Ebbe Eldrup

Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes

The purpose of the current study was to test the hypothesis that an altered fat distribution in elderly healthy subjects and in patients with type-2 diabetes contributes to high circulating levels of interleukin (IL)-6 and tumor necrotic factor (TNF)-alpha, which secondly is related to lower muscle mass. Twenty young controls, (20-35 yr), 20 healthy elderly subjects (65-80 yr) and 16 elderly patients with type 2 diabetes (65-80 yr) were included in a cross sectional study. Plasma levels of TNF-alpha and IL-6 were measured after an overnight fast. Dual-energy X-ray absorptiometry and total body potassium counting measured truncal fat, appendicular skeletal muscle mass (ASM) and body cell mass (BCM), respectively. TNF-alpha, IL-6 and the relative truncal fat mass were higher in elderly compared with young controls. ASM was lower in diabetic men than in young controls and BCM was lower in elderly men compared with young men. TNF-alpha and IL-6 were correlated with the absolute as well as the relative truncal fat mass in univariate regression analyses. Similar results were found in multivariate linear regression analyses after adjusting for the effect of age and gender. TNF-alpha was related to lower ASM and BCM in elderly men both in a univariate regression analysis and a multivariate regression analysis. In conclusion, high plasma levels of TNF-alpha and IL-6 in elderly healthy people and in patients with type 2 diabetes are associated with increased truncal fat mass, suggesting that cytokines are partly derived from this adipose tissue bed. Furthermore, TNF-alpha was related to lower ASM and BCM, suggesting that TNF-alpha contributes to sarcopenia in ageing.

Dopaminergic regulation of gonadotropin levels and pulsatility in normal women.

This study was done to define the concentration of dopamine (DA) that inhibits gonadotropin secretion and to study the effect of DA D-2 receptor blockade during the infusions. Normal women received 5-hour infusions of either glucose (n = 14) or DA at rates of 0.04 (n = 6), 0.4 (n = 6), and 4.0 micrograms/kg X minute (n = 9). After 3 hours, metoclopramide (MTC) was administered. Mean serum luteinizing hormone (LH) concentration declined during 0.4 (P less than 0.01) and 4.0 micrograms/kg X minute (P less than 0.05) infusion doses of DA. This effect of DA was not consistently (P greater than 0.05) antagonized by MTC. Six women received DA (4.0 micrograms/kg X minute) or glucose for 18 hours. After 17 hours, MTC was given. Blood samples were collected every 10 minutes during the last 8 hours. No significant effect on LH pulse frequency and pulse amplitude was observed (P greater than 0.05). A marked (P less than 0.01) rise in LH occurred after MTC administration. The authors conclude that (1) physiologic doses of DA may inhibit LH secretion with only little, if any, effect on the pulsatile release; and (2) low-affinity DA receptors responsive to DA D-2 antagonists may regulate LH secretion.

Possible epithelial sodium channels visualized by freeze-fracture

The coprodeum is a very efficient Na+-retaining epithelium. Coprodeum from birds on a high Na+ diet has virtually no ion transport, while an Amiloride-sensitive Na+ absorption of 10--12 mu equiv . cm-2 . h-1 is induced in the coprodeal epithelium from birds on a low Na+ diet. Both measurements of the Na+ influx and Na+-diffusion potentials across the luminal cell membrane have revealed a selective opening of this membrane to Na+ in birds on a low Na+ diet. Freeze-fracture P faces of the luminal membrane in coprodea taken from birds on a low Na+ diet have rod-shaped particles, 100 x 240 A, in more than 20% of the principal cells. Rod-shaped particles appear in less than 1% of these cells in coprodea from high Na+-diet birds. Thus a low Na+ diet induces rod-shaped particles in the luminal cell membrane of the hen coprodeum. These new particles may function as Na+-channels mediating the increased Na+-influx across the apical cell membrane.

Plasma dihydroxyphenylalanine (DOPA) is independent of sympathetic activity in humans

Abstract. To clarify the origin of plasma DOPA (3,4‐Dihydroxyphenylalanine), the relationship between plasma DOPA and acute or chronic changes in sympathetic activity has been studied. Plasma DOPA and noradrenaline (NA) concentrations were measured by reverse‐phase high‐performance liquid chromatography with electrochemical detection. Administration of clonidine to healthy men decreased plasma NE markedly compared to no drug. Plasma DOPA decreased slightly but significantly with time, but values were identical after clonidine compared to no drug. Baseline plasma NE concentrations were significantly reduced in diabetic patients with autonomic neuropathy compared to diabetics without neuropathy, whereas baseline plasma DOPA concentrations were similar in the three groups investigated: 6–55 (5.03 7.26, median [interquartile range], n= 8) nmol 1‐1 in diabetics with neuropathy, 7.41 (5.79–7.97, n= 8) nmol 1‐1 in diabetics without neuropathy, and 6.85 (5.58–7.36, n=8) nmol 1–1 in controls. No relationship was obtained between baseline values of plasma NE and plasma DOPA. Plasma DOPA did not change in the upright position, whereas plasma NE increased significantly. Our results indicate that plasma DOPA is not related to sympathetic activity and may be of non‐neuronal origin.

