With increased adiposity, GH secretion is blunted with a decrease in the mass of GH secreted per burst but without any major impact on GH secretory burst frequency (69). Moreover, the metabolic clearance rate of GH is accelerated (70). The serum insulin-like growth factor I (IGF-I) concentration is primarily GH dependent and influences GH secretion though a negative feedback system (71). The serum levels of IGF-I are inversely related to the percentage of body fat (69). In addition, the low serum IGF-I concentration in obesity is predominantly related to the amount of visceral adipose tissue and not to the amount of subcutaneous fat mass (72). Serum free IGF-I concentration may, on the other hand, be increased in abdominal obesity (73) possibly as an effect of the concomitant insulin-induced suppression of serum IGF binding protein-1 levels.
The relationship between regional fat distribution and GH secretion has only recently been considered. No significant correlation was found between the waist-to-hip ratio and 24-hour GH secretion rates in a study of 21 healthy men (74). However, in healthy non-obese men and women intra-abdominal fat mass had a strong negative exponential relationship with mean 24-hour serum GH concentrations which was independent of age, gender and physical fitness (75). This indicates that, for each increment in intra-abdominal fat mass, there is a more than linear reduction in mean 24hour GH concentration.
Striking similarities exist between the metabolic syndrome and untreated GH deficiency in adults (76). The central findings in both these syndromes are abdominal/visceral obesity and insulin resistance. Other features common to both conditions are high triglyceride and HDL cholesterol concentrations, an increased prevalence of hypertension, elevated levels of PAI-1 activity, premature atherosclerosis and increased mortality from cardiovascular diseases (77). Due to the similarities between two syndromes, undetectable and low levels of GH may be of importance for the metabolic aberrations observed in both these conditions.
Low levels of GH may be of importance for the metabolic consequences and the maintenance of the obese condition. One trial has demonstrated near normalization of 24-hour GH secretion and serum IGF-I in nine obese subjects after massive weight loss (78) whereas others have not found a normalization of the GH response to provocative testing in response to weight loss (79,80). Amount of intraabdominal fat was, however, not considered in these studies.
There is now considerable evidence that the metabolic syndrome might be considered to be a consequence of perturbations in the hypothalamo-pituitary-adrenocortical (HPA) axis due to environmental pressure which are expressed in individuals with molecular genetic susceptibility in the feedback, inhibitory mechanism exerted by central glucocorticoid receptors (GRs). This together with attenuating activity of the gonadotrophic and GH axis may be responsible for the development of the metabolic syndrome with visceral obesity, insulin resistance, dyslipoproteinaemia and hypertension. Attenuated GH secretion is therefore an important component of this cascade of events. Interestingly, the metabolic syndrome may apparently also develop with only low GH secretion (reduced serum IGF-I concentration), i.e. without involvement of the HPA axis inhibition. This condition seems to have a prevalence of 5% in middle-aged Swedish men (81).
Patients with acromegaly have reduced adipose tissue mass. After successful treatment which normalizes their GH secretion they demonstrate an in crease of predominantly visceral adipose tissue mass (82). The reverse scenario is seen in adults with hypopituitarism and untreated GH deficiency who have increased body fat mass with adbominal preponderance; after GH administration there is a profound reduction of visceral adipose tissue and less marked effects on other adipose tissue depots (83,84). These observations indicate that GH has profoundly effects on adipose tissue mass and distribution.
Insulin resistance is a common conditions and can be seen, for example, in type 2 diabetes, obesity and hypertension. The interrelationship between insulin resistance and these conditions, as well as the exact mechanisms for insulin resistance, have not yet been fully clarified. It recently became clear that even adults with GH deficiency have insulin resistance in peripheral tissues as measured using the hyperin-sulinaemic euglycemic clamp technique (85,86). The glucose disposal rate (GDR) in GH-deficient adults is found to be less than half that of controls, both when calculated according to body weight and when corrected for amount of body fat. The decreased lean body mass and the increased abdominal obesity in GH deficiency may be of importance for this finding as the association between increased body fat mass and insulin resistance is stronger in the presence of abdominal obesity (87). The attenuated GDR seen in abdominal obesity has in some studies been quantitatively similar to that seen in overtly hyperglycaemic type 2 diabetes (88). Low levels of serum IGF-I may also contribute to insulin resistance as IGF-I stimulates glucose transport in skeletal muscle. Other factors such as different composition of skeletal muscle fibres with a decrease in the slow-twitch, insulin-sensitive type I fibres and an increase in the fast-twitch, type Ib fibres, the degree of capillary rarefaction and decreased physical activity in adults with GH deficiency may be of importance just as it is in healthy adults (89,90).
