The Valsalva manoeuvre (VM), a forced expiratory effort against a closed airway, has a wide range of applications in several medical disciplines, including diagnosing heart problems or autonomic ...nervous system deficiencies. The changes of the intrathoracic and intra‐abdominal pressure associated with the manoeuvre result in a complex cardiovascular response with a concomitant action of several regulatory mechanisms. As the main aim of the reflex mechanisms is to control the arterial blood pressure (BP), their action is based primarily on signals from baroreceptors, although they also reflect the activity of pulmonary stretch receptors and, to a lower degree, chemoreceptors, with different mechanisms acting either in synergism or in antagonism depending on the phase of the manoeuvre. A variety of abnormal responses to the VM can be seen in patients with different conditions. Based on the arterial BP and heart rate changes during and after the manoeuvre several dysfunctions can be hence diagnosed or confirmed. The nature of the cardiovascular response to the manoeuvre depends, however, not only on the shape of the cardiovascular system and the autonomic function of the given patient, but also on a number of technical factors related to the execution of the manoeuvre including the duration and level of strain, the body position or breathing pattern. This review of the literature provides a comprehensive analysis of the physiology and pathophysiology of the VM and an overview of its applications. A number of clinical examples of normal and abnormal haemodynamic response to the manoeuvre have been also provided.
1 Department of Physiology and Pharmacology, University of Georgia College of Veterinary Medicine, Athens, Georgia; 2 Institute of Biomedical Engineering of the Italian National Research Council, ...Padua, Italy; and 3 Nestle Purina Research, St. Louis, Missouri
Submitted 10 May 2006
; accepted in final form 8 August 2006
Obesity is a major health problem in cats and a risk factor for diabetes. It has been postulated that cats are always gluconeogenic and that the rise in obesity might be related to high dietary carbohydrates. We examined the effect of a high-carbohydrate/low-protein (HC) and a high-protein/low-carbohydrate (HP) diet on glucose and fat metabolism during euglycemic hyperinsulinemic clamp, adipocytokines, and fat distribution in 12 lean and 16 obese cats before and after weight loss. Feeding diet HP led to greater heat production in lean but not in obese cats. Regardless of diet, obese cats had markedly decreased glucose effectiveness and insulin resistance, but greater suppression of nonesterified fatty acids during the euglycemic hyperinsulinemic clamp was seen in obese cats on diet HC compared with lean cats on either diet or obese cats on diet HP. In contrast to humans, obese cats had abdominal fat equally distributed subcutaneously and intra-abdominally. Weight loss normalized insulin sensitivity; however, increased nonesterified fatty acid suppression was maintained and fat loss was less in cats on diet HC. Adiponectin was negatively and leptin positively correlated with fat mass. Lean cats and cats during weight loss, but not obese cats, adapted to the varying dietary carbohydrate/protein content with changes in substrate oxidation. We conclude that diet HP is beneficial through maintenance of normal insulin sensitivity of fat metabolism in obese cats, facilitating the loss of fat during weight loss, and increasing heat production in lean cats. These data also show that insulin sensitivity of glucose and fat metabolism can be differentially regulated in cats.
euglycemic hyperinsulinemic clamp; indirect calorimetry; obesity; diabetes; leptin; adiponectin; magnetic resonance imaging
Address for reprint requests and other correspondence: M. Hoenig, Dept. of Physiology and Pharmacology, Univ. of Georgia, Athens, GA 30602 (e-mail: mhoenig{at}vet.uga.edu )
Related articles in AJP - Regu:
Corrigendum
AJP - Regu 2009 296: R1291.
Full Text
Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular ...autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects.
Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively.
After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences.
Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out.
NCT01182948, clinicaltrials.gov.
•Both aerobic and resistance exercise have a favorable impact on cardiovascular autonomic control in type 2 diabetes.•Baroreceptor function indexes suggest possible greater benefits with aerobic than resistance training in these subjects.•Exercise training may have specific interest in diabetes care, as there is no therapy for diabetic autonomic dysfunction.
