respiratory Syncytial Virus Infections virology, Respiratory Tract Infections complications, Respiratory Tract Infections immunology, Respiratory Tract Infections virology, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction methods, Ribavirin therapeutic use, Hematologic Diseases virology, Respiratory Syncytial Virus Infections complications, Respiratory Syncytial Viruses isolation & purification
- Abstract
Background: Respiratory syncytial virus (RSV) causes significant mortality in patients with hematological diseases, but diagnosis and treatment are uncertain., Methods: We retrospectively identified RSV-infected patients with upper or lower respiratory tract infection (RTI) by culture, antigen testing, and polymerase chain reaction from November 2002 through April 2007. Patients with severe immunodeficiency (SID; defined as transplantation in the previous 6 months, T or B cell depletion in the previous 3 months, graft-versus-host disease [grade, >or=2], leukopenia, lymphopenia, or hypogammaglobulinemia) preferentially received oral ribavirin, intravenous immunoglobulin, and palivizumab. The remaining patients with moderate immunodeficiency (MID) preferentially received ribavirin and intravenous immunoglobulin., Results: We identified 34 patients, 22 of whom had upper RTI (10 patients with MID and 12 with SID) and 12 of whom had lower RTI (2 with MID and 10 with SID). Thirty-one patients were tested by polymerase chain reaction (100% of these patients had positive results; median RSV load, 5.46 log(10) copies/mL), 30 were tested by culture (57% had positive results), and 25 were tested by antigen testing (40% had positive results). RSV-attributed mortality was 18% (6 patients died) and was associated with having >or=2 SID factors (P=.04), lower RTI (P=.01), and preengraftment (P=.012). Among 12 patients with MID (7 of whom received treatment), no progression or death occurred. Nine patients with SID and upper RTI received treatment (7 patients received ribavirin, intravenous immunoglobulin, and palivizumab); infection progressed to the lower respiratory tract in 2 patients, and 1 patient died. Ten patients with SID and lower RTI were treated, 5 of whom died, including 4 of 6 patients who received ribavirin, intravenous immunoglobulin, and palivizumab. The duration of RSV shedding correlated with the duration of symptoms in patients with SID but exceeded symptom duration in patients with MID (P<.05)., Conclusions: Lower RTI, >or=2 SID criteria, and preengraftment are risk factors for RSV-attributed mortality. Polymerase chain reaction may optimize diagnosis and monitoring. Oral ribavirin therapy seems safe, but trials are needed to demonstrate its efficacy.
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- 2008
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6. Cardiovascular fitness and exercise as determinants of insulin resistance in postpubertal adolescent females.
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Kasa-Vubu JZ, Lee CC, Rosenthal A, Singer K, and Halter JB
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- Absorptiometry, Photon, Adipose Tissue anatomy & histology, Adolescent, Blood Glucose, Body Composition, Body Mass Index, Female, Humans, Insulin blood, Models, Biological, Multivariate Analysis, Oxygen Consumption physiology, Puberty, Insulin Resistance physiology, Physical Fitness physiology
- Abstract
In obese adolescents, body mass index (BMI) is a poor predictor of insulin resistance, and the potential role of diminished physical activity has not been quantitated. We measured possible determinants of sensitivity to insulin in 53 adolescent females with a BMI between the 10th and the 95th percentile. We hypothesized that across weight and fitness spectra, relative fat mass, rather than BMI, and cardiovascular fitness would be predictors of insulin resistance. We measured body composition by total-body dual x-ray absorptiometry. Self-reported weekly frequency of aerobic exercise for 1 h (RDE) was recorded, and maximal oxygen consumption (VO(2)max) was measured. Insulin sensitivity was estimated by homeostasis model assessment index (HOMA(IR)) derived from fasting glucose and insulin concentrations. BMI was not related to HOMA(IR) (P = 0.20), RDE showed a marginal relationship (P = 0.049), whereas percent body fat and VO(2)max were significantly related to HOMA(IR) (P = 0.01 and 0.0008, respectively). In a multiple regression model, VO(2)max was a more critical determinant of insulin resistance than percent body fat (P = 0.03 vs. P = 0.67) or RDE (P = 0.01 vs. 0.51). For prevention strategies in youth, physical inactivity may represent a greater metabolic risk than obesity alone.
- Published
- 2005
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7. Pneumocystis carinii pneumonia in chronic lymphocytic leukaemia.
- Author
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Vavricka SR, Halter J, Hechelhammer L, and Himmelmann A
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- Anti-Infective Agents therapeutic use, Chlorambucil administration & dosage, Dyspnea etiology, Fatal Outcome, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Middle Aged, Opportunistic Infections drug therapy, Pedigree, Pneumonia, Pneumocystis drug therapy, Prednisone administration & dosage, Trimethoprim, Sulfamethoxazole Drug Combination therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Opportunistic Infections complications, Pneumonia, Pneumocystis complications
- Abstract
Pneumocystis carinii pneumonia in patients with chronic lymphocytic leukaemia (CLL) who have not been treated with fludarabin are rare, although clinically relevant CD4 T-cell depletion can occur in longstanding CLL without prior treatment with purine analogues. A 52 year old woman is reported who was on long term treatment with chlorambucil and taking a short course of prednisone for familial CLL before she developed progressive dyspnoea, and P carinii pneumonia was diagnosed in bronchoalveolar lavage fluid. Despite treatment with high dose co-trimoxazole the patient died.
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- 2004
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8. Norepinephrine infusion during moderate-intensity exercise increases glucose production and uptake.
- Author
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Kreisman SH, Ah Mew N, Halter JB, Vranic M, and Marliss EB
- Subjects
- Adult, Humans, Lactic Acid blood, Male, Norepinephrine blood, Oxygen Consumption drug effects, Pyruvic Acid blood, Exercise, Glucose metabolism, Norepinephrine pharmacology
- Abstract
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.
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- 2001
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9. Glucoregulation during and after intense exercise: effects of beta-adrenergic blockade in subjects with type 1 diabetes mellitus.
- Author
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Sigal RJ, Fisher SJ, Halter JB, Vranic M, and Marliss EB
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- Adolescent, Adult, Epinephrine blood, Fatty Acids, Nonesterified blood, Glycerol blood, Humans, Insulin blood, Insulin metabolism, Insulin Secretion, Lactic Acid blood, Male, Norepinephrine blood, Oxygen Consumption, Propranolol, Pyruvic Acid blood, Receptors, Adrenergic, beta physiology, Adrenergic beta-Antagonists, Blood Glucose metabolism, Diabetes Mellitus, Type 1 blood, Exercise physiology, Homeostasis
- Abstract
In intense exercise (>80% maximum oxygen uptake) a huge, up to 8-fold increase in glucose production (Ra) is tightly correlated to marked increases in plasma norepinephrine (NE) and epinephrine. Both Ra and glucose uptake (Rd) are enhanced, not reduced, during beta-adrenergic blockade in normal subjects. Beta-blockade also caused a greater fall in immunoreactive insulin (IRI) during exercise, which could, in turn, have increased Ra directly or via an increased glucagon/insulin ratio. To control for adrenergic effects on endogenous insulin secretion, we tested type 1 diabetic subjects (DM) made euglycemic by overnight i.v. insulin that was kept constant in rate during and after exercise. Their responses to postabsorptive cycle ergometer exercise at 85-87% maximum oxygen uptake for approximately 14 min were compared to those of similar male control (CP) subjects. Six DM and seven CP subjects received i.v. 150 microg/kg propranolol over 20 min, then 80 microg/kg x min from -30 min, during exercise and for 60 min during recovery. Plasma glucose increased from similar resting values to peaks of 6.8 mmol/L in DM and 6.5 mmol/L in CP, then returned to resting values in CP within 20 min, but in DM, remained higher than in CP from 8-60 min (P = 0.049). Ra rose rapidly until exhaustion, to 13.3 mg/kg x min in CP and 11.6 in DM (P = NS). Ra declined rapidly in recovery, although somewhat more slowly in DM (P = 0.013 from 2-15 min). The Rd increased to 10.6 in CP and 9.2 mg/kg x min in DM (P = NS), then declined similarly in early recovery, but remained higher in CP from 50-100 min (P = 0.05). The rises in plasma glucose during exercise in both groups were thus due to the increments in Rd less than those in Ra. The higher recovery glucose in DM was due to the slower decline in Ra and the lower Rd in later recovery. IRI was higher in DM than in CP before exercise (P = 0.011), and whereas it decreased in CP (P < 0.05), it increased approximately 2-fold in DM, thus being higher throughout exercise (P = 0.003). The glucagon/insulin ratio was unchanged in DM, but increased in CP during exercise (P = 0.002). NE showed a rapid, marked increment during exercise to peak values of 23.7 nmol/L in CP and 25.7 nmol/L in DM (P = NS), and epinephrine showed parallel responses. Both correlated significantly with the Ra responses. In summary, the Ra responses of both DM and CP during exercise were greater than those of control unblocked subjects (previously reported) despite higher IRI (all exogenous) in DM. This suggests an important contribution of direct alpha-adrenergic stimulation to this Ra effect.
