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Visceral obesity, impaired glucose tolerance, metabolic syndrome, and growth hormone therapy
Growth Hormone & IGF Research 16 (2006) S62–S67 www.elsevier.com/locate/ghir
Visceral obesity, impaired glucose tolerance, metabolic syndrome, and growth hormone therapy Hamdee Attallah a, Anne L. Friedlander b, Andrew R. Hoffman
c,d,*
a Department of Medicine, Wayne State University, Detroit, MI, United States Geriatrics Research and Education Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, United States Medical Service (111), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, United States d Department of Medicine, Stanford University, Palo Alto, CA, United States
b c
Available online 18 April 2006
Abstract Overweight adults with impaired glucose tolerance have a 5–10% risk of developing diabetes per year, and insulin resistance is an important cause of progression to diabetes in these individuals. Weight loss has been shown to improve insulin sensitivity and prevent or delay progression to diabetes. According to recent studies, the improvement in insulin sensitivity that occurs with weight loss is closely linked to the reduction of visceral adipose tissue (VAT), the collection of intra-abdominal adipose depots that includes omental and intrahepatic fat. After controlling for BMI, whole body fat, and subcutaneous fat, only VAT is an independent predictor of endogenous insulin sensitivity and glucose tolerance before or after weight loss. This, in turn, suggests that reducing VAT is crucial to improving insulin sensitivity and preventing diabetes in high-risk individuals. Recombinant human growth hormone (GH) is a lipolytic drug that reduces total body, abdominal, and visceral fat in growth hormone-deficient (GHD) adults. Several studies have reported substantial reductions in VAT following GH treatment in this population. Like GHD adults, abdominally obese individuals have increased VAT, insulin resistance, and growth hormone levels that are below normal during continuous 24-h monitoring. These similarities have prompted a number of recent investigations in abdominally obese adults that reported significant reductions in truncal and visceral fat and an improvement in insulin sensitivity following prolonged GH administration. However, other studies have shown that insulin resistance and glucose concentrations transiently worsen during the first few weeks of GH treatment and that these deleterious effects can persist even after VAT reduction has occurred. Prior studies involving GH treatment were generally limited to adults who were normoglycemic at baseline. Less is known about the effects of GH in adults with impaired glucose tolerance or diabetes. The effects of GH used in conjunction with insulin sensitizers on glycemic control and VAT in patients with impaired glucose tolerance will be reviewed. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Insulin resistance; Visceral obesity; Adults; Growth hormone
1. Link between visceral adipose tissue (VAT) and cardiovascular disease In recent years, clinicians have gained a better understanding of the relationship between cardiovascular dis* Corresponding author. Address: Medical Service (111), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, United States. Tel.: +1 650 858 3930; fax: +1 650 856 802. E-mail address: arhoff[email protected] (A.R. Hoffman).
1096-6374/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2006.03.004
ease and various components of body fat such as total body, subcutaneous, and intra-abdominal (or visceral) fat. According to several epidemiological studies, visceral fat – a combination of omental and mesenteric adipose tissue – is the fat component most predictive of cardiovascular (CV) disease and events in both older men and women. Baik et al. studied the relationship between body fat and CV outcome in 40,000 older men over a 10-year period. Men with an increased waist circumference, which correlates strongly with VAT, had
H. Attallah et al. / Growth Hormone & IGF Research 16 (2006) S62–S67
the highest number of CV events [1]. Rexrode et al. prospectively followed 45,000 women aged 40–65 over 8 years to determine the effect of VAT on CV outcome. Women with android obesity – that is, an increased waist circumference (>98.5 cm) and an elevated waistto-hip ratio (>0.88) – had more than a twofold increased risk of coronary heart disease even after adjustment for hypertension, diabetes, and high cholesterol levels, and even when body mass index (BMI) was normal [2]. On the other hand, loss of body fat is associated with a reduction in CV risk [3]. Several prospective studies have indicated that a selective reduction in VAT reduces CV disease risk through improvements in hypertension, dyslipidemia, diabetes, and other components of intermediary metabolism [4–8]. Moreover, GH treatment has been shown to reduce VAT in obese GH-deficient (GHD) as well as GH-replete adults and to ameliorate metabolic variables such as hyperlipidemia that are often associated with visceral adiposity (see below). Therefore, GH might be expected to improve long-term cardiovascular outcome indirectly by reducing VAT. In men with adult GH deficiency, for example, 3–6 months of GH treatment has been shown to return the carotid artery intima media thickness (as measured by ultrasound) toward the normal age- and sex-matched healthy range and to improve brachial artery blood flow [9]. These data suggest a possible therapeutic role for rhGH in reducing longterm cardiovascular disease and stroke risk by directly improving vascular morphology and function.