Glucagon-like peptide-1 (GLP-1) is known to be a potent stimulator of insulin secretion. However, whether GLP-1 also affects insulin clearance is not known. To explore this, we developed a technique ...to determine prehepatic insulin secretion in mice, based on deconvolution of plasma C-peptide concentrations. The estimated beta cell secretion was then related to plasma insulin levels to allow determination of clearance rate of endogenously produced insulin.
Kinetic parameters of C-peptide were estimated after i.v. injection of human C-peptide (0.8 or 3 nmol/kg) or glucose (1 g/kg), either alone or together with GLP-1 (10 nmol/kg), in anaesthetised NMRI mice.
C-peptide was distributed in two compartments (distribution volume 11.4+/-0.4 ml, 42+/-2% of which was in the accessible compartment). Fractional C-peptide clearance was 8.2+/-0.6% of the total distribution volume per minute. GLP-1 markedly enhanced prehepatic insulin secretion; more than 80% of prehepatic secretion occurred during the first minute after injection. Fractional clearance of endogenously released insulin after glucose was 0.66+/-0.11 min(-1) and this was reduced to 0.36+/-0.10 min(-1) by GLP-1 (p=0.04).
It is possible to perform C-peptide deconvolution for estimating prehepatic insulin secretion in mice. GLP-1 reduces the clearance of endogenously released insulin; therefore, it may affect insulin levels by increasing prehepatic insulin secretion and by reducing insulin clearance.
BACKGROUND: Pioglitazone is a thiazolidinedione (TZD) insulin sensitizer approved for use in human type 2 diabetes mellitus. Therapeutic options for diabetes in cats are limited. OBJECTIVE: To ...evaluate the effects of pioglitazone in obese cats, which are predisposed to insulin resistance, to assess its potential for future use in feline diabetes mellitus. ANIMALS: A total of 12 obese purpose‐bred research cats (6 neutered males and 6 spayed females, 5–7 years of age, weighing 5.4–9.8 kg). METHODS: Randomized, placebo‐controlled 3‐way crossover study. Oral placebo or pioglitazone (Actos™; 1 or 3 mg/kg) was administered daily for 7‐week periods, with IV glucose tolerance testing before and after each period. RESULTS: Three mg/kg pioglitazone significantly improved insulin sensitivity (geometric mean 95% CI 0.90 0.64–1.28 to 2.03 1.49–2.78 min⁻¹pmol⁻¹L; P = .0014 versus change with placebo), reduced insulin area under the curve during IVGTT (geometric mean range 27 9–64 to 18 6–54 min∙nmol/L; P = .0031 versus change with placebo), and lowered serum triglyceride (geometric mean range 71 29–271 to 48 27–75 mg/dL; P = .047 versus change with placebo) and cholesterol (geometric mean range 187 133–294 to 162 107–249 mg/dL; P = .0042 versus change with placebo) concentrations in the obese cats. No adverse effects attributable to pioglitazone were evident in the otherwise healthy obese cats at this dosage and duration. CONCLUSIONS AND CLINICAL IMPORTANCE: Results of this study support a positive effect of pioglitazone on insulin sensitivity and lipid metabolism in obese cats, and suggest that further evaluation of the drug in cats with diabetes mellitus or other metabolic disorders might be warranted.
Aims The purpose of the study was to determine long‐term cardiovascular autonomic adaptation to moderate endurance aerobic exercise in people with Type 2 diabetes in order to test the hypothesis of ...an enhanced vagal drive.
Methods We analysed the power spectral density of heart rate cyclic variations at rest, while lying, and while standing in 12 sedentary, non‐smoking, Type 2 diabetic individuals. Testing was performed before and after a 6‐month, supervised, progressive, aerobic training programme, twice weekly. Heart rate variability was assessed by autoregressive power spectral analysis (PSA); this method allows reliable quantification of low‐frequency (LF) and high‐frequency (HF) components, which are considered to be under mainly sympathetic and purely parasympathetic control, respectively.