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- 1999
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10. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity.
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Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, and Supiano MA
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- Acetylcholine administration & dosage, Blood Flow Velocity, Dose-Response Relationship, Drug, Female, Forearm blood supply, Humans, Insulin Resistance, Male, Middle Aged, Nitroprusside administration & dosage, Vasodilator Agents, Diabetes Mellitus, Type 2 physiopathology, Endothelium, Vascular physiopathology, Vasodilation
- Abstract
In subjects with type 2 diabetes in whom an impaired response to an endothelial-dependent vasodilator has been characterized, the populations have also been at least moderately obese. Obesity has been characterized as an independent predictor of endothelial dysfunction in nondiabetic subjects. We hypothesized that in normotensive subjects with type 2 diabetes compared with age-matched control subjects, 1) endothelium-dependent vasodilation, as demonstrated by the forearm blood flow (FABF) response to intraarterial acetylcholine, would be decreased; 2) endothelium-independent vasodilation, as demonstrated by the FABF response to intraarterial nitroprusside, would be similar; 3) the degree of insulin resistance, as measured by the insulin sensitivity index (SI), would predict greater impairment in the FABF response to acetylcholine; and 4) these relationships would be independent of obesity. We measured FABF by venous occlusion plethysmography during brachial arterial infusions of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroprusside in 20 control and 17 subjects with type 2 diabetes. We measured SI using the frequently sampled i.v. glucose tolerance test. Among the diabetic relative to the control subjects we identified a decrease in the acetylcholine-mediated percent increase in FABF (P = 0.02). Using the absolute FABF response to acetylcholine and including adjustments for body mass index and other covariates, the overall group difference remained and was noted to be greatest in those subjects who had lower baseline FABFs. In contrast, no significant difference in the nitroprusside-mediated increase in the percent change FABF was identified between groups (P = 0.30). Finally, the degree of insulin resistance, as measured by SI, did not independently predict greater impairment of the FABF response to acetylcholine. This study is the first to identify specific endothelial cell dysfunction that remains significant after adjustment for obesity in a population of normotensive subjects with type 2 diabetes.
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- 1998
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11. Interdisciplinary team training in geriatrics: reaching out to small and medium-size communities.
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Anderson LA, Persky NW, Whall AL, Campbell R, Algase DL, Gillis GL, and Halter JB
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- Community Participation, Geriatrics organization & administration, Humans, Inservice Training organization & administration, Michigan, Program Development, Program Evaluation, Geriatrics education, Health Services for the Aged organization & administration, Patient Care Team organization & administration
- Abstract
Since 1989, six teams in the state of Michigan have been involved in a team training program designed to promote the development of geriatric services in small to medium-size communities. The program was enthusiastically received by participants, but after 18 months, only half of the teams had implemented clinical services for older adults. Monitoring the progress of the teams over 18 months and analyzing the activities of two teams revealed that financially stable and supportive sponsoring agencies and the community were critical factors in the implementation of interdisciplinary clinical services in geriatrics. Future team training programs trying to promote the development of geriatric services in small to medium-size communities should try to address these issues through community organization interventions.
- Published
- 1994
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12. Hyperinsulinemia prevents prolonged hyperglycemia after intense exercise in insulin-dependent diabetic subjects.
- Author
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Sigal RJ, Purdon C, Fisher SJ, Halter JB, Vranic M, and Marliss EB
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- Adolescent, Adult, Blood Glucose analysis, Catecholamines blood, Fatty Acids, Nonesterified blood, Humans, Insulin blood, Male, Oxygen Consumption, Reference Values, Diabetes Mellitus, Type 1 physiopathology, Hyperglycemia prevention & control, Hyperinsulinism physiopathology, Physical Endurance, Physical Exertion
- Abstract
Hyperglycemia with accompanying hyperinsulinemia occurs after brief, greater than 85% maximum oxygen consumption exercise to exhaustion in normal subjects and persists up to 60 min of recovery. To determine the importance of endogenous insulin secretion during and after intense exercise, responses to exercise of lean fit male post-absorptive insulin-dependent diabetes mellitus (IDDM) subjects, aged 18-34 yr, were compared with those of control subjects (C; n = 6). Three iv insulin protocols were employed: hyperglycemic (HG; n = 7) and euglycemic (EG1; n = 6) with constant insulin infusion, and euglycemic with doubled insulin infusion during recovery (EG2; n = 6). Overnight iv insulin was adjusted to achieve prolonged euglycemia (5.4 +/- 0.3 mmol/L) or hyperglycemia (8.6 +/- 0.3 mmol/L) before exercise. This allowed for comparisons between HG and EG1 (constant infusion) and between C and EG2 (to approximate physiological hyperinsulinemia by doubling the infusion rates at exhaustion for 56 +/- 7 min during recovery). Subjects exercised to 89-98% of their individual maximum oxygen consumption for 12.8 +/- 0.3 min. Glycemia increased to maximum values at 6 min of recovery (9.8 +/- 0.5 in HG, 6.9 +/- 0.4 in EG1, 7.3 +/- 0.3 in EG2, and 6.9 +/- 0.4 mmol/L in C). Whereas in EG2 and C, glucose returned to resting values in 50-80 min, it remained elevated at 120 min recovery in HG and EG1. During exercise, [3-3H]-glucose-determined glucose production increased markedly and exceeded disappearance in all groups, but less so in the HG subjects than in the other groups. An early recovery decline in glucose production did not differ among groups, but MCR (rate of glucose disappearance/glycemia) were markedly lower in HG and EG1, in whom plasma free insulin remained unchanged from 15 min of recovery onward (MCR, 1.6-1.9 vs. 2.3-2.8 mL/kg.min in C). Doubling the insulin infusion rate in EG2 restored the MCR response to that of C subjects. In summary, constant insulin infusion is insufficient to prevent prolonged postexercise hyperglycemia in IDDM subjects, even when provided at a rate sufficient to maintain normal resting glycemia and glucose turnover. The finding that increasing the rate of insulin infusion restored plasma glucose to normal in IDDM subjects suggests that the postexercise increase in insulin levels observed in normal subjects is essential to return plasma glucose to resting levels. Therefore, special strategies, differing from those for less strenuous exercise, are required for the management of insulin therapy in IDDM during and after intense exercise.
- Published
- 1994
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13. Glucoregulation during and after intense exercise: effects of beta-blockade.
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Sigal RJ, Purdon C, Bilinski D, Vranic M, Halter JB, and Marliss EB
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- Adolescent, Adult, Blood Glucose analysis, Epinephrine blood, Ergometry, Glucagon blood, Humans, Insulin blood, Male, Norepinephrine blood, Oxygen Consumption drug effects, Oxygen Consumption physiology, Propranolol blood, Adrenergic beta-Antagonists pharmacology, Exercise physiology, Glucose metabolism
- Abstract
To define the roles of beta- and alpha-adrenergic receptors in intense exercise, 17 lean healthy fit young males underwent 13.6 +/- 0.2 (+/-SE) min of cycle ergometer exercise: 6 at 100% maximum oxygen uptake (VO2max; MAX), 7 at their maximum possible (87 +/- 2.3%) during iv propranolol (P; 150 micrograms/kg bolus 30 min preexercise, then 80 micrograms/kg.min), and 7 (including 3 of the P subjects) at 87% VO2max (C) as controls for P. Plasma glucose increased from similar resting values to a peak in the early recovery period at 7.2 +/- 0.44 in MAX and 6.8 +/- 0.37 in P, but only 5.2 +/- 0.3 mmol/L in C. The rate of glucose appearance (Ra) rose about 8-fold in both MAX and P, but only 4-fold in C (P = 0.001). The rate of glucose disappearance (Rd) increased 4-fold in MAX, 5.5-fold in P, and 3-fold in C (P = 0.001). Plasma insulin declined during exercise (P < 0.05) in MAX and P, but not in C, whereas plasma glucagon increased modestly in all groups. The mean peak plasma norepinephrine level was 36.3 +/- 4.5 in MAX, 20.2 +/- 3.4 in P, and 15.2 +/- 2.9 nmol/L in C (P = 0.002); epinephrine reached 7141 +/- 1790 in MAX and 5605 +/- 1532 in P (P = NS), but only 1715 +/- 344 pmol/L in C (P = 0.03). Therefore, 1) an "unmasked" alpha-adrenergic effect, directly and/or via an altered glucagon/insulin ratio, probably contributed to increased Ra with P treatment; and 2) the marked facilitation of the increase in Rd with P supports a major role for beta-adrenergic restraint of Rd at this exercise intensity.
- Published
- 1994
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14. The roles of insulin and catecholamines in the glucoregulatory response during intense exercise and early recovery in insulin-dependent diabetic and control subjects.