GH has important effects on lipoprotein metabolism. For example, hypophysectomy in the rat changes the lipoprotein pattern from being predominantly HDL to a pattern with a predominately LDL peak, suggesting that the presence of GH is essential for maintaining a normal lipoprotein profile. Moreover, in response to GH the serum LDL cholesterol and apolipoprotein B concentrations decrease (91,92), probably as a result of the increased clearance of these lipoproteins through increased hepatic LDL receptor activity (93).
A common finding in both GH deficiency and the metabolic syndrome is high levels of serum triglycerides and low HDL cholesterol concentrations. This may be associated with increased adbominal adiposity and insulin resistance in both conditions. However, although a dramatic reduction in visceral adipose tissue occurs in response to GH treatment in adults with GH deficiency, serum triglyceride concentration is not reduced while the concentration of HDL cholesterol is increased (92).
This may be an effect of the lipolytic action of GH treatment which may increase the flux of FFA to the liver which in turn may increase the synthesis and secretion of VLDL from the liver. The LPL activity in adipose tissue is attenuated and the post-heparin plasma LPL is not affected by GH treatment (94). As serum triglyceride concentrations do not increase under conditions of increased VLDL secretion the peripheral catabolism must be enhanced. Increased LPL activity in other tissues such as muscle is therefore likely (94). Furthermore, the strong association between glucose/insulin homeostasis and VLDL metabolism (95) might be reflected in the response to GH. The unaffected triglyceride levels might thus be explained by essentially unchanged insulin sensitivity during more prolonged GH treatment in GH-deficient adults.
Both GH deficiency in adults and the metabolic syndrome are associated with increased prevalence of hypertension. The insulin resistance in the metabolic syndrome syndrome X) has been linked with hypertension through increased activity of the sympathetic nervous system (96). Direct evidence for this assumption is provided by an apparent parallel activation of hypothalamic centres regulating the sympathetic nervous sysem and the HPA axis, a 'hypohalamic arousal syndrome' (97). Central arousal of the sympathetic nervous system is considered to be a main pathogenic pathway for essential hypertension (98).
In adults with hypopituitarism and untreated GH deficiency augmented activity of the sympathetic nervous system has been demonstrated by direct intraneural recordings (99) linking this condition to increased prevalence of hypertension. In addition, GH deficiency has been found to be associated with low levels of nitric oxide (NO), a para-crine vasodilator produced in endothelial cells, which normalizes in response to GH treatment (100).
We have learned that GH treatment can improve several of the aberrations that GH deficiency has in common with the metabolic syndrome. Thus, in adults with GH deficiency the lipolytic effects of GH result in a preferential reduction in visceral adipose tissue (83). Furthermore, GH reduces diastolic blood pressure, total cholesterol, LDL cholesterol and increases HDL cholesterol concentrations (91,101,102). Long-term GH treatment does not impair insulin sensitivity (103). Against this background we have, in a 9-month randomized doubleblind placebod-controlled trial, studied the effects of GH on the metabolic, circulatory and anthropometric aberrations associated with abdominal/visceral obesity and the metabolic syndrome (104).
The men who were studied were moderately obese with a prepondernace of abdominal localization of body fat. As a group, they had slight to moderate metabolic changes known to be associated with abdominal/visceral obesity. Nine months of GH treatment in these middle-aged men with abdominal/visceral obesity reduced their total body fat and resulted in a specific and marked decrease in both abdominal subcutaneous and visceral adipose tissue. Moreover, insulin sensitivity improved and serum concentrations of total cholesterol and triglyceride decreased. Diastolic blood pressure decreased while plasma fibrinogen increased slightly.
GH exerts direct insulin-antagonistic effects even after the administration of physiologic doses of GH. GH has been considered to be the principal factor in the decrease in insulin sensitivity observed in the early morning, the so-called 'dawn phenomenon' and the insulin resistance following hypoglycaemia. Thus, our observation of increased insulin sensitivity during prolonged GH treatment could be explained by the decrease in visceral adipose tissue mass induced by GH, followed by a decrease in free fatty acid (FFA) exposure to the liver counteracting the insulin-antagonistic effects of GH. Alternatively, as the major site of glucose disposal is in the skeletal muscle, the improvement in GDR in response to more prolonged GH treatment might also be an effect of increased glucose transport in the skeletal muscle. This might be mediated hrough the IGF-I receptor and/or be an effect of an increased proportion of insulin-sensitive type I muscle fibres in response to the treatment.
This is the first trial clearly to demonstrate favourable effects of GH on the multiple perturbations associated with abdominal/visceral obesity. We therefore suggest that a blunted GH secretion could be an important factor in the development of the metabolic and circulatory consequences of abdominal/visceral obesity.
The abnormal activity of the HPA axis, low levels of sex steroids and attenuated GH secretion in abdominal obesity suggest a central neuroendocrine dysregulation. The finding that replacement therapy with testosterone and GH in men with abdominal obesity is able to diminish the negative metabolic consequences of visceral obesity suggests that the low levels of these hormones are of importance for the metabolic aberrations associated with visceral/abdominal obesity.
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