2. Link between VAT and impaired glucose tolerance Many viscerally obese people are also insulin resistant. When the pancreas is unable to release enough insulin to overcome the insulin resistance, impaired glucose tolerance (IGT) develops. According to the World Health Organization, IGT is a prediabetic condition in which serum glucose concentrations range between 140 and 200 mg/dL 2 h after a 75 g glucose load. IGT is more common in viscerally obese men and women. Despres et al. found that, of all fat regions, VAT is most significantly correlated with postprandial glucose levels in the IGT range (measured as glucose area under the curve during a 75 g oral glucose tolerance test) [10]. Other investigators have also found a close association between VAT and IGT [11]. The health consequences of IGT are twofold: an increased risk of CV disease and an increased risk of developing type 2 diabetes mellitus [12–14]. While the exact cause of the increased CV risk in patients with IGT is unknown, postprandial hyperglycemia itself may be responsible. Postprandial hyperglycemia appears to generate oxidative stress, increase protein glycation, increase hypercoagulability, and damage endothelial
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cells, all of which promote atherosclerosis [15]. Even after adjustment is made for insulin levels and other confounders, postprandial glucose elevation remains a significant predictor of subsequent CV events [16,17]. Loss of VAT reduces postprandial glucose levels in patients with IGT [18–24]. Fujioka et al. studied the effects of weight loss in viscerally obese women, many of whom also had IGT [25]. Weight loss, and VAT reduction in particular, resulted in a significant improvement in postprandial glucose levels. Erikkson et al. also prospectively showed that IGT subjects who had lowered their postprandial glucose levels after weight loss also had a lower risk of developing type 2 diabetes [26]. These findings were confirmed by the Diabetes Prevention Program (DPP) study, which showed that a 5–7% weight loss in IGT subjects may reduce the risk of developing type 2 diabetes by as much as 58% [27]. The growing health care burden of type 2 diabetes mellitus in the US demands that newer, more effective diabetes prevention strategies be implemented. One way to achieve diabetes prevention is to target adults who are at greatest risk for developing diabetes, such as viscerally obese adults with IGT.
3. GH, VAT reduction, and enhanced insulin sensitivity 3.1. GHD adults GHD adults have increased VAT and abnormal lipid profiles and are at increased risk of developing cardiovascular disease. GH replacement with or without diet and exercise interventions effectively reduces VAT and improves lipid abnormalities in GHD adults [28–32]. In 1989, Salomon et al. published one of the first placebo-controlled trials involving GH replacement in GHD adults. After 6 months, GH-treated subjects experienced a significant decline in total body fat mass compared to subjects receiving placebo [33]. Using computed tomography (CT) scanning, Bengtsson et al. [28] demonstrated that GH exerts its most potent lipolytic effect on VAT depots. In a recent study in which GHD patients received a fortnightly injection of depot GH, VAT declined by more than 9%, as assessed by abdominal CT scan [34], confirming similar data in GHD adults who received daily GH [35,36]. 3.2. Healthy elders Investigators at Stanford and VA Palo Alto Health Care Systems have performed several clinical trials to determine the effects of GH on body composition and a variety of metabolic indices in postmenopausal obese women. In a 12-month placebo-controlled clinical trial, Holloway and colleagues compared the effects of GH versus placebo in 27 healthy elderly women [37].