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Purdon C, Brousson M, Nyveen SL, Miles PD, Halter JB, Vranic M, and Marliss EB
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- Adult, Analysis of Variance, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 physiopathology, Humans, Insulin blood, Male, Osmolar Concentration, Reference Values, Blood Glucose metabolism, Diabetes Mellitus, Type 1 metabolism, Epinephrine physiology, Insulin physiology, Norepinephrine physiology, Physical Exertion
- Abstract
Intense exercise is associated with a marked stimulation of glucose production (Ra), a somewhat smaller increment in its utilization (Rd) (and therefore hyperglycemia), large increases in plasma catecholamines, and moderate hyperglucagonemia. The hyperglycemia increases in recovery and is accompanied by hyperinsulinemia. Because these adaptations are unique to intense exercise, we tested the physiological significance of the hyperinsulinemia by exercising six fit, postabsorptive young male subjects with insulin-dependent diabetes mellitus (IDDM) after overnight glycemic normalization by iv insulin, keeping its infusion rate constant during and for 2 h after 100% maximum VO2 cycle ergometer exercise to exhaustion (12 min) (no postexercise hyperinsulinemia). Their responses were compared with those of matched control subjects studied on two separate occasions, once without intervention (physiological hyperinsulinemia, n = 6) and again with a 0.05 U/kg iv bolus at exhaustion (postexercise supraphysiological hyperinsulinemia, n = 5). In all three study protocols, Ra increased by 7-fold, and Rd by 4-fold at exhaustion, and Ra declined in early recovery at the same rates. Therefore, the early recovery hyperinsulinemia is not required to return Ra to preexercise levels, and excessive hyperinsulinemia does not accelerate this decline. We infer that the catecholamine increments and decrements are the prime regulators of Ra (correlations of Ra vs. norepinephrine or epinephrine, P < 0.001 in the three studies), with a smaller contribution from the concurrent hyperglucagonemia. Rd, in contrast, was significantly affected by insulin. In the IDDM subjects, Rd remained at the same rate as Ra through most of recovery, resulting in sustained hyperglycemia and decreased glucose MCR, vs. the control subjects. This hyperglycemia compensated for the abnormal MCR, such that Rd was comparable to that in the control subjects. With the insulin bolus, the Rd elevation was sustained longer compared to the study without bolus, resulting in mild hypoglycemia successfully counterregulated by an increase in Ra. Thus, the principal regulators of the marked exercise increase and rapid recovery decrease in Ra are probably the catecholamines. The postexercise hyperinsulinemia is required for the MCR response and to return plasma glucose concentrations to preexercise levels. Different therapeutic strategies are required in persons with IDDM undergoing strenuous vs. moderate exercise, because of their inability to generate the postexercise hyperinsulinemia.
- Published
- 1993
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15. Mechanisms of impaired acute insulin release in adult onset diabetes: studies with isoproterenol and secretin.
- Author
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Halter JB and Porte D Jr
- Subjects
- Aged, Blood Glucose analysis, Glucose Tolerance Test, Humans, Insulin Secretion, Male, Middle Aged, Reference Values, Diabetes Mellitus, Type 2 physiopathology, Insulin metabolism, Isoproterenol, Secretin
- Abstract
Previous work has suggested that impaired islet glucose recognition occurs in patients with adult onset diabetes, as acute insulin release is absent after iv glucose but present after beta adrenergic stimulation with isoproterenol (Iso). However, insulin responses to Iso were variably reduced as compared to normal in the diabetics. In order to evaluate the importance of the Iso dose, dose-response studies were performed in 9 diabetics (fasting plasma glucose greater than 150 mg/dl) and 10 age-matched controls. In both control subjects and diabetics, 0.5 microgram Iso produced no insulin response; 2 micrograms Iso produced an intermediate response; and 8 and 12 micrograms Iso produced a higher response. The insulin responses to the larger doses of Iso were lower in diabetics than control subjects (8 micrograms, 20 +/- 5 vs. 39 +/- 6 (P less than 0.025); 12 micrograms, 21 +/- 6 vs. 37 +/- 4 (P less than 0.05); means +/- SEM, microU/ml). Of 16 diabetics who received 12 micrograms Iso, 5 had insulin responses greater than 2 SD below the control mean, while others had responses that spanned the entire range of normal. Seven diabetics also were given iv secretin (150 U). Their insulin responses to secretin correlated with the responses to Iso (r = 0.83, P less than 0.02). Thus, patients with subnormal responses to Iso also had low secretion responses. The abnormalities of acute insulin secretion in diabetics can be explained by a lesion variably affecting islet membrane receptors; some patients may have glucose receptor damage, but intact responses to other stimuli, and others may have more widespread damage affecting beta-adrenergic and secretin responses as well. Alternatively, there may be heterogeneity in adult onset diabetes, as patients with low responses to all stimuli could have a qualitatively different lesion affecting insulin secretory capacity rather than membrane receptors.
- Published
- 1978
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16. Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for imparied glucose potentiation.
- Author
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Halter JB, Graf RJ, and Porte D Jr
- Subjects
- Adult, Catecholamines blood, Humans, Insulin Secretion, Middle Aged, Blood Glucose metabolism, Diabetes Mellitus blood, Glucose, Hyperglycemia blood, Insulin metabolism, Isoproterenol
- Published
- 1979
- Full Text
- View/download PDF
17. Sodium salicylate potentiates neurohumoral responses to insulin-induced hypoglycemia.
- Author
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Metz S, Halter J, and Robertson RP
- Subjects
- Adult, Blood Glucose metabolism, Humans, Hypoglycemia chemically induced, Insulin, Kinetics, Male, Prostaglandins E antagonists & inhibitors, Sweating drug effects, Epinephrine blood, Glucagon blood, Hypoglycemia blood, Norepinephrine blood, Sodium Salicylate pharmacology
- Published
- 1980
- Full Text
- View/download PDF
18. Effect of hyperglycemia per se on glucose disposal and clearance in noninsulin-dependent diabetics.
- Author
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Best JD, Beard JC, Taborsky GJ Jr, Halter JB, and Porte D Jr
- Subjects
- Adult, Aged, Epinephrine blood, Glucagon blood, Glucose, Humans, Insulin blood, Male, Metabolic Clearance Rate, Middle Aged, Somatostatin, Blood Glucose metabolism, Diabetes Mellitus blood, Hyperglycemia blood
- Published
- 1983
- Full Text
- View/download PDF
19. Differential effects of tolbutamide on first and second phase insulin secretion in noninsulin-dependent diabetes mellitus.
- Author
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Pfeifer MA, Halter JB, Beard JC, and Porte D Jr
- Subjects
- Adult, Aged, Blood Glucose metabolism, Diabetes Mellitus drug therapy, Humans, Insulin Secretion, Male, Middle Aged, Diabetes Mellitus metabolism, Glucose, Insulin metabolism, Tolbutamide therapeutic use
- Abstract
Immunoreactive insulin responses to a 20-g iv glucose challenge during a 7.5 mg/m2/min tolbutamide infusion were studied in 21 untreated noninsulin-dependent male diabetics. All data were analyzed by paired t tests. During the tolbutamide infusion, compared to the saline control period in the same subjects, glucose levels were lowered [217 +/- 17 vs. 196 +/- 16 mg/dl (mean +/- SEM); P less than 0.005], and there was an increase in both first phase (2 +/- 1 vs. 16 +/- 4 micro U/ml; P less than 0.005) and second phase insulin responses (296 +/- 71 vs. 499 +/- 101 micro U. min/ml; P less than 0.05; n = 21). However, when the prestimulus glucose level was lowered by an insulin infusion (214 +/- 20 vs. 145 +/- 17 mg/dl; P less than 0.001), no effect on first phase insulin secretion was observed, and the second phase response decreased (290 +/- 78 vs. 124 +/ 55 micro U. min/ml; P less than 0.005; n = 11; saline control vs. insulin infusion). In 8 subjects, the plasma glucose level during the tolbutamide infusion was kept constant by a concurrent variable glucose infusion. First phase insulin secretion was still increased, though no more than in studies were plasma glucose was not kept constant. However, there was further augmentation of the second phase response (tolbutamide alone, 443 +/- 142 micro U. min/ml; tolbutamide plus glucose, 802 +/- 232 micro U. min/ml; P less than 0.05). These findings indicate that tolbutamide augments first phase insulin secretion in untreated diabetics independently of the prestimulus glucose level. However, changes in the glucose level significantly modulate the sulfonylurea influence on the second phase insulin response to glucose. This effect of glucose level is an important consideration when evaluating the insulinotropic effects of a sulfonylurea.