Results In 10‐min electrocardiogram recordings, mean RR intervals values lying and standing were similar before and after physical exercise. Likewise, total heart rate variability, expressed as total power spectral density (PSD), was not altered by exercise. In contrast, on standing, the HF component, expressed in normalized units, was significantly higher (20.1 ± 4 vs. 30.4 ± 5, P < 0.01), whereas the LF component was significantly lower (68.1 ± 7 vs. 49.8 ± 8, P < 0.01) after exercise; hence, on standing, the LF/HF ratio, reflecting the sympathetic vs. parasympathetic balance, was markedly lower (16.2 ± 11 vs. 5.2 ± 3.2, P = 0.003). No significant exercise‐related changes in these PSA components were observed on lying.
Conclusions A twice‐weekly, 6‐month, moderate, aerobic exercise programme, without a concomitant weight loss diet, is associated with significant improvements in cardiovascular autonomic function in overweight, non‐smoking, Type 2 diabetic individuals.
Clark, M., Thomaseth, K., Heit, M., Hoenig, M. Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs. J. vet. Pharmacol. Therap. 35, 342–350. Protamine ...zinc insulins are generally considered to be long acting, with slow absorption from subcutaneous tissue. Protamine zinc recombinant human insulin (PZIR) may be useful to treat diabetic dogs. The purpose of this study was to describe the pharmacokinetics and pharmacodynamics of PZIR in dogs. PZIR was administered subcutaneously to 10 healthy Beagles using an incomplete crossover design, at doses of 0.3 or 0.5 U/kg (each n = 5), 0.8 U/kg (n = 10), or 0.8 U/kg at three separate sites (n = 6). Insulin and glucose concentrations were measured over 24 h. The shapes of insulin and glucose curves were variable among dogs, and the relationship between insulin dose, concentration, and glucose‐lowering effect was nonlinear. For single‐site 0.8 U/kg, median (range) onset of action was 3.5 h (0.5–10 h), time to glucose nadir was 14 h (5 to >24 h), and duration of action was >24 h (16 to >24 h). Mathematical model predictions of times to 50% and 90% insulin absorption, and fraction of insulin absorbed in 24 h, were not significantly different among protocols. Results confirm the tendency toward a late onset and long duration of action for PZIR in dogs. This insulin may be an alternative treatment option for diabetic dogs.
Insulin sensitivity (
S
I) of glucose disposal can be quantified with the euglycemic hyperinsulinemic clamp (EHC) with tracer glucose infusion. True steady state is, however, difficult to achieve, ...and non-steady state analysis of EHC data is preferred. This analysis requires information on glucose kinetics that can be obtained from bolus injection of cold and tracer glucose. The aim of this study was to assess glucose kinetics in cats. Mathematical modeling and non-steady state analysis was applied to assess effects of obesity on glucose turnover, glycolysis/glycogen synthesis,
S
I, and inhibition of endogenous glucose production (EGP) in lean cats (L) and obese cats (O).
d-3-
3H-glucose kinetics and
3H-H
2O production were analyzed in 4
L and 4
O with three-compartment modeling. Frequently sampled insulin-modified intravenous glucose tolerance tests (FSIGT) with minimal model analysis were performed in 5
L and 3
O to assess glucose kinetics and
S
I. EHC was performed in 10
L and 10
O with primed-constant infusion of
3H-glucose. Data were analyzed with a modified minimal model segregating suppression of EGP by insulin using a non-linear mixed-effects population approach. FSIGT provided estimates of
S
I, glucose effectiveness
S
G, and distribution volume. EHC provided estimates of
S
I,
S
G, glycolysis, and suprabasal insulin concentration for 50% EGP inhibition. Obesity appears to affect glucose distribution but not utilization at basal insulin, and reduces
S
I estimated by FSIGT and EHC. Differences in
S
I between FSIGT and EHC depend on different descriptions of EGP inhibition by insulin. Finally, glucose disposal at basal insulin appears to occur entirely through glycolysis, whereas significant amounts of glucose are sequestrated from oxidation during EHC.