EFFECT OF DOPAMINE AND A DOPAMINE D‐1 RECEPTOR AGONIST ON PULSATILE THYROTROPHIN SECRETION IN NORMAL WOMEN

The inhibitory effect of a pharmacological dose of dopamine and the specific dopamine D‐1 receptor agonist fenoldopam on basal and pulsatile TSH secretion was investigated in normal women. The TSH response to fenoldopam and subsequent releasing hormone administration was also studied. Six women received placebo or dopamine infusion (4.0 μg/kg min) for 17 h. After 9 h, blood samples were collected every 10 min between 0800 and 1600 h for measurement of TSH. Eight women received 8‐h (0900‐1700 h) infusions of either fenoldopam (0.5 μg/kg min) or placebo. After 7 h of infusion 10 μg TRH, 5 μg GnRH and 25 CRF was given i.v. Blood samples were collected every 10 min. Dopamine infusion as well as fenoldopam infusion significantly reduced both mean basal TSH secretion and TSH pulse frequency compared with corresponding control infusions (P < 0.05). However, while the effect on TSH pulsatility was comparable (P > 0.05), the percentage decrease in basal TSH levels after 16 h of dopamine infusion was 51±16% (mean±SD) and after 7 h of fenoldopam infusion 19±12% (P < 0.05). Neither of the drugs affected TSH pulse amplitude and fenoldopam did not influence TRH‐stimulated TSH release (P> 0.05). The results suggest that dopamine D‐1 receptors are involved in modulation of TSH pulsatility probably at the hypothalamic level. It is argued that dopaminergic inhibition of basal TSH secretion and TSH pulsatility is predominantly regulated through dopamine D‐2 receptors at the pituitary level, and through D‐1 receptors at the hypothalamic level, respectively.

Screening for diabetic cardiac autonomic neuropathy using a new handheld device.

Background: Cardiac autonomic neuropathy (CAN) is a serious complication of longstanding diabetes and is associated with an increased morbidity and reduced quality of life in patients with diabetes. The present study evaluated the prevalence of CAN diagnosed by reduced heart rate variability (HRV) using a newly developed device in a large, unselected, hospital-based population of patients with diabetes. Methods: The study examined 323 patients consisting of 206 type 1 diabetes (T1DM) patients and 117 type 2 diabetes (T2DM) patients. The new handheld prototype Vagus™ was used to screen for CAN. Three different standardized cardiac reflex tests were performed to calculate HRV: 30:15 ratio, E:I ratio, and the Valsalva maneuver. An abnormal HRV in one test is indicative of early CAN, and if two or more tests show abnormal HRV, the diagnosis of CAN is established. Results: In total, 86% of examined patients completed all three tests. Each test was completed by more than 90% of the patients. The prevalence of established CAN was 23%, whereas 33% of the patients had early signs of CAN. The prevalence was higher in T2DM patients (27.8%) than in T1DM patients (20.6 %), p = .02. Patients with CAN were older and had a longer duration of diabetes, higher systolic blood pressure, more nephropathy and retinopathy, and a higher vibration threshold. Conclusions: Cardiac autonomic neuropathy is frequent in both T2DM and T1DM patients, especially in those with other late diabetes complications. Screening for CAN with the new device is feasible.

EFFECT OF FENOLDOPAM, A DOPAMINE D‐1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D‐1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4‐h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 μg/kg min, 12–16 ml/h, adjusted according to weight. After 3 h of infusion, 50 μg GnRH and 100 μg TRH was given i. v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P < 0.01) to 128%, range 87–287, of preinfusion levels, compared to the decline during control infusion (85%, 78–114). Basal TSH levels declined significantly to 71% (60–91) during fenoldopam compared with 82% (65–115) during control infusion (P < 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P > 0.05). The LH response to GnRH/TRH was significantly (P < 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P > 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D‐1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.

Pulsatile gonadotropin secretion and basal prolactin levels during dopamine D-1 receptor stimulation in normal women *

The effect of the specific dopamine D-1 receptor agonist Fenoldopam on pulsatile gonadotropin secretion and prolactin (PRL) secretion was investigated in normal women. The gonadotropin response to subsequent gonadotropin-releasing-hormone (GnRH) administration was also studied. Eight women received 8-hour infusions of either Fenoldopam (0.5 microgram/kg per minute) (Smith Kline and French, Harrow, United Kingdom) or placebo. After 7 hours of infusion, GnRH was given intravenously. The luteinizing hormone (LH) response to GnRH was significantly higher during Fenoldopam compared with placebo (LH; 13.1 +/- 9.0 versus 9.4 +/- 4.3 IU/L). Basal LH levels, pulse amplitude, and pulse frequency during Fenoldopam infusion were not different from placebo. Prolactin levels increased significantly during Fenoldopam (24 +/- 2 micrograms/L) compared with placebo (16 +/- 2). The results suggest that D-1 receptor stimulation does not affect pulsatile gonadotropin secretion but increases the pituitary responsiveness to GnRH. Additionally, dopamine and Fenoldopam have opposite effects on PRL secretion, the latter increasing PRL levels.

Increase in plasma 3,4‐dihydroxyphenylalanine (DOPA) appearance rate after inhibition of DOPA decarboxylase in humans

Abstract. Concentrations of DOPA in plasma are relatively high as compared to norepinephrine. The significance of plasma DOPA has not been elucidated. One would expect that substantial amounts of DOPA are derived from sympathetic nerves. There appears, however, neither to be a depot of DOPA in nerves nor is there a close correlation between plasma DOPA and sympathetic activity. The aim of the present study was to obtain further information about plasma DOPA by studying DOPA kinetics in healthy humans both with and without inhibition of DOPA decarboxylase by benserazide. Plasma DOPA and other catecholamines were measured by reverse‐phase HPLC with electrochemical detection and DOPA clearance and appearance rate were studied using infusion of 3H‐DOPA.

The Degree of Autonomic Modulation Is Associated With the Severity of Microvascular Complications in Patients With Type 1 Diabetes

Objective: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes. Methods: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed. Results: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients. Conclusions: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.