Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy. METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made. RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); P < 0.0001]. Cardiac vagal tone was positively associated with time (r = 0.8, P < 0.0001) and frequency domain markers of heart rate variability (r = 0.75, P < 0.0001), representing established measures of parasympathetic function. Cardiac vagal tone was negatively associated with age (r=-0.32, P = 0.003), disease duration (r=-0.43, P < 0.0001) and cardiovascular risk score (r=-0.32, P = 0.006). CONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method of assessing parasympathetic nervous system tone, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing.

Diagnosis of growth hormone (GH) deficiency in adults with hypothalamic-pituitary disorders: comparison of test results using pyridostigmine plus GH-releasing hormone (GHRH), clonidine plus GHRH, and insulin-induced hypoglycemia as GH secretagogues.

The insulin tolerance test (ITT) is widely accepted as the method of choice to evaluate GH secretion capacity in adults with hypothalamic-pituitary disorders. However, the test is not suitable in the elderly or in patients with cardiovascular disease or seizure disorders. In recent years alternatives to the ITT have been introduced. The purpose of the present study was to investigate the diagnostic outcome with the ITT, the pyridostigmine plus GHRH (PD + GHRH) test, the clonidine plus GHRH (CLO+GHRH) test, and insulin-like growth factor I (IGF-I) in an unselected group of patients with hypothalamic-pituitary disease. An evaluation of the reproducibility of the different stimulation tests was included in the study. Based on repeated testing with the various GH stimulation tests in healthy adult males and females, the lower limits of normality for the ITT, the PD+GHRH test, and the CLO+GHRH test were 3.92, 12.8, and 19.0, microg/L, respectively. A consecutive group of 26 unselected patients with hypothalamic-pituitary disorders, 13 males and 13 females (median age, 44 ys), were tested twice with all stimulation tests, except that only 10 patients were tested once with the CLO+GHRH test due to side-effects related to clonidine. The peak GH responses between test 1 and test 2 correlated significantly in both the ITT and the PD + GHRH test (P < 0.02), and no significant difference was observed in the median peak response to repeated testing. In addition, no sex difference was observed. The coefficients of variation (CV) were 96% (ITT) and 45% (PD + GHRH), but in the majority of patients low values were repeatedly low. The peak GH response was significantly higher during the PD+GHRH test than during the ITT (P = 0.008). In the 10 patients tested with the PD+GHRH and CLO+GHRH tests there was no significant difference in the peak GH response (P = 0.398). When the test specific cut-off values were used, no significant difference in diagnostic outcome was observed between the various tests (P > 0.3). In contrast, the diagnosis obtained with IGF-I differed significantly from all GH stimulation tests (P < 0.03). Twenty (77%) and 22 (85%) patients were diagnosed to be GH deficient with the ITT and the PD+GHRH test, respectively. Of the 14 patients with multiple pituitary failure (>2 hormones affected), GH deficiency was present in more than 90% regardless of the type of stimulation test used. The IGF-I levels were only subnormal in 42% of the patients and did not correlate with the peak GH responses in any of the stimulation tests (P > 0.05). Except for 1 patient all patients with subnormal IGF-I were GH deficient in all stimulation tests. It is concluded that in patients with hypothalamic-pituitary disease and a normal IGF-I level 2 stimulation tests should be performed to establish a diagnosis of GH deficiency. In patients with a subnormal IGF-I value a single GH stimulation test should be sufficient to confirm the presence of GH deficiency.

Differences in reproducibility and peak growth hormone responses to repeated testing with various stimulators in healthy adults.

In healthy adults, GH responses to provocative testing are variable between subjects. Information on the intra-subject variability is limited, despite the importance attached to GH stimulation tests in the diagnosis of GH deficiency. We have investigated and compared the variability of different GH stimulation tests in a group of healthy control subjects. In 16 healthy non-obese adults, two insulin tolerance tests (ITT) (0.15 IU/kg body weight i.v. and a fall in blood glucose < or = 2.2 mmol/l) two GHRH tests (1 microgram/kg body weight i.v.), and two clonidine (CLO) (300 micrograms p.o.) + GHRH (60 min later) tests were performed in the morning after an overnight fast. A pyridostigmine (PD) (120 mg p.o. 60 min before GHRH) + GHRH test was performed twice in an extended group of 31 healthy adult subjects. A wide range of GH responses was observed. Both during the ITT and the GHRH test, low values in the range generally recognized to reflect impairment of GH secretory status were encountered. The median (range) peak GH responses in tests 1 and 2 were: (a) ITT: 14.4 micrograms/l (4.1-71.1) and 14.0 micrograms/l (0.09-69.5), (b) GHRH test: 21.7 micrograms/l (0.71-56.2) and 18.4 micrograms/l (1.6-55.1); (c) CLO + GHRH test: 57.4 micrograms/l (22.9-209) and 65.8 micrograms/l (12.2-206); (d) PD + GHRH test: 36.5 micrograms/l (9.1-125) and 44.6 micrograms/l (6.3-101). The coefficients of variation (CV) were: 58% (ITT), 45% (GHRH), 46% (CLO + GHRH) and 26% (PD + GHRH). The peak GH responses were significantly different in all tests (CLO + GHRH > PD + GHRH > GHRH > ITT). In the individual subject, there was no systematic correlation between the peak GH responses in the different stimulation tests. In conclusion, we found that the stimulated GH responses were highly variable in all tests, and that the peak GH responses differed. Test results in patients should be evaluated against test-specific reference values, and caution is justified in the interpretation of low responses in a single test.

