Impaired responses of catecholamines, growth hormone, and cortisol to graded exercise in diabetic autonomic neuropathy.
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Biomedical subjects
Publications and source records attributed to J Hilsted.
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In order to elucidate the physiological significance of autonomic neuropathy in juvenile diabetics, cardiovascular, hormonal and metabolic functions have been investigated in three groups of juvenile diabetics: One group had no signs of neuropathy, one group had presumably slight autonomic neuropathy (reduced beat-to-beat variation in heart rate during hyperventilation) and one group had clinically severe autonomic neuropathy, defined by presence of orthostatic hypotension. In all three experimental situations we found sympathetic dysfunction causing cardiovascular and/or hormonal maladjustments in patients with autonomic neuropathy. Regarding metabolic functions we found normal responses to graded exercise and insulin-induced hypoglycemia in patients with autonomic neuropathy in spite of blunted catecholamine responses, suggesting increased sensitivity of glycogen stores and adipose tissue towards the action of catecholamine in patients with autonomic neuropathy.
The pancreatic polypeptide (PP) response to insulin-induced hypoglycaemia was studied in 18 juvenile diabetics and was calculated as the difference between the prestimulatory PP concentration and the maximal concentration measured. The response was severely impaired in patients with autonomic neuropathy (mean +/- SE of mean 22 +/- 12 pmol/l) as compared with patients without neuropathy (252 +/- 51 pmol/l). Patients whose diabetes was of only a few years' duration showed a normal PP response to hypoglycaemia, and the response diminished significantly with increasing duration of diabetes. The decreased PP response to hypoglycaemia was significantly correlated with an increased threshold of the sense of vibration, (rs = 0.86). These results suggest that impaired, secretion of PP may serve as an early sign of autonomic neuropathy in diabetes.
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The reproducibility of a simple method for determining the beat-to-beat variation during maximal respiration (duration of inspiration = duration of expiration = 5 sec), using an ordinary ECG apparatus and a ruler, was tested in 10 normals and 40 insulin-treated diabetics. The results were reproducible and beat-to-beat variation was found to be independent of a 25-minute period of rest. The method was subsequently applied to 126 insulin-treated diabetics and the results are in accordance with previous investigations on cardiac vagal neuropathy. The method is applicable as a clinical routine test for cardiac vagal neuropathy.
6 young men had venous blood drawn during 4 experiments. The concentration of VIP in plasma increased markedly (from 1.8 (0--4.5) to 22.3 (7.8--43.8) pmol.1(-1), mean and range) during 3 h of mild bicycle exercise but not at all during an equivalent period of rest or during short term submaximal and maximal exercise. During 59 h of fasting, VIP increased from 3.6 (0.6--6.6) to 10.2 (6.6--13.8) pmol.1(-1) (p less than 0.05). The concentration of glucose in plasma decreased significantly during the prolonged exercise as well as during fasting. The known metabolic actions of VIP and the demonstrated increases in its plasma concentration during negative energy balance indicate that VIP is "a polypeptide of substrate need".
In normals, subcutaneous blood flow in the ankle region, measured by means of the 133Xe washout technique, decreases about 45% when the position of the ankle is changed from cardiac level to 50 cm below the heart. A sympathetic vascular axon reflex is responsible for this flow reduction. A normal response [mean blood-flow reduction, 49% (range, 40 to 64%)] was found in seven diabetics without neuropathy. In nine diabetics with autonomic neuropathy (beat-to-beat variation in heart rate less than or equal to 15 min-1 during hyperventilation), the reduction in blood flow on lowering of the ankle was also normal. A significant deterioration of the response was found in six diabetics with autonomic neuropathy, including orthostatic hypotension, in whom blood flow increased 23% (range, -35 to +77%). Autoregulation of blood flow, i.e., constancy of blood flow in the ankle region on lowering and elevating of the ankle 20 cm below and above cardiac level was intact in the patients with orthostatic hypotension, indicating a normal vascular smooth muscle function. In conclusion, in diabetic patients with orthostatic hypotension, the subcutaneous axon reflex is absent. This may be one of several factors responsible for their orthostatic hypotension.
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Seven men ran at 60% of individual maximal oxygen uptake to exhaustion during beta-adrenergic blockade with propranolol (P), during lipolytic blockade with nicotinic acid (N), or without drugs (C). The total work times (83 +/- 9 (P), 122 +/- 8 (N), 166 +/- 10 (C) min, mean and SE) differed significantly. Epinephrine rose progressively above preexercise levels (0.06 +/- 0.01 ng/ml); at exhaustion concentrations in P experiments (2.15 +/- 0.41) were larger than in N (1.08 +/- 0.31) and C (0.72 +/- 0.28) experiments. Norepinephrine increased consistently while insulin decreased. After an initial decrease glucagon concentrations increased progressively in parallel with declining plasma glucose and were at exhaustion always three times preexercise values. Thus beta-adrenergic blockade did not diminish the glucagon response. Nor was this response increased when alpha-receptor stimulation in P experiments was intensified. Carbohydrate combustion was smaller and NEFA and glycerol concentrations in serum larger during C experiments. Alanine concentrations were never raised at exhaustion. Accordingly, neither stimulation of adrenergic receptors nor NEFA and alanine concentrations are major determinants for the exercise-induced glucagon secretion in man. It is suggested that decreased glucose availability enhances the secretion of glucagon and epinephrine during prolonged exercise.
Polymorphonuclear leucocyte (PMN) ingestion of particles coated with lipopolysaccharide (LPS) from Escherichia coli was compared to other PMN functions in seven patients with insulin dependent diabetes mellitus (IDDM) during short-term controlled metabolic changes from normo- to hyperglycemia without ketoacidosis. Factors known to interfere with PMN functions were excluded. PMN ingestion of particles coated with both LPS and bovine serum albumin became reduced from normo- to hyperglycemia. PMN motility was impaired in IDDM, but did not seem to be affected by short-term changes in metabolic control. PMN metabolism did not change from normo-to hyperglycemia. Particle-uptake by diabetic PMN is impaired after short term hyperglycemia in the range normally occurring in diabetics in every-day life.
BACKGROUND: Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years. METHODS: Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat. FINDINGS: 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4.64, p<0.001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9). INTERPRETATION: This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.
Hypoglycemia was induced by intravenous infusion of insulin in six juvenile-onset diabetic subjects. Hemostatic parameters were assessed before insulin infusion and 0, 1, and 2 h after discontinuation of insulin infusion. The onset of hypoglycemia coincided with an enhancement of ADP-induced platelet aggregation in five of the patients; platelet aggregation returned to normal levels during the next 2 h. The recalcification time was significantly shortened at the onset of hypoglycemia and continued to decrease for the next 2 h despite the return of serum glucose to normal levels. Correspondingly, a significant increase in fibrinogen was found. The ethanol gelation test was positive in two patients 2 h after stopping insulin infusion. Platelet counts decreased significantly after stopping insulin infusion. Thus, insulin-induced hypoglycemia markedly affects hemostatic balance and may potentially lead to intravascular coagulation in juvenile-onset diabetic patients.