- Published
- 1981
- Full Text
- View/download PDF
20. Modulation of arginine-induced glucagon release by epinephrine and glucose levels in man.
- Author
-
Beard JC, Weinberg C, Pfeifer MA, Best JD, Halter JB, and Porte D Jr
- Subjects
- Adult, Blood Glucose, Dose-Response Relationship, Drug, Glucagon blood, Humans, Hyperglycemia chemically induced, Hyperglycemia metabolism, Infusions, Parenteral, Male, Middle Aged, Regression Analysis, Arginine pharmacology, Epinephrine pharmacology, Glucagon metabolism, Glucose pharmacology
- Abstract
To assess how physiological epinephrine (EPI) elevations and EPI-induced hyperglycemia interact in the regulation of glucagon secretion, we measured acute glucagon responses (AGR) to arginine at controlled glucose levels during EPI infusions in man. With glucose levels matched at 166 +/- 5 mg/dl using glucose clamp techniques, the AGR (mean change at 2-5 min) to a 5-g iv arginine injection was greater in each subject during the infusion of 15 ng/kg . min EPI (low EPI) than during the control glucose infusion and was still greater during the infusion of 80 ng/kg . min EPI (high EPI; 69 +/- 15, 76 +/- 13, and 142 +/- 22 pg/ml, respectively; n = 8; P less than 0.003). With glucose levels matched at 256 +/- 5 mg/dl, a similar dose-related enhancement of AGR by EPI was seen (control, 53 +/- 12 pg/ml; low EPI, 63 +/- 5 pg/ml; high EPI, 130 +/- 20 pg/ml; P less than 0.008). During control infusions, raising the glucose level from 102 +/- 2 to 166 +/- 5 to 256 +/- 5 mg/dl suppressed AGR from 77 +/- 17 to 69 +/- 15 to 53 +/- 12 pg/ml (P less than 0.002). During low EPI, the same glycemic increments lowered GR from 108 +/- 19 to 76 +/- 13 to 63 +/- 5 pg/ml (P less than 0.02). This suppression of AGR by hyperglycemia was sufficient to obscure stimulation by EPI: at a glucose level of 102 +/- 2 mg/dl during control infusions, AGR was 77 +/- 17 pg/ml, compared to only 76 +/- 13 pg/ml during low EPI with the glucose level higher (166 +/- 5 mg/dl). Multiple linear regression analysis showed a highly significant dependence of AGR on both EPI and glucose levels, accounting for 80% of the within-subject variation in AGR (P less than 0.0001). These data show that 1) EPI is a dose-dependent amplifier of arginine-induced glucagon secretion in man, and 2) hyperglycemia suppresses arginine-induced glucagon secretion, potentially masking the stimulation caused by EPI. The findings suggest that the feedback effect of hyperglycemia on glucagon secretion may help regulate the level of hyperglycemia resulting from adrenergic stimulation.
- Published
- 1983
- Full Text
- View/download PDF
21. The effects of age on the plasma catecholamine response to mental stress in man.
- Author
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Barnes RF, Raskind M, Gumbrecht G, and Halter JB
- Subjects
- Adult, Aged, Anxiety, Blood Pressure, Heart Rate, Humans, Male, Middle Aged, Aging, Epinephrine blood, Norepinephrine blood, Stress, Psychological blood
- Abstract
To determine if sympathetic nervous system activity is heightened during psychological stress in older adults, plasma norepinephrine (NE), epinephrine (EPI), heart rate, and blood pressure were measured in 10 healthy old (mean age, 68.5 yr) men and 10 healthy young (mean age, 26.6 yr) men during a 12-min mental stress test. Basal NE was higher in old than in young men (400 +/- 33 vs. 286 +/- 32 pg/ml: p less than 0.01). Consistent significant increases in plasma NE occurred only in the elderly and mean increases (delta) in NE during testing were significantly greater (P less than 0.01) in the old than in the young men. Compared to basal levels, plasma EPI increased by 2 min in both young (delta EPI, 50 +/- 20 pg/ml; P less than 0.02) and old subjects (delta EPI, 41 +/- 11; P less than 0.01) and remained significantly increased throughout the test. There was no difference in either basal or delta EPI between young and old men. Heart rate and blood pressure were significantly increased throughout testing for both age groups. Although the delta blood pressure during testing tended to be greater in the old men, this difference was not statistically significant. Conversely, the delta heart rate was greater in the young subjects (P less than 0.005). Since EPI increases were similar in old and young men, mental stress-related adrenomedullary activation does not appear to change with age. However, the increased plasma NE response in the elderly suggests that they have heightened activity of postganglionic sympathetic neurons during psychological stress.
- Published
- 1982
- Full Text
- View/download PDF
22. Suppression of glucagon secretion during a tolbutamide infusion in normal and noninsulin-dependent diabetic subjects.
- Author
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Pfeifer MA, Beard JC, Halter JB, Judzewitsch R, Best JD, and Porte D Jr
- Subjects
- Adult, Blood Glucose analysis, Humans, Infusions, Parenteral, Insulin therapeutic use, Male, Middle Aged, Secretory Rate drug effects, Diabetes Mellitus blood, Glucagon metabolism, Tolbutamide pharmacology
- Abstract
To determine the effect of tolbutamide on glucagon release in noninsulin-dependent diabetic and normal subjects and how plasma glucose levels may modulate this effect, the acute glucagon response (AGR) to a 5-g iv arginine pulse was determined before and during a tolbutamide infusion. There was a decrease in plasma glucose concentration in both normal and diabetic subjects (both P less than 0.001); there tended to be a suppression of the AGR (4 of 6 normals and 8 of 11 diabetics), but this suppression was not statistically significant. In separate studies, when the plasma glucose level was clamped at baseline values by a variable rate of glucose infusion, the AGR was suppressed during the tolbutamide infusion in all 7 normal [change in AGR (delta AGR) = -35 +/- 12 pg/ml; P less than 0.05] and all 6 noninsulin-dependent diabetic subjects (delta AGR = -14 +/- 5 pg/ml, p less than .05). In 6 insulin-dependent diabetic subjects, there was no evidence of glucagon suppression by tolbutamide (delta AGR = +2 +/- 2 pg/ml). These results are consistent with the hypothesis that sulfonylureas suppress glucagon secretion by augmenting insulin secretion, an effect that falling glucose levels can mask. Consideration of this observation is necessary when interpreting the effects of a sulfonylurea on islet cell responses.
- Published
- 1983
- Full Text
- View/download PDF
23. Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose.
- Author
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Judzewitsch RG, Pfeifer MA, Best JD, Beard JC, Halter JB, and Porte D Jr
- Subjects
- Aged, Arginine, Diabetes Mellitus physiopathology, Fasting, Female, Humans, Insulin Secretion, Male, Middle Aged, Blood Glucose metabolism, Chlorpropamide therapeutic use, Diabetes Mellitus drug therapy, Insulin metabolism, Islets of Langerhans physiopathology
- Abstract
To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.
- Published
- 1982
- Full Text
- View/download PDF
24. Release and clearance rates of epinephrine in man: importance of arterial measurements.
- Author
-
Best JD and Halter JB
- Subjects
- Arteries, Humans, Kinetics, Male, Metabolic Clearance Rate, Propranolol, Veins, Epinephrine blood
- Abstract
Previous estimates of catecholamine kinetics in human subjects have been based on the measurement of the catecholamine levels in forearm venous plasma. However, the use of forearm venous measurements may introduce considerable error, since venous catecholamine levels may primarily reflect metabolism in the organ drained rather than in the total body. In this study, arterial levels of epinephrine were found to significantly exceed forearm venous levels, both basally (mean +/- SEM, 71 +/- 13 vs. 50 +/- 7 pg/ml; n = 6; P less than 0.05) and during infusions of epinephrine [0.1 microgram/min (112 +/- 9 vs. 77 +/- 11 pg/ml; P less than 0.005) or 2 micrograms/min (862 +/- 71 vs. 437 +/- 66 pg/ml; P less than 0.001)]. During the 2 micrograms/min epinephrine infusion, arterial plasma norepinephrine rose from 191 +/- 37 to 386 +/- 78 pg/ml (P less than 0.001), while venous norepinephrine levels did not change significantly. Fractional extraction (arterial - venous + arterial X 100) of epinephrine across the forearm was 26 +/- 8% in the basal state and increased to 33 +/- 6% and further to 51 +/- 4% during the epinephrine infusions. The addition of propranolol (5 mg, iv, plus an 80 micrograms/min infusion) reduced fractional extraction from 51 +/- 4% to 35 +/- 5%. Whole body clearance of epinephrine, calculated from arterial measurements, was 33 +/- 3 ml/kg . min during the 0.1 microgram/min infusion and 35 +/- 3 ml/kg . min during the 2 micrograms/min epinephrine infusion, values 50% lower than the clearance rates calculated from venous measurements. Propranolol infusion resulted in a fall in whole body clearance to 20 +/- 2 ml/kg . min (P less than 0.001), suggesting that epinephrine clearance is partly dependent on a beta-adrenergic mechanism. Basal endogenous release rate (clearance X basal epinephrine level) was estimated to be approximately 0.18 microgram/min, a value much less than that reported in studies using venous measurements. We conclude that arterial rather than venous measurements should be used to estimate catecholamine kinetics in vivo.
