Gh Treatment Of Patients With Abdominal Obesity

As GH promotes lipolysis low levels of GH has therefore been suggested to be of importance for the maintenance of the obese condition. The calorigenic effects of GH in obese subjects has also been known for many years (99). Some trials have therefore addressed the question of whether GH administration through its calorigenic and lipolytic action might enhance weight loss during dietary restriction in obese subjects. Both short-term (100) and several weeks of GH treatment (101,102) in combination with dietary restriction were unable to enhance the loss of body fat or body weight as compared with saline treatment. The GH administration may, however, decrease the loss of lean body mass during dietary restriction (100,102). These results, therefore, suggest that GH is not useful in the induction or enhancement of weight loss in obese subjects.

We have learned that GH can improve several of the aberrations that occur both in GH deficiency and Syndrome X. Thus, in GH-deficient adults the lipolytic effects of GH results in a preferential reduction in visceral adipose tissue (66). Furthermore, GH reduces the diastolic blood pressure (103), reduces total cholesterol, LDL-cholesterol (57,104-106), and increases HDL-cholesterol concentrations (78,105,107). Furthermore, long-term GH treatment does not impair insulin sensitivity (82). With this background we have studied the effects of GH on the metabolic, circulatory, and anthropodometric aberrations associated with abdominal/visceral obesity and Syndrome X (108).

The men who were studied were moderately obese with a preponderance of abdominal and/or visceral localization of body fat. As a group, they had slight to moderate metabolic changes known to be associated with abdominal/visceral obesity with serum IGF-1 concentrations in the low normal range and moderate insulin resistance as judged from the GDR values obtained during the euglycemic glucose clamp. None had overt diabetes. Nine months of GH treatment in a randomized, double-blind placebo controlled trial, 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 (Fig. 1). Moreover, insulin sensitivity improvement (Fig. 2) 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" (109) and the insulin resistance following hypoglycemia (110). Thus, our observation of increased insulin sensitivity during prolonged GH treatment is unexpected although not inexplicable. This improvement could be explained by the decrease in visceral adipose tissue mass induced by GH, followed by a decrease in 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 (111), the possibility has to be considered that the improvement in GDR in response to the more prolonged GH treatment might also be an effect of increased glucose transport in the skeletal muscle, possibly mediated through the IGF-1 receptor (71) and an increased proportion of insulin-sensitive type 1 muscle fibers (72).

Hormone Transition Photoshot

Fig. 1. Mean total body fat calculated from total body potassium, abdominal subcutaneous adipose tissue (AT) area at the level of L4-L5 and total volume of visceral AT assessed with computed tomography during 9 mo of treatment with rhGH or placebo in 30 men with abdominal/visceral obesity. The horizontal bars indicate the SE for the mean values shown and ^-values denote the differences between the two groups by two-way ANOVA for repeated measurements.

Fig. 1. Mean total body fat calculated from total body potassium, abdominal subcutaneous adipose tissue (AT) area at the level of L4-L5 and total volume of visceral AT assessed with computed tomography during 9 mo of treatment with rhGH or placebo in 30 men with abdominal/visceral obesity. The horizontal bars indicate the SE for the mean values shown and ^-values denote the differences between the two groups by two-way ANOVA for repeated measurements.

The reduction in total cholesterol is conceivably an effect of enhanced hepatic LDL-receptor activity in response to GH (74). In healthy adults, short-term GH administration has been reported to increase serum triglyceride concentrations (112). In this study, the serum triglyceride concentration also displayed an initial increase in response

Fig. 2. Mean fasting blood glucose, serum insulin, and glucose disappearance rate (GDR) assessed with a euglycemic hyperinsulinemic glucose clamp during 9 mo of treatment with rhGH or placebo in 30 men with abdominal/visceral obesity. The horizontal bars indicate the SE for the mean values shown and ^-values denote the differences between the two groups by two-way ANOVA for repeated measurements.

Fig. 2. Mean fasting blood glucose, serum insulin, and glucose disappearance rate (GDR) assessed with a euglycemic hyperinsulinemic glucose clamp during 9 mo of treatment with rhGH or placebo in 30 men with abdominal/visceral obesity. The horizontal bars indicate the SE for the mean values shown and ^-values denote the differences between the two groups by two-way ANOVA for repeated measurements.

to GH treatment. This could be an effect of both an increased flux of FFA to the liver and a direct stimulatory effect on the esterification of oleic acid into triglyceride and phospholipids in hepatocytes (113) in response to GH, which in turn enhances the very low density lipoprotein production from the liver. However, after nine months of GH treat ment, the serum triglyceride concentration had decreased again, probably as an effect of the increased insulin-stimulated glucose uptake. The GH treatment reduced diastolic blood pressure without affecting systolic blood pressure. This is in line with results from GH-deficient adults where GH administration reduced diastolic blood pressure, possibly as an effect of reduced peripheral vascular resistance (103). The mechanisms behind the reduction in peripheral vascular resistance might be indirect through the reduced abdominal obesity and increased insulin sensitivity (114) or more direct through the action of IGF-1 on the vascular wall (115) with increased levels of NO (98).

The multiple endocrine alterations associated with abdominal/visceral obesity can either be primarily responsible or be the consequence of the obese condition. This is the first trial to clearly demonstrate favorable effects by 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.

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