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Skinfold thickness measurements in GH-treated women not taking estrogen revealed a 2.7 kg decline in total body fat mass and a 9.3% decline in percent fat at 6 months. In contrast, no change in VAT was observed in the placebo group. After 2 months, women taking both GH and estrogen experienced a non-significant trend toward decreased fat mass [37]. 3.3. Obese adults Abdominally obese adults without pituitary pathology also have low serum GH concentrations [38]. Viscerally obese adults have significantly lower integrated 24-h GH concentrations compared with non-viscerally obese young adult controls [39]. This association between visceral obesity and an apparent ‘‘underproduction’’ of GH has prompted investigators to study the effects of GH on body composition and metabolism in viscerally obese adults. Studies involving viscerally obese adult men have demonstrated that VAT quantity, as measured by CT scan or magnetic resonance imaging (MRI), diminishes by at least 10– 20% after 6 months of standard-dose GH treatment [40,41]. Although 1 week of treatment with low doses of GH (2.5 or 3.3 lg/kg/d; average weight 107 kg) stimulates lipolysis in viscerally obese men [42], a similar dose (0.4 mg/d) of GH, when given for 8 months, did not actually alter fat mass in a group of obese men [43]. We examined the effects of GH and/or recombinant human insulin-like growth factor I (IGF-I) on body composition in elderly women undergoing weight loss through diet and exercise. Thirty-four postmenopausal women, aged 59–79 years, were included in this placebo-controlled, double-blind trial [44]. Using dual X-ray absorptiometry to assess regional and whole body fat mass, we determined that GH, either alone or combined with IGF-I, augmented the loss of central, or truncal, fat as well as peripheral fat in these women on a diet-plus-exercise regimen (Fig. 1). In viscerally obese adult women, however, the effects of GH are variable. Estrogen may attenuate the effect of GH in premenopausal and estrogen-replete postmenopausal women [45]. These women often exhibit lower IGF-I levels and a less pronounced reduction in body fat compared to men in response to a given dose of GH. Munzer et al. showed that elderly women treated with GH alone (without estrogen) experienced a reduction in waist circumference as well as a decrease in total abdominal area as measured by MRI [40]. However, this study failed to reveal any reduction in MRI-measured visceral fat area in women treated with GH with or without estrogen. One explanation for this finding may be that IGF-I levels were quite low in this group of GHtreated women, indicating that an inadequate GH dose might have been used.
Fig. 1. Mean (±SE) limb and truncal fat in postmenopausal women at baseline and following growth hormone (GH) and insulin-like growth factor I (IGF-I) given alone or in combination versus placebo for 12 weeks. *P < 0.01 versus baseline; P < 0.05 GH plus IGF-I versus IGF-I plus placebo; §P < 0.01 GH plus IGF-I versus placebo. (Reproduced with permission from [44].)
Other studies involving GH-treated obese women have demonstrated a significant reduction in body fat as measured by hydrodensitometry [46]. Richelsen et al. demonstrated a 5% reduction in VAT area as measured by CT scan in abdominally obese women treated with rhGH for only 5 weeks [47]. In a randomized, double-blind, placebo-controlled study, Franco and colleagues treated 40 middle-aged, abdominally obese postmenopausal women with GH for 12 months. VAT decreased in GH-treated patients who maintained a stable weight. Moreover, insulin sensitivity increased in GH-treated subjects, and this improvement correlated with a reduction in hepatic fat content [48].
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3.4. Effects of rhGH in viscerally obese, insulin-resistant adults Johannsson et al. examined the effects of GH in viscerally obese, insulin-resistant men with normal glucose tolerance [41]. Thirty men between the ages of 48 and 66 were treated with GH in a double-blind, placebo-controlled trial. During the first 6 months of the study, subjects receiving GH lost 18.1% of VAT as measured by CT scan. In addition, while overall glucose levels did not change during the study, an interesting paradoxical effect on short-term versus long-term insulin sensitivity was observed in GH-treated subjects. GH-treated subjects developed a transient decrease in insulin sensitivity during the first 6 weeks of therapy. However, after 9 months of rhGH treatment, the glucose disposal rate (GDR), a measure of tissue insulin sensitivity, increased by 1.2 ± 0.7 mg/kg per minute compared to baseline, indicating that insulin sensitivity increases with long-term GH administration. Similar results have been observed in adults with documented GH deficiency and insulin resistance, in whom endogenous insulin sensitivity improved following prolonged GH administration. Using the modified insulin suppression test (MIST) to measure insulin sensitivity, Hwu and colleagues demonstrated that 12 months of GH improves morning steady-state plasma glucose (SSPG) in GHD adults compared to untreated GH-deficient controls [49]. This improvement was also associated with a reduction in total body and visceral fat.