Reproducibility of growth hormone and cortisol responses to the insulin tolerance test and the short ACTH test in normal adults.

Previous studies have demonstrated poor reproducibility of growth hormone (GH) responses to insulin tolerance testing (ITT). In order to investigate whether this is a particular feature of GH secretion we studied the reproducibility of the GH and cortisol responses to ITT simultaneously and also compared the latter with the reproducibility during short ACTH testing (SAT). Eight normal men (age 26-50) and 8 normal women (age 27-45) underwent 2 ITT and 2 SAT. In the ITT no systematic differences were observed between test 1 and 2 concerning blood glucose, GH and cortisol before and after stimulation. Similar results were obtained for cortisol during SAT. During ITT reproducibility was good for the cortisol response (coefficient of variation [CV] 10%, no sex differences) but poor for the GH response (CV 41% in men, 104% in women). Reproducibility was good for the cortisol response in SAT (CV 12%, no sex differences). The peak cortisol values during ITT (mean 585, range 448-775 nmol/l) were significantly lower than in the 2 SAT (mean 723, range 486-918 nmol/l). We conclude that the GH response during testing is more variable than the cortisol response. This could account for some of the difficulties encountered in the diagnosis of GH deficiency in adults.

Test of growth hormone secretion in adults: poor reproducibility of the insulin tolerance test.

The insulin tolerance test (ITT) is regarded as the most reliable provocative test in the diagnosis of growth hormone (GH) deficiency in adults. In the present study the test was evaluated by investigating the range of GH responses in normal adult males and females and the intra-individual reproducibility of the test. Sixteen healthy non-obese adults, eight males (median age 31.5 years) and eight females (median age 31.8 years) were tested twice with the ITT, with a minimum of 72 h between each test. The females were tested between day 3 and day 10 of their menstrual cycles. Adequate hypoglycemia was achieved in all cases with a median nadir blood glucose of 1.3 mmol/l (range 0.8-2.0). Growth hormone in serum was measured by immunoradiometric assay and low values were confirmed by a different assay. Median peak GH concentration responses to the ITT were: in males 27.9 micrograms/l, range 5.0-71.1 (test 1) and 30.5 micrograms/l, range 7.9-69.5 (test 2); and in females 9.0 micrograms/l, range 4.1-17.9 (test 1) and 8.4 micrograms/l, range 0.09-42.4 (test 2). The rise in GH concentration during the ITT was higher in males than in females. In the males, all stimulated GH values were > or = 5.0 micrograms/l. In the females, four out of 16 tests gave values below 5.0 micrograms/l and in one test the GH value was around the detection limit of the assays. There was poor reproducibility during repeated testing, with no correlation between the results of the two tests. The results did not correlate to the magnitude of the hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone and thyroid function: is secondary thyroid failure underdiagnosed in growth hormone deficient patients?

Thyroid hormones and the GH/IGF-1 system show considerable mutual interference which may have physiological, pathophysiological and clinical importance. GH therapy of children and adults may induce a fall in serum T4, which seems to be due to an effect on the deiodination of T4 to T3. Animal studies suggest that the alterations in thyroid hormones in tissue may be much more prominent than the changes observed in serum. It is possible that the GH deficiency seen in the majority of patients with pituitary/hypothalamic disorders may mask secondary hypothyroidism in some patients by giving a relatively high serum T4. GH therapy may then unmask the hypothyroidism. In accordance with such a mechanism GH deficient children evaluated thoroughly to exclude secondary thyroid failure before GH administration do not develop thyroid insufficiency during GH substitution therapy. It is suggested that thyroid insufficiency should be considered in GH deficient patients with low normal serum T4.

The influence of dietary iodine and enviromental temperature on the activity of mitochondria in liver and kidney.

It was found that both effect of temperatures and diets influence metabolic changes in rabbits. In animals fed basal and PTU diets (propyl-thiouracil diets) at 34 degrees C for 4 weeks the metabolic response showed a marked reduction in feed intake and body weight, compared with animals fed at normal temperatures. In the animals fed the iodine diet, there was an increase in daily food consumption and weekly body weight gain at 34 degrees C. This indicates a rise in metabolic activity in this case. Studying the activity of kidney mitochondria of the three groups of animals using succinate as a substrate revealed that the P/O ratio tends to decrease in animals kept at 6 degrees C while the RCR value was not altered by changing conditions or produced by the different diets. At the temperature of 6 degrees C both the P/O ratios and the RCR values of liver mitochondria using succinate as a substrate decreased in the group of rabbits fed the basal and iodine diets, but were not significantly different in the group fed the PTU diet. In the experiment on kidney mitochondrial activity using alpha-ketoglutarate as a substrate it was found that both the P/O ratios and the RCR values from animals fed basal and PTU diets at 6 degrees C decreased slightly as compared with animals fed at 20 degrees C and 34 degrees C. In liver mitochondria, using alpha-ketoglutarate as a substrate a significant decrease in the P/O ratio and the RCR value was found for both rabbits fed the basal and the iodine diets at 6 degrees C. In the group of rabbits fed the PTU diet, the P/O ratio also decreased but the fall was not significant. These results suggested that the activity of succinate dehydrogenase in liver mitochondria increases in animals fed basal and iodine diets at 6 degrees C. The enzyme dehydrogenase involved in oxidation of alpha-ketoglutarate which is localized in the outer membrane of mitochondria seems to be affected by different temperatures and diets as compared with succinate dehydrogenase localized in the matrix. The kidney mitochondria activity is less sensitive than that of liver mitochondria. Mitochondrial respiration and phosphorylation due to the tightness of their coupling may respond differently depending on the degree of thyroid activity.