- Published
- 1982
- Full Text
- View/download PDF
25. Functional uncoupling of the platelet alpha 2-adrenergic receptor-adenylate cyclase complex in the elderly.
- Author
-
Supiano MA, Linares OA, Halter JB, Reno KM, and Rosen SG
- Subjects
- Adult, Aged, Aged, 80 and over, Cyclic AMP antagonists & inhibitors, Cyclic AMP biosynthesis, Dose-Response Relationship, Drug, Epinephrine antagonists & inhibitors, Epinephrine pharmacology, Female, Humans, Male, Sodium Fluoride antagonists & inhibitors, Sodium Fluoride pharmacology, Adenylyl Cyclases metabolism, Aging, Blood Platelets metabolism, Receptors, Adrenergic, alpha metabolism
- Abstract
Elderly humans demonstrate decreased responsiveness in several hormone-receptor systems, including adrenergic receptors. Studies of the beta-adrenergic receptor (beta-AR) system have shown that reduced beta-adrenergic sensitivity in the elderly may be due to reduced beta-AR affinity for agonists. To determine the mechanisms underlying altered alpha-adrenergic sensitivity in the elderly, we assessed the relationships between age and platelet membrane alpha 2-adrenergic receptor (alpha 2-AR)-binding properties, receptor-linked adenylate cyclase (AC) activity, and the affinity of the alpha 2-AR-AC complex for agonists in 18 young (mean age, 24 yr; range 19-34) and 13 elderly (mean age, 69 yr; range, 63-85) normal subjects. In platelet membrane preparations from elderly compared to young subjects, we found similar antagonist-binding properties and similar activity of the catalytic unit of platelet AC, as indicated by the cAMP response to sodium fluoride stimulation. However, mean epinephrine-mediated inhibition of sodium fluoride-stimulated platelet AC activity was less in the elderly [20 +/- 4% (+/- SEM) vs. 31 +/- 2% inhibition; P less than 0.005). In addition, platelet alpha 2-AR affinity for agonist was lower in the elderly, as indicated by the higher concentration of epinephrine needed to inhibit 50% of specific [3H]yohimbine binding (IC50, 3.2 +/- 0.6 vs. 1.4 +/- 0.3 microM; P less than 0.02). These data provide evidence that platelet membranes from elderly humans have decreased responsiveness to alpha-adrenergic stimulation, which can be attributed to reduced alpha 2-AR-AC affinity for agonists. Similarly to reported age-related alterations in beta-adrenergic receptor function, these results suggest that there is also functional uncoupling of the alpha 2-AR-AC complex in elderly humans.
- Published
- 1987
- Full Text
- View/download PDF
26. Dose-dependent suppression of norepinephrine appearance rate in plasma by clonidine in man.
- Author
-
Veith RC, Best JD, and Halter JB
- Subjects
- Adult, Blood Pressure drug effects, Clonidine blood, Dose-Response Relationship, Drug, Epinephrine blood, Female, Heart Rate drug effects, Humans, Kinetics, Male, Metabolic Clearance Rate drug effects, Middle Aged, Clonidine pharmacology, Norepinephrine blood
- Abstract
Clonidine is an alpha 2-receptor agonist which lowers both blood pressure and plasma norepinephrine (NE) levels in man. To determine whether the clonidine-induced fall in plasma NE is due to decreased NE appearance into plasma or increased NE clearance from plasma, NE infusions [( 3H]NE; 15 microCi/m2 bolus and 0.35 microCi/m2 X min infusion) were performed in 10 normal subjects, aged 25-56 yr. Arterialized plasma samples were obtained for measurements of steady state [3H]NE specific activity and plasma NE to allow calculation of plasma NE appearance rate and NE clearance before and 120-140 min after 1.5 and 5.0 micrograms/kg oral clonidine. Using an identical protocol, responses were compared in 4 subjects after placebo administration. Clonidine produced a dose-related reduction in mean arterial blood pressure, but no significant change in heart rate. The basal supine plasma NE concentration of 204 +/- 21 pg/ml (mean +/- SEM) fell by 27% (P less than 0.02) after low dose clonidine and by 51% (P less than 0.001) after high dose clonidine. There was no change in plasma epinephrine levels. The basal plasma NE appearance rate of 0.25 +/- 0.03 microgram/m2 X min was reduced by 32% (P less than 0.01) after low dose clonidine and by 52% (P less than 0.001) after high dose clonidine. The basal plasma NE clearance of 1.2 +/- 0.08 liters/m2 X min was unchanged after clonidine treatment. There was no change in mean plasma NE levels, plasma NE appearance rate, or mean arterial pressure after placebo administration. These findings demonstrate that the clonidine-induced fall in plasma NE levels is due to a dose-dependent suppression of plasma NE appearance rate and provide evidence for alpha 2-adrenergic inhibition of sympathetic nervous system activity in normotensive subjects.
- Published
- 1984
- Full Text
- View/download PDF
27. Relationship of impaired insulin secretion during surgical stress to anesthesia and catecholamine release.
- Author
-
Halter JB and Pflug AE
- Subjects
- Blood Glucose analysis, Humans, Insulin blood, Insulin Secretion, Male, Anesthesia, Inhalation, Anesthesia, Spinal, Epinephrine blood, Insulin metabolism, Norepinephrine blood, Stress, Physiological physiopathology, Surgical Procedures, Operative
- Abstract
Impaired insulin secretion has been observed during surgical stress in man. To determine the relationship between insulin secretion during anesthesia and surgical stress and plasma levels of norepinephrine (NE) and epinephrine (Epi), studies were performed in 16 patients before and during elective minor surgical procedures. In 8 patients studied during halothane inhalation anesthesia before operation, the acute insulin response (AIR) to glucose (5 g, IV) fell to 51 +/- 3% of the preanesthesia AIR (mean +/- SEM; P < 0.001). This inhibition of AIR appeared unrelated to increased adrenergic activity, since during anesthesia alone, plasma NE did not change significantly and plasma Epi fell from 94 +/- 11 to 34 +/- 10 pg/ml (P < 0.01). During the postoperative recovery period in these patients, after discontinuation of the anesthesia, the AIR to glucose was 50 +/- 5% of the preanesthesia baseline response (P < 0.001). At this time, both plasma NE and Epi were increased compared to preanesthesia levels [NE: 240 +/- 40 (preanesthesia) vs. 340 +/- 43 (postoperative); Epi: 219 +/- 43 (preanesthesia) vs. 94 +/- 11 (postoperative); both P < 0.05]. In eight patients undergoing similar operations during low spinal anesthesia, no inhibition of the AIR to glucose occurred, and plasma NE and Epi did not increase significantly during or after the operation. During the recovery period, there was a relationship between plasma Epi and the degree of inhibition of the AIR to glucose (r = 0.70; n = 11; P < 0.05). Thus, inhibition of insulin secretion during surgical stress may be mediated both by direct effect of the anesthesia used and by activation of the sympathetic nervous system.
- Published
- 1980
- Full Text
- View/download PDF
28. Circadian variation of plasma catecholamines in young and old men: relation to rapid eye movement and slow wave sleep.
- Author
-
Prinz PN, Halter J, Benedetti C, and Raskind M
- Subjects
- Adult, Age Factors, Aged, Heart Rate, Humans, Male, Middle Aged, Sleep, REM, Wakefulness, Circadian Rhythm, Epinephrine blood, Norepinephrine blood, Sleep Stages
- Abstract
Young and old healthy subjects with indwelling venous cannulae were found to undergo significant diurnal variations in plasma catecholamine levels. Both norepinephrine and epinephrine levels peaked in late morning and reached lowest values at night during sleep. Catecholamine levels were similar during slow wave and rapid eye movement sleep. While epinephrine levels were unaffected by age, norepinephrine levels were greater in older subjects by 28% during the day (at 1100 h; P less than 0.01) and by 75% at night (between 2200--0900 h; P less than 0.01). Older subjects slept less well; they had 90% less stage 4 sleep, 27% less rapid eye movement sleep, and twice as much wakefulness at night (P less than 0.05). These findings raise the possibility that this well known age effect on sleep may be related to increased sympathetic nervous system activity.