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3.5. GH plus antidiabetic drugs GH is generally well tolerated and is effective in promoting VAT loss. Although GH may transiently exacerbate insulin resistance, prolonged GH administration might help to prevent diabetes in viscerally obese adults with IGT. If prospective studies demonstrate this outcome, the long-term savings in health care dollars accrued through diabetes prevention may offset the short-term cost of this drug. In addition, the co-administration of an insulin sensitizer with GH might counteract the transient rise in insulin resistance that sometimes occurs with GH. If this is prospectively shown to occur, then GH could be safely used to treat visceral obesity and its associated metabolic complications not only in adults with IGT but also in those with frank diabetes mellitus and other disorders of glucose metabolism. Herrmann et al. studied 25 middle-aged men with the metabolic syndrome using metformin (850 mg bid) with or without GH (9.5 lg/kg/d) for 18 months in a doubleblind, placebo-controlled trial [50]. Their results showed no significant differences between GH- and placebotreated groups in BMI, total body fat, or waist circumference. At 6 months, the group receiving GH plus metformin demonstrated a transient increase in fasting plasma glucose. At 18 months, the glucose disposal rate increased by 20% in patients receiving GH plus metformin, while it decreased by 11% in the metformin alone group. In summary, it did not appear that adding metformin mitigated the diabetogenic potential of GH, but there was a trend to suggest that combined
Fig. 2. Computed tomography scan in a subject who received combined treatment with growth hormone (GH) and pioglitazone. At baseline (left), visceral adipose tissue (VAT) area and subcutaneous (SC) fat area at L 4–5 were 180 and 568 cm2, respectively. After 40 weeks of treatment with GH and pioglitazone, these values declined to 120 cm2 (33%) and 534 cm2 (6%), respectively.
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treatment was more effective at increasing glucose disposal than metformin alone. Long-term administration of thiazolidinediones (TZDs) or GH have been shown to reduce VAT and improve insulin sensitivity in insulin-resistant adults. However, GH is rarely administered to individuals with abnormal glucose metabolism because of its short-term insulin-antagonizing effects. Since adults with increased VAT and IGT are at risk for developing diabetes, and VAT reduction can lower this risk, we studied the effects of GH (8 lg/kg/d) and the TZD pioglitazone (30 mg/d) on VAT and insulin sensitivity in viscerally obese adults with IGT in a double-blind, placebo-controlled trial [51]. Subjects received double placebo (n = 16), GH + pioglitazone placebo (n = 16), GH placebo + pioglitazone, or GH + pioglitazone (n = 15) for 40 weeks. Significant declines in VAT were observed in both groups receiving GH, with a trend toward greater VAT loss in the group that also received pioglitazone (Fig. 2). Fasting plasma glucose increased transiently (week 12) in the group receiving GH alone but remained unchanged in patients receiving GH plus pioglitazone. Steady-state plasma glucose, an index of insulin resistance, was unchanged in patients treated with GH alone but was approximately 15% lower in the group receiving GH plus pioglitazone. Thus, 40 weeks of GH with or without pioglitazone reduced VAT, while the addition of pioglitazone to GH prevented the short-term diabetogenic effects of GH and actually improved insulin sensitivity over time.
4. Conclusion GH therapy decreases VAT in subjects with adult GH deficiency and in GH-replete viscerally obese adults. It is generally agreed that adults with GHD and visceral obesity should be given GH replacement therapy. The use of GH, with or without insulin sensitizers, represents a novel, albeit expensive, adjunct to diet and exercise in GH-replete obese individuals who are striving to reduce their cardiovascular risk.
