P. H. Sönksen

The Effects of Treatment with Recombinant Human Growth Hormone on Body Composition and Metabolism in Adults with Growth Hormone Deficiency

In a double-blind, placebo-controlled trial, we studied the effects of six months of growth hormone replacement in 24 adults with growth hormone deficiency. Most of the patients had acquired growth hormone deficiency during adulthood as a consequence of treatment for pituitary tumors, and all were receiving appropriate thyroid, adrenal, and gonadal hormone replacement. The daily dose of recombinant human growth hormone (rhGH) was 0.07 U per kilogram of body weight, given subcutaneously at bedtime. The mean (+/- SE) plasma concentration of insulin-like growth factor I increased from 0.41 +/- 0.05 to 1.53 +/- 0.16 U per liter during rhGH treatment. Treatment with rhGH had no effect on body weight. The mean lean body mass, however, increased by 5.5 +/- 1.1 kg (P less than 0.0001), and the fat mass decreased by 5.7 +/- 0.9 kg (P less than 0.0001) in the group treated with growth hormone; neither changed significantly in the placebo group. The basal metabolic rate, measured at base line and after one and six months of rhGH administration, increased significantly; the respective values were 32.4 +/- 1.4, 37.2 +/- 2.2, and 34.4 +/- 1.6 kcal per kilogram of lean body mass per day (P less than 0.001 for both comparisons). Fasting plasma cholesterol levels were lower (P less than 0.05) in the rhGH-treated group than in the placebo group, whereas plasma triglyceride values were similar in the two groups throughout the study. We conclude that growth hormone has a role in the regulation of body composition in adults, probably through its anabolic and lipolytic actions.

A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population

SummaryA cross-sectional multicentre study of randomly selected diabetic patients was performed using a standardised questionnaire and examination, to establish the prevalence of peripheral neuropathy in patients attending 118 hospital diabetes clinics in the UK. Vibration perception threshold was performed in two centres to compare with the clinical scoring systems. A total of 6487 diabetic patients were studied, 53.9% male, median age 59 years (range 18– 90 years), 37.4% Type 1 (insulin-dependent) diabetes mellitus, with a median duration of diabetes 8 years (0–62 years). The overall prevalence of neuropathy was 28.5% (27.4– 29.6 %) (95 % confidence interval) in this population. The prevalence in Type 1 diabetic patients was 22.7% (21.0– 24.4 %) and in Type 2 (non-insulin-dependent) diabetic patients it was 32.1 % (30.6–33.6 %). The prevalence of diabetic peripheral neuropathy increased with age, from 5% (3.1– 6.9 %) in the 20–29 year age group to 44.2 % (41.1–47.3 %) in the 70–79 year age group. Neuropathy was associated with duration of diabetes, and was present in 20.8 % (19.1–22.5 %) of patients with diabetes duration less than 5 years and in 36.8 % (34.9–38.7 %) of those with diabetes duration greater than 10 years. Mean vibration perception threshold measured at the great toe was 21.1±13.5 SD volts and correlated with the neuropathy disability score, r=0.8 p<0.001. In conclusion, diabetic peripheral neuropathy is a common complication associated with diabetes. It increases with both age and duration of diabetes, until it is present in more than 50% of Type 2 diabetic patients aged over 60 years. An increased awareness of the high prevalence of peripheral neuropathy, especially in older patients, should result in improved screening programmes in order to reduce the high incidence of neuropathic diabetic foot ulceration.

Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non-diabetic subjects

A series of 519 non-diabetic subjects had vibration thresholds at three points measured using a biothesiometer. Thresholds appeared to be log normally distributed and increased with age. Centile charts of this relation were derived from the data giving a range for normal thresholds. The biothesiometer provides a quick and reliable assessment of vibration thresholds, which when related to the centile charts gives an objective measure of the progress of diabetic peripheral neuropathy.

The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis

Homeostatic mechanisms normally maintain the plasma glucose concentration within narrow limits despite major fluctuations in supply and demand. There is increasing evidence that the growth hormone (GH)–insulin‐like growth factor (IGF) axis may play an important role in glucose metabolism. GH has potent effects on intermediary metabolism, some of which antagonize the actions of insulin. In contrast, IGF‐I has insulin‐like actions, which are, in the case of glucose metabolism, opposite to those of GH. There is often deranged glucose metabolism in situations where GH is deficient or in excess. The clinical administration of GH or IGF‐I results in altered glucose metabolism and changes in insulin resistance. Despite these observations, the precise role of GH and IGF‐I and their interactions with insulin in controlling normal glucose homeostasis are unknown. In diabetes, GH secretion is abnormally increased as a result of reduced portal insulin resulting in impaired hepatic IGF‐I generation. Evidence suggests that this may contribute to the development of diabetic microvascular complications. IGF‐I ‘replacement’ in diabetes is under investigation and new methods of delivering IGF‐I as a complex with IGFBP‐3 offer exciting new prospects.

The effect of growth hormone replacement on serum lipids, lipoproteins, apolipoproteins and cholesterol precursors in adult growth hormone deficient patients

OBJECTIVE Adult patients with growth hormone deflciency are thought to be at higher risk of mortallty from cardiovascular disease. We therefore investlgated the effect of recombinant human growth hormone (rhGH) replacement therapy on fasting serum concentrations of IIplds, lipoproteins and cholesterol precursors in adult growth hormone deficient patients.

Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM

SummaryWe measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable isotope gas-chromatography mass-spectrometry method in six patients with non-insulin-dependent diabetes mellitus (NIDDM) (four males, two females, age 57.5±2.2 years (mean±SEM), weight 88.2±5.5 kg, glycated haemoglobin (HbA1) 8.5±0.5%, plasma total cholesterol concentration 5.7±0.5 mmol/l, triglyceride 3.8±0.9 mmol/l, high-density lipoprotein (HDL) cholesterol 1.0±0.1 mmol/l) and six non-diabetic subjects matched for age, sex and weight (four males, two females, age 55.7±2.8 years, weight 85.8±5.6 kg, HbA1 6.5±0.1%, plasma total cholesterol concentration 5.7±0.5 mmol/l, triglyceride 1.2±0.1 mmol/l, HDL cholesterol 1.4±0.1 mmol/l). HbA1, plasma triglyceride and mevalpnic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the diabetic patients than in the non-diabetic subjects (p=0.006, p=0.02 and p=0.004, respectively). VLDL apoB absolute secretion rate was significantly higher in the diabetic patients compared with the non-diabetic subjects (2297±491 vs 921±115 mg/day, p<0.05), but there was no significant difference in the fractional catabolic rate of VLDL apoB. There was a positive correlation between VLDL apoB secretion rate and (i) fasting C-peptide (r=0.84, p=0.04) and (ii) mevalonic acid concentration (r=0.83, p<0.05) in the diabetic patients but not in the non-diabetic subjects. There was also a significant positive association between plasma mevalonic acid and plasma C-peptide (r=0.82, p<0.05) concentrations in the diabetic patients. We conclude that in NIDDM, there is increased hepatic secretion of VLDL apoB which may partly explain the dyslipoproteinaemia seen in this condition. We suggest that increased secretion of this apolipoprotein may be a consequence of resistance to the inhibitory effect of insulin on VLDL apoB secretion. Insulin resistance may also be the mechanism by which cholesterol synthesis, a regulator of apoB secretion, is increased in NIDDM.

The Growth Hormone/Insulin-Like Growth Factor-I Axis in Exercise and Sport

The syndrome of adult GH deficiency and the effects of GH replacement therapy provide a useful model with which to study the effects of the GH/IGF-I axis on exercise physiology. Measures of exercise performance including maximal oxygen uptake and ventilatory threshold are impaired in adult GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition, and improved thermoregulation. In normal subjects, in addition to the long-term effects of GH/IGF-I status, there is evidence that the acute GH response to exercise is important in regulating substrate metabolism after exercise. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss, particularly during exercise, and increases lean body mass. Despite a lack of evidence that these metabolic effects translate to improved performance, GH abuse by athletes is widespread. Tests to detect GH abuse have been developed based on measurement in serum of 1) indirect markers of GH action, and 2) the relative proportions of the two major naturally occurring isoforms (20 and 22kDa) of GH. There is evidence that exercise performance and strength are improved by administration of GH and testosterone in combination to elderly subjects. The potential benefits of GH in these situations must be weighed against potential adverse effects.

Skeletal Muscle Performance in Adults with Growth Hormone Deficiency

Skeletal muscle mass and function were assessed in 24 adults (16 males, 8 females) with severe, long-standing GH deficiency. Compared to 41 untrained controls (26 males, 15 females), adults with GH deficiency had reduced cross-sectional area of thigh muscle/body weight (p = 0.01), reduced quadriceps force/weight (males: p = 0.002; females: p less than 0.0001), and reduced quadriceps force/muscle area (males: p = 0.005). This suggests (a) that adults with GH deficiency have reduced skeletal muscle mass due, in part, to the absence of the anabolic effects of GH, and (b) that skeletal muscle force may be reduced due to altered muscle mass, contractile elements/muscle fibre, anaerobic energy supply, neural recruitment of fibres, or a combination of these.

Growth hormone, IGF‐I and insulin and their abuse in sport

There is widespread anecdotal evidence that growth hormone (GH) is used by athletes for its anabolic and lipolytic properties. Although there is little evidence that GH improves performance in young healthy adults, randomized controlled studies carried out so far are inadequately designed to demonstrate this, not least because GH is often abused in combination with anabolic steroids and insulin. Some of the anabolic actions of GH are mediated through the generation of insulin‐like growth factor‐I (IGF‐I), and it is believed that this is also being abused. Athletes are exposing themselves to potential harm by self‐administering large doses of GH, IGF‐I and insulin. The effects of excess GH are exemplified by acromegaly. IGF‐I may mediate and cause some of these changes, but in addition, IGF‐I may lead to profound hypoglycaemia, as indeed can insulin. Although GH is on the World Anti‐doping Agency list of banned substances, the detection of abuse with GH is challenging. Two approaches have been developed to detect GH abuse. The first is based on an assessment of the effect of exogenous recombinant human GH on pituitary GH isoforms and the second is based on the measurement of markers of GH action. As a result, GH abuse can be detected with reasonable sensitivity and specificity. Testing for IGF‐I and insulin is in its infancy, but the measurement of markers of GH action may also detect IGF‐I usage, while urine mass spectroscopy has begun to identify the use of insulin analogues.

The effects of growth hormone on protein metabolism in adult growth hormone deficient patients

OBJECTIVE Growth hormone treatment given to adult growth hormone deficient patients leads to an increase in lean body mass by an unknown mechanism. The aim of this study was to investigate the actions of growth hormone treatment on protein metabolism in adult growth hormone deficient patients.