Simultaneous application of the euglycemic hyperinsulinemic clamp (EHC) and indirect calorimetry was used to examine heat production, fat, and glucose metabolism in lean and obese adult neutered male ...and female cats. The results show that in lean insulin-sensitive cats glucose oxidation predominated during fasting, whereas lipid oxidation became more prominent in obese cats. Insulin infusion during the EHC in lean cats and obese male cats led to a large increase in glucose oxidation, glycogenesis, and lipogenesis. It also led to an increase in glucose oxidation and glycogenesis in obese female cats but it was significantly less compared to lean cats and obese males. This indicates that obese females show greater metabolic inflexibility. In obese cats of either gender, insulin caused greater suppression of non-esterified fatty acids compared to lean cats suggesting that obese cats show greater fatty acid clearance than lean cats. The heat production per metabolic size was lower in obese cats than lean cats. This would perpetuate obesity unless food intake is decreased. The higher glucose oxidation rate in obese neutered male cats suggests that they are able to replete their glycogen and lipid stores at a faster rate than females in response to insulin and it implies that they gain weight more rapidly. Further studies are needed to investigate if the different response to insulin of male cats is involved in their higher risk to develop diabetes.
Pronounced insulin resistance and inadequate beta-cell secretion characterize lean gestational diabetes during and after pregnancy.
A Kautzky-Willer ,
R Prager ,
W Waldhausl ,
G Pacini ,
K Thomaseth ...,
O F Wagner ,
M Ulm ,
C Streli and
B Ludvik
Department of Medicine III, University of Vienna, Austria.
Abstract
OBJECTIVE: To evaluate beta-cell secretion and glucose metabolism in lean subjects with gestational diabetes mellitus (GDM)
compared with that in subjects with normal pregnancy and obesity. RESEARCH DESIGN AND METHODS: Insulin secretion, insulin
sensitivity (S1), and hepatic insulin extraction were assessed in pregnant women with GDM before and after delivery and in
those with normal glucose tolerance (NGT) in comparison to healthy nonpregnant lean and obese women. Kinetic analysis of glucose,
insulin, and C-peptide plasma concentrations during oral and intravenous glucose tolerance tests was performed by mathematical
modeling. RESULTS: S1 was blunted in pregnant women with GDM by 84% and in those with NGT by 66% compared with lean nonpregnant
women (P < 0.005 vs. healthy nonpregnant lean control subjects; P < 0.05, GDM vs. pregnant women with NGT), whereas glucose
effectiveness was decreased by 33% in both pregnant groups (P < 0.05 vs. healthy nonpregnant lean control subjects). Insulin
secretion was 30% higher (P < 0.05) in subjects with GDM than in pregnant women with NGT or in nonpregnant lean women, but
decreased (P < 0.005) when compared with obese women with a comparable degree of insulin resistance. Fractional hepatic insulin
extraction was similar in both pregnant groups, being lower (P < 0.0001) by 30% versus nonpregnant females. beta-cell sensitivity
to glucose for insulin release was decreased in subjects with GDM versus pregnant women with NGT as well as nonpregnant women
by 40-50% (P < 0.01). Twelve weeks after delivery, GDM returned to normal glucose tolerance, but S1 remained 50% lower than
that in lean nonpregnant women, while beta-cell sensitivity to glucose did not change (P < 0.01 vs. healthy nonpregnant lean
control subjects). CONCLUSIONS: Pregnancy is characterized by insulin resistance, diminished hepatic insulin extraction, and
glucose effectiveness. Lean subjects with GDM are additionally characterized by having more pronounced insulin resistance
and inadequate insulin secretion, which persist after delivery. Compared with other insulin-resistant prediabetic states like
impaired glucose tolerance (IGT), defective insulin secretion seems to be a predominant defect in lean GDM subjects, indicating
that it might represent a specific prediabetic condition.
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