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Visceral obesity, impaired glucose tolerance, metabolic syndrome, and growth hormone therapy Hamdee Attallah a, Anne L. Friedlander b, Andrew R. Hoffman
c,d,*
a Department of Medicine, Wayne State University, Detroit, MI, United States Geriatrics Research and Education Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, United States Medical Service (111), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, United States d Department of Medicine, Stanford University, Palo Alto, CA, United States
b c
Available online 18 April 2006
Abstract Overweight adults with impaired glucose tolerance have a 5–10% risk of developing diabetes per year, and insulin resistance is an important cause of progression to diabetes in these individuals. Weight loss has been shown to improve insulin sensitivity and prevent or delay progression to diabetes. According to recent studies, the improvement in insulin sensitivity that occurs with weight loss is closely linked to the reduction of visceral adipose tissue (VAT), the collection of intra-abdominal adipose depots that includes omental and intrahepatic fat. After controlling for BMI, whole body fat, and subcutaneous fat, only VAT is an independent predictor of endogenous insulin sensitivity and glucose tolerance before or after weight loss. This, in turn, suggests that reducing VAT is crucial to improving insulin sensitivity and preventing diabetes in high-risk individuals. Recombinant human growth hormone (GH) is a lipolytic drug that reduces total body, abdominal, and visceral fat in growth hormone-deficient (GHD) adults. Several studies have reported substantial reductions in VAT following GH treatment in this population. Like GHD adults, abdominally obese individuals have increased VAT, insulin resistance, and growth hormone levels that are below normal during continuous 24-h monitoring. These similarities have prompted a number of recent investigations in abdominally obese adults that reported significant reductions in truncal and visceral fat and an improvement in insulin sensitivity following prolonged GH administration. However, other studies have shown that insulin resistance and glucose concentrations transiently worsen during the first few weeks of GH treatment and that these deleterious effects can persist even after VAT reduction has occurred. Prior studies involving GH treatment were generally limited to adults who were normoglycemic at baseline. Less is known about the effects of GH in adults with impaired glucose tolerance or diabetes. The effects of GH used in conjunction with insulin sensitizers on glycemic control and VAT in patients with impaired glucose tolerance will be reviewed. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Insulin resistance; Visceral obesity; Adults; Growth hormone
1. Link between visceral adipose tissue (VAT) and cardiovascular disease In recent years, clinicians have gained a better understanding of the relationship between cardiovascular dis* Corresponding author. Address: Medical Service (111), VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, United States. Tel.: +1 650 858 3930; fax: +1 650 856 802. E-mail address: arhoff[email protected] (A.R. Hoffman).
1096-6374/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2006.03.004
ease and various components of body fat such as total body, subcutaneous, and intra-abdominal (or visceral) fat. According to several epidemiological studies, visceral fat – a combination of omental and mesenteric adipose tissue – is the fat component most predictive of cardiovascular (CV) disease and events in both older men and women. Baik et al. studied the relationship between body fat and CV outcome in 40,000 older men over a 10-year period. Men with an increased waist circumference, which correlates strongly with VAT, had
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the highest number of CV events [1]. Rexrode et al. prospectively followed 45,000 women aged 40–65 over 8 years to determine the effect of VAT on CV outcome. Women with android obesity – that is, an increased waist circumference (>98.5 cm) and an elevated waistto-hip ratio (>0.88) – had more than a twofold increased risk of coronary heart disease even after adjustment for hypertension, diabetes, and high cholesterol levels, and even when body mass index (BMI) was normal [2]. On the other hand, loss of body fat is associated with a reduction in CV risk [3]. Several prospective studies have indicated that a selective reduction in VAT reduces CV disease risk through improvements in hypertension, dyslipidemia, diabetes, and other components of intermediary metabolism [4–8]. Moreover, GH treatment has been shown to reduce VAT in obese GH-deficient (GHD) as well as GH-replete adults and to ameliorate metabolic variables such as hyperlipidemia that are often associated with visceral adiposity (see below). Therefore, GH might be expected to improve long-term cardiovascular outcome indirectly by reducing VAT. In men with adult GH deficiency, for example, 3–6 months of GH treatment has been shown to return the carotid artery intima media thickness (as measured by ultrasound