- Published
- 1979
- Full Text
- View/download PDF
29. Selective osmoreceptor dysfunction in the syndrome of chronic hypernatremia.
- Author
-
Halter JB, Goldberg AP, Robertson GL, and Porte D Jr
- Subjects
- Humans, Hypertonic Solutions, Hypothalamus injuries, Iatrogenic Disease, Male, Middle Aged, Sodium Chloride pharmacology, Trimethaphan pharmacology, Arginine Vasopressin blood, Hypernatremia metabolism, Pressoreceptors metabolism, Vasopressins analogs & derivatives, Water-Electrolyte Balance
- Abstract
A patient with the syndrome of chronic hypernatremia (serum Na+: mean = 154, range 139-184 mEq/l, n = 30) and hypodipsia due to a hypothalamic injury was studied to evaluate osmolar and baroreceptor control of arginine vasopressin (AVP) secretion. Resting plasma AVP levels measured by radioimmunoassay were inappropriately low for the degree of plasma hyperosmolality: range = less than 0.5-2.1 pg/ml, n = 10, with corresponding levels of plasma osmolality (P osM) greater than 300 m osmol/kg, suggesting either direct damage to the AVP synthesis and storage area or impaired afferent osmoreceptor function. Direct pituitary damage seemed unlikely, since anterior pituitary function was normal by standard testing. The existence of adequate neurohypophyseal stores of AVP was demonstrated by baroreceptor stimulation with the hypotensive agent trimethaphan (Arfonad): plasma AVP rising to 50.0 pg/ml during transient hypotension (BP = 70/0). Osmoreceptor function was evaluated during acute water loading followed by hypertonic saline infusion. During hypertonic saline infusion plasma AVP levels correlated with P osM (R = .87, P less than .01, n = 8), suggesting some residual osmotic regulation of AVP release. The osmotic threshold for AVP release (the x-axis intercept of the plasma AVP-P osM regression line) was not higher than normal. However, the AVP levels throughout this study remained markedly subnormal for the degree of plasma hyperosmolality (maximum plasma AVP = 1.9 PG/ML when P os M = 327 M OSMOL/KG). Since a substantial amount of AVP was released with baroreceptor stimulation, the inadequate rise in plasma AVP level with hyperosmolality indicates that afferent input from the osmoreceptor/thirst area of the hypothalamus is selectively impaired in this patient. These findings directly demonstrate a dissociation of osmoreceptor function from the AVP secretory apparatus in man.
- Published
- 1977
- Full Text
- View/download PDF
30. Sodium-restricted diet increases nighttime plasma norepinephrine and impairs sleep patterns in man.
- Author
-
Vitiello MV, Prinz PN, and Halter JB
- Subjects
- Adult, Humans, Male, Wakefulness physiology, Diet, Sodium-Restricted, Norepinephrine blood, Sleep physiology
- Abstract
Plasma norepinephrine levels in 10 healthy young males were significantly elevated after 3 days of a low sodium (less than 500 mg/day) diet. The low sodium diet was also associated with disturbed sleep patterns: decreased rapid eye movement and slow wave sleep and increased wakefulness. These sleep changes are similar to those seen in normal aged adults, who also undergo elevations of daytime and nighttime plasma norepinephrine. These results suggest the possibility that increased sympathetic nervous system activity may affect sleep patterns, and that therapies altering sympathetic activity may affect sleep.
- Published
- 1983
- Full Text
- View/download PDF
31. Effect of pentobarbital anesthesia on plasma norepinephrine kinetics in dogs.
- Author
-
Best JD, Taborsky GJ Jr, Flatness DE, and Halter JB
- Subjects
- Animals, Dogs, Kinetics, Metabolic Clearance Rate, Radioisotope Dilution Technique, Anesthesia, Norepinephrine blood, Pentobarbital pharmacology
- Abstract
To assess the effect of barbiturate anesthesia on sympathetic nervous system activity, plasma norepinephrine (NE) kinetics were measured in trained dogs with an indwelling right atrial catheter before and during iv administration of pentobarbital sodium (30 mg/kg, iv, plus continuous infusion at 0.1-0.2 mg/kg X min). Plasma NE levels fell by 64 +/- 6% from 103 +/- 22 to 42 +/- 18 pg/ml (mean +/- SEM; n = 6; P less than 0.001) during pentobarbital anesthesia. As measured with the isotope dilution method using steady state kinetics, basal NE spillover rate into plasma was 203 +/- 92 ng/min; this level fell by 91 +/- 2% (P less than 0.001) to 24 +/- 13 ng/min during anesthesia. Clearance of NE from plasma was also impaired by the anesthesia. Before pentobarbital administration, the NE clearance rate from plasma was 1.7 +/- 0.4 liters/min; this rate fell during anesthesia by 71 +/- 6% (P less than 0.001) to 0.5 +/- 0.2 liters/min. During control studies in which no barbiturate was administered, there was no change in plasma NE levels (111 +/- 11 vs. 116 +/- 19 pg/ml; n = 3), NE spillover rate into plasma (209 +/- 56 vs. 204 +/- 61 ng/min), or clearance of NE from plasma (1.8 +/- 0.4 vs. 1.7 +/- 0.2 liters/min). The marked suppression of the NE spillover rate into plasma during pentobarbital administration suggests that this type of anesthesia causes a profound suppression of baseline sympathetic nervous system activity in trained dogs. The observed fall of plasma NE levels underestimated the degree of suppression of sympathetic nervous activity by the anesthesia, since there was a concurrent fall in NE clearance from plasma.
- Published
- 1984
- Full Text
- View/download PDF
32. Paradoxical inhibition of insulin secretion by glucose in human diabetes mellitus.
- Author
-
Metz SA, Halter JB, and Robertson RP
- Subjects
- Adult, Aged, Epinephrine, Female, Galactose, Humans, Insulin blood, Insulin Secretion, Male, Middle Aged, Phentolamine, Diabetes Mellitus physiopathology, Glucose Tolerance Test, Insulin metabolism
- Published
- 1979
- Full Text
- View/download PDF
33. Epinephrine kinetics in humans: radiotracer methodology.
- Author
-
Rosen SG, Linares OA, Sanfield JA, Zech LA, Lizzio VP, and Halter JB
- Subjects
- Adult, Epinephrine blood, Female, Humans, Kinetics, Male, Mathematics, Models, Theoretical, Radioisotope Dilution Technique, Tritium, Epinephrine metabolism
- Abstract
The use of the plasma epinephrine (EPI) level as an index of adrenomedullary activity in humans is complicated by the rapid removal of EPI from plasma by many tissues. To determine whether the kinetics of distribution and metabolism of EPI could be best quantified using the isotope dilution method or a mathematical modeling technique, eight human subjects received a [3H]EPI infusion for 50-60 min. Analysis of the steady state arterialized plasma levels of EPI and [3H]EPI using the isotope dilution technique showed that the basal plasma EPI appearance rate is 0.87 +/- 0.11 nmol/m2.min, and the basal plasma EPI clearance rate is 1.63 +/- 0.14 L/min.m2. Mathematical modeling of the [3H]EPI levels revealed that a biexponential curve fit was superior to monoexponential and triexponential curve fits. A two-compartment model was the minimal compartment model that accurately described EPI kinetics. The basal plasma EPI appearance (0.82 +/- 0.16 nmol/m2.min) and EPI clearance (1.67 +/- 0.15 L/min.m2) rates that were estimated from this two-compartment model are similar to the results derived from the isotope dilution method. Mathematical modeling revealed a large extravascular mass of EPI. We conclude that the isotope dilution and mathematical modeling techniques similarly describe plasma EPI kinetics in humans. Kinetic analysis using mathematical modeling provides new insights into adrenomedullary function in humans.
- Published
- 1989
- Full Text
- View/download PDF
34. Plasma catecholamines, dietary carbohydrate, and glucose intolerance: a comparison between young and old men.
- Author
-
Chen M, Halter JB, and Porte D Jr
- Subjects
- Adolescent, Adult, Aged, Blood Glucose metabolism, Dietary Carbohydrates administration & dosage, Humans, Male, Middle Aged, Aging, Catecholamines blood, Dietary Carbohydrates pharmacology, Glucose Tolerance Test
- Abstract
Catecholamines play an important role in glucose homeostasis. This study was designed to determine whether circulating catecholamine changes in the elderly play a role in the glucose intolerance of aging and whether these changes are related to dietary carbohydrate intake. Plasma catecholamines (epinephrine and norepinephrine) and glucose were measured before and for 2 h after the administration of 100 g oral glucose in both 18 young (age, 18-39 yr) and 20 old (age, 60-82 yr) normal men during ad libitum home diet and after 3-day weight-maintaining, high or low carbohydrate formula diets in the Clinical Research Center. The elderly men had higher plasma norepinephrine levels before and after oral glucose than the young men even when eating matched formula diets. Plasma epinephrine levels were similar and decreased significantly after oral glucose in both groups. There was no relationship between catecholamine levels and degree of glucose tolerance. A high carbohydrate diet improved glucose tolerance in both old and young subjects. However, changes in dietary carbohydrates were not associated with consistent changes in plasma catecholamines. Therefore, we conclude that 1) glucose intolerance of aging cannot be explained by changes in plasma catecholamines, 2) the age-related increase in plasma norepinephrine is unrelated to dietary carbohydrate intake, and 3) there is no effect of age on suppression of plasma epinephrine after oral glucose administration.
- Published
- 1986
- Full Text
- View/download PDF
35. Autonomic nervous system control of glucagon secretion during neuroglucopenia.
- Author
-
Asplin CM, Werner PL, Halter JB, Hollander PM, and Palmer JP
- Subjects
- Animals, Atropine pharmacology, Blood Glucose metabolism, Epinephrine blood, Glucagon blood, Insulin blood, Kinetics, Male, Papio, Phentolamine pharmacology, Propranolol pharmacology, Autonomic Nervous System physiology, Deoxy Sugars pharmacology, Deoxyglucose pharmacology, Glucagon metabolism
- Abstract
The role which the autonomic nervous system (ANS) plays in controlling glucagon (IRG) secretion is controversial. Strong activation of the ANS was achieved in baboons with 500 mg/kg 2-deoxyglucose, producing a 20-fold rise in epinephrine and a 15-fold rise in IRG. Under such circumstances, the IRG response was attenuated by both alpha- and beta-adrenergic blockade, strongly suggesting that this part of the IRG rise post 2-deoxyglucose was mediated via adrenergic mechanisms. The baboon is similar to man, with the sympatho-adrenal axis having little influence on IRG secretion during mild activation of the ANS. However, during stronger ANS activation with 2-deoxyglucose, a clear effect of the sympatho-adrenal axis on IRG secretion was demonstrated. Whether experiments in primates demonstrate an effect of the ANS on IRG secretion may depend primarily on the strength of the neural response elicted.
- Published
- 1983
- Full Text
- View/download PDF
36. Prolonged infusion of somatostatin with glucagon replacement increases plasma glucose and glucose turnover in man.
- Author
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Ward WK, Best JD, Halter JB, and Porte D Jr
- Subjects
- Adolescent, Adult, Glucose biosynthesis, Humans, Insulin blood, Insulin physiology, Male, Blood Glucose metabolism, Glucagon blood, Somatostatin
- Abstract
To determine the effect of isolated beta-cell impairment on glucose turnover, we administered a 46-h infusion of somatostatin (200 micrograms/h) with glucagon replacement (0.75 ng/kg X min) to eight normal men. Fasting plasma insulin levels fell slightly, but significantly, from 8 +/- 2 (+/- SEM; control) to 6 +/- 2 microU/ml 46 h after beginning the infusion (P less than 0.001). Over the same period, fasting plasma glucose rose from 89 +/- 2 to 114 +/- 2 mg/dl (P less than 0.001), and plasma glucagon levels remained unchanged (79 +/- 5 vs. 82 +/- 8 pg/ml P = NS). Glucose turnover was measured by isotope dilution using [3-3H]glucose. The glucose production rate rose consistently from a baseline value of 2.08 +/- 0.04 to 2.45 +/- 0.06 mg/kg X min (P less than 0.01). The glucose disposal rate also rose consistently from 2.11 +/- 0.04 to 2.53 +/- 0.09 mg/kg X min (P less than 0.01). We conclude that prolonged mild selective insulin deficiency produced by infusion of somatostatin with glucagon replacement in normal men causes an elevation of the fasting plasma glucose level, which is maintained by glucose overproduction rather than by glucose underutilization. Overproduction of glucose may also be important in maintaining basal hyperglycemia in patients with noninsulin-dependent diabetes mellitus who have a similar impairment of insulin secretion.
- Published
- 1984
- Full Text
- View/download PDF
37. Suppression of plasma catecholamines and flushing by clonidine in man.
- Author
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Metz SA, Halter JB, Porte D Jr, and Robertson RP
- Subjects
- Adenoma, Islet Cell metabolism, Adult, Blood Pressure drug effects, Diabetes Mellitus metabolism, Face drug effects, Female, Humans, Hypertension metabolism, Male, Malignant Carcinoid Syndrome metabolism, Middle Aged, Norepinephrine pharmacology, Phentolamine pharmacology, Catecholamines blood, Clonidine administration & dosage, Clonidine therapeutic use, Face blood supply
- Abstract
Administration of the anti-hypertensive agent clonidine as a single (0.5 mg) oral dose or as multiple doses (0.2-0.4 mg/day for 4 days) markedly reduced plasma catecholamines (decrement = 81 +/- 3% and 68 +/- 5%, respectively; X +/- SE, % of basal; both P less than 0.001) in normal male volunteers. Five patients with various metabolic disorders showed similar responses. The absolute decrements in plasma catecholamines correlated significantly with basal catecholamine levels (P less than 0.001). Clonidine-induced decrements in mean arterial blood pressure correlated significantly with decrements in plasma catecholamines (P less than 0.001). The clonidine effect upon catecholamine levels was reversed by phentolamine (clonidine = -68 +/- 5%; clonidine with phentolamine = -1 +/- 16%). The decrements in catecholamines induced by clonidine in normal subjects were associated with increased sensitivity to the pressor effect of infusion of exogenous norepinephrine. In an analogous fashion flushing associated with endogenous adrenergic discharge was blocked by clonidine, whereas that due to exogenous catecholamines was intensified. These data are compatible with data in experimental animals suggesting that clonidine acts at least in part by interaction with a central alpha adrenergic receptor.
- Published
- 1978
- Full Text
- View/download PDF
38. Mechanism of plasma catecholamine increases during surgical stress in man.
- Author
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Halter JB, Pflug AE, and Porte D Jr
- Subjects
- Adult, Aged, Anesthesia, General, Blood Pressure drug effects, Epinephrine blood, Female, Halothane pharmacology, Humans, Male, Middle Aged, Norepinephrine blood, Stress, Physiological etiology, Catecholamines blood, Stress, Physiological blood, Surgical Procedures, Operative adverse effects
- Published
- 1977
- Full Text
- View/download PDF
39. Age differences in the plasma clearance mechanisms for epinephrine and norepinephrine in humans.
- Author
-
Morrow LA, Linares OA, Hill TJ, Sanfield JA, Supiano MA, Rosen SG, and Halter JB
- Subjects
- Adult, Aged, Female, Humans, Male, Metabolic Clearance Rate, Middle Aged, Aging blood, Epinephrine blood, Norepinephrine blood
- Abstract
There is an age-related increase in plasma norepinephrine (NE) in humans that is due to both an increase in NE appearance into plasma and a decrease in plasma NE clearance. However, previous studies demonstrated no difference in plasma epinephrine (EPI) in young and old subjects, and the effect of aging on plasma EPI appearance and clearance is unclear. To study age differences in basal NE and EPI metabolism we infused eight young (aged 19-26 yr) and eight old (aged 64-74 yr) normal subjects with [3H]NE or [3H]EPI (15 microCi/m2 bolus dose plus 0.35 microCi/m2/min for 50 min) to achieve steady state conditions on separate days. The old subjects had higher arterialized plasma NE levels [mean, 217 +/- 13 (+/- SE) vs. 149 +/- 12 pg/mL; P less than 0.005] and plasma NE appearance. In contrast, neither plasma EPI levels (98 +/- 8 vs. 104 +/- 10 pg/mL; P = NS) nor EPI appearance rates were different in the old and young subjects. The plasma clearance rates of EPI and NE were nearly identical in the young subjects (1.63 +/- 0.14 vs. 166 +/- 0.09 L/min X m2; P = NS). Plasma NE clearance was lower in the old compared to the young subjects (1.38 +/- 0.06 vs. 1.64 +/- 0.10 L/min X m2; P less than 0.05) and was lower than EPI plasma clearance in the same subjects. Although NE and EPI can be removed by both neuronal and nonneuronal uptake mechanisms, and mean plasma clearance values for NE and EPI are the same in the young, the age-related decline in catecholamine clearance is specific for NE. This finding implies a differential effect of age on a catecholamine removal mechanism that is specific for NE.
- Published
- 1987
- Full Text
- View/download PDF
40. Morphine: dual effects on plasma catecholamines.
- Author
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Taborsky GJ Jr, Halter JB, and Porte D Jr
- Subjects
- Animals, Dogs, Laparotomy, Pentobarbital pharmacology, Epinephrine blood, Morphine pharmacology, Norepinephrine blood
- Abstract
The present studies demonstrate that morphine can increase, decrease, or not affect plasma catecholamines depending on the dose and on the experimental conditions under which it is given. In the conscious dog, morphine (30 mg s.c.) produces a marked elevation of plasma epinephrine but not norepinephrine. In contrast, morphine (15 mg i.v.) prevents the rise of both plasma epinephrine and norepinephrine in the anesthetized, laparotomized dog. Since neither dose of morphine changes plasma catecholamines significantly in the non-laparotomized, anesthetized dog, we suggest (a) that the catechol-lowering effect is due to the analgesic properties of morphine, and (b) that the catechol-raising effect is due to activation of separate central nervous system pathways which are suppressed by barbiturate anesthesia.
- Published
- 1981
- Full Text
- View/download PDF
41. Comparison of double- and single-isotope enzymatic derivative methods for measuring catecholamines in human plasma.
- Author
-
Evans MI, Halter JB, and Porte D Jr
- Subjects
- Adult, Carbon Radioisotopes, Dopamine blood, Epinephrine blood, Evaluation Studies as Topic, Humans, Methods, Middle Aged, Norepinephrine blood, Tritium, Catecholamines blood
- Abstract
We directly compared the reliability of a single-isotope enzymatic derivative technique for measurement of plasma catecholamines with that of the well-established double-isotope method. A significant (p less than 0.001) correlation was observed between measurements (n = 52) in the two assays, both for norepinephrine (r = 0.97) and epinephrine (r = 0.80). Means and coefficients of variation for the two analytes in a pooled specimen of plasma, measured repeatedly during six months, were virtually identical by each assay method. Basal plasma catecholamine concentrations in two different groups of apparently healthy subjects were also similar by each method. Dopamine concentrations in plasma were consistently below the limits measurable by either technique. The single-isotope assay requires half the assay time and 1/200th the sample as the double-isotope method. We conclude that this assay is just as reliable as the double-isotope technique and gives virtually identical values for norepinephrine and epinephrine concentrations in the physiological range.
- Published
- 1978
42. Sodium salicylate augments the plasma adrenocorticotropin and cortisol responses to insulin hypoglycemia in man.
- Author
-
Halter JB and Metz SA
- Subjects
- Adult, Humans, Kinetics, Male, Prostaglandin Antagonists, Adrenocorticotropic Hormone blood, Blood Glucose metabolism, Hydrocortisone blood, Insulin, Sodium Salicylate
- Abstract
To test the hypothesis that prostaglandins attenuate neuroendocrine responses to changes in circulating glucose levels in man, we studied the effects of sodium salicylate (SS), a prostaglandin synthesis inhibitor, on the plasma ACTH and cortisol responses to insulin hypoglycemia. Six normal men were given insulin (0.05 U/kg, iv) on 2 different days during the infusion of either SS (40 mg/min) or saline. Compared to the saline control, SS had no significant effect on either the rate of fall of plasma glucose after insulin or the glucose nadir (mean +/- SEM, 33 +/- 3 vs. 36 +/- 3 mg/dl; P = NS). Peak ACTH levels after insulin were higher during SS compared to those during saline in all six subjects (316 +/- 95 vs. 102 +/- 26 pg/ml; P less than 0.05), and SS had a clear effect to increase both the overall ACTH response (F = 21.3; P less than 0.01, by analysis of variance) and the plasma cortisol response (F = 6.72; P less than 0.05, by analysis of variance). The most striking example of this effect of SS occurred in one subject whose peak plasma ACTH was only 44 pg/ml during saline but reached 750 pg/ml during SS despite an identical fall of plasma glucose to 42 mg/dl. Augmentation of the ACTH and cortisol responses to insulin hypoglycemia may be the result of an alteration by SS of recognition of glucose levels by glucose-sensitive cells of the brain, and effect which could be due to the inhibition of prostaglandin synthesis.
- Published
- 1982
- Full Text
- View/download PDF
43. Increased plasma and cerebrospinal fluid norepinephrine in older men: differential suppression by clonidine.
- Author
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Raskind MA, Peskind ER, Veith RC, Beard JC, Gumbrecht G, and Halter JB
- Subjects
- Adult, Humans, Male, Middle Aged, Norepinephrine blood, Norepinephrine cerebrospinal fluid, Reference Values, Aging, Clonidine pharmacology, Norepinephrine metabolism
- Abstract
To evaluate the effect of advanced age on central nervous system noradrenergic activity, cerebrospinal fluid (CSF) and plasma norepinephrine (NE) concentrations were measured concurrently in 14 older [mean, 65 +/- 9 (+/- SD) yr] and 33 younger (25 +/- 2 yr) normal men. CSF NE was significantly higher in older men than in young men [214 +/- 75 (+/- SD) vs. 164 +/- 56 pg/mL (1.26 +/- 0.44 vs. 0.97 +/- 0.33 nmol/L); P less than 0.02] as was plasma NE [282 +/- 103 vs. 211 +/- 63 pg/mL (1.67 +/- 0.61 vs. 1.25 +/- 0.37 nmol/L); P less than 0.02]. Subgroups of young and older men underwent two lumbar punctures, one of which was performed 100 min after the administration of 5 micrograms/kg oral clonidine. The young (n = 7) and older (n = 7) men had similar plasma clonidine levels [1.0 +/- 0.1 vs. 0.8 +/- 0.1 ng/mL (4.35 +/- 0.43 vs. 3.48 +/- 0.78 nmol/L)] and CSF clonidine levels [0.18 +/- 0.02 vs. 0.22 +/- 0.03 ng/mL (0.78 +/- 0.09 vs. 0.96 +/- 0.13 nmol/L)]. The suppression of CSF NE by clonidine was significantly greater (P less than 0.015) in young men [189 +/- 44 to 104 +/- 26 pg/mL (1.12 +/- 0.26 to 0.62 +/- 0.15 nmol/L)] than in older men [190 +/- 49 to 164 +/- 58 pg/mL (1.12 +/- 0.29 to 0.97 +/- 0.34 nmol/L)]. In contrast, the suppression of plasma NE by clonidine did not significantly differ between young [242 +/- 72 to 93 +/- 24 pg/mL (1.43 +/- 0.43 to 0.55 +/- 0.14)] and older men [285 +/- 102 to 167 +/- 84 pg/mL (1.68 +/- 0.60 to 0.99 +/- 0.50 nmol/L)]. These data suggest that decreased sensitivity of alpha 2-adrenergic mechanisms regulating CNS noradrenergic activity may contribute to increased CNS noradrenergic activity with aging.
- Published
- 1988
- Full Text
- View/download PDF
44. Glucose infusion potentiates the acute insulin response to nonglucose stimuli during the infusion of somatostatin.
- Author
-
Taborsky GJ Jr, Smith PH, Halter JB, and Porte D Jr
- Subjects
- Animals, Arginine pharmacology, Blood Glucose metabolism, Dogs, Drug Synergism, Isoproterenol pharmacology, Glucose pharmacology, Insulin blood, Somatostatin pharmacology
- Abstract
These studies assessed the ability of glucose infusions to potentiate the acute insulin response (AIR) to iv isoproterenol (12 micrograms), arginine (750 mg), or glucose (5 g) that was previously inhibited by an infusion of somatostatin (SRIF). SRIF (1.7 micrograms/min) markedly inhibited the AIR to isoproterenol (AIR before SRIF, 28 +/- 1 microU/ml; AIR during SRIF, 8 +/- microU/ml; P less than 0.025), arginine (AIR before SRIF, 6 +/- 2 microU/ml; AIR during SRIF, 1 +/- 1 microU/ml; P less than 0.01), and glucose (AIR before SRIF, 19 +/- 7 microU/ml; AIR during SRIF, 1 +/- microU/ml; P less than 0.05). The administration of a glucose infusion of 105 mg/min partially restored the AIR to isoproterenol and arginine. Glucose infused at 440 mg/min fully restored the AIR to both isoproterenol (AIR during SRIF plus glucose, 31 +/- 4 microU/ml) and arginine (AIR during SRIF plus glucose, 9 +/- 2 microU/ml). In contrast, the AIR to glucose was not affected by infusion of glucose (AIR during SRIF plus glucose, 0 +/- 1 microU/ml). In the absence of SRIF, glucose infusion potentiates the AIR to isoproterenol and arginine but not to glucose. Therefore, during SRIF infusion, glucose retains the ability to potentiate the AIR to nonglucose stimuli despite the loss of the ability to stimulate insulin release directly. These data suggest that the potentiating effects of glucose and the inhibiting effects of SRIF may be mediated by a common mechanism affecting insulin release.
- Published
- 1979
- Full Text
- View/download PDF
45. Relationship of islet function to insulin action in human obesity.
- Author
-
Beard JC, Ward WK, Halter JB, Wallum BJ, and Porte D Jr
- Subjects
- Adult, Arginine pharmacology, Blood Glucose metabolism, Female, Humans, Insulin blood, Insulin Resistance, Isoproterenol pharmacology, Male, Middle Aged, Insulin physiology, Islets of Langerhans physiopathology, Obesity physiopathology
- Abstract
To analyze B-cell mechanisms in obesity, we measured the relationship (slope of potentiation) between glucose levels and acute insulin responses (AIR) to isoproterenol or arginine in nondiabetic subjects ranging from lean to markedly obese. Obese men (n = 9) had higher AIRs to isoproterenol than lean men (n = 11) at basal glucose levels [52 +/- 9 (SEM) vs. 32 +/- 5 microU/mL; P less than 0.05], and the difference increased as the ambient glucose level was raised (at 230 mg/dL; 263 +/- 22 vs. 140 +/- 21 microU/mL; P less than 0.0008). The individuals' slopes of glucose potentiation of AIR to isoproterenol were positively correlated with their excess weight (r = 0.72; P less than 0.001). Similar results were found when arginine was used as the secretagogue in other men and in women; the slope of potentiation was positively correlated with excess weight in both men and women (both P less than 0.005), although the effect of excess weight on slope was 51% greater among men (P less than 0.03). An independent measurement of insulin sensitivity (the Bergman SI) was made in the women. The potentiation slope was inversely correlated with SI (P less than 0.0001), indicating that the effect of obesity on insulin secretion is correlated with insulin resistance. These results characterize one mechanism contributing to the hyperinsulinemia of obesity and highlight the importance of considering the prevailing insulin sensitivity when assessing islet function.
- Published
- 1987
- Full Text
- View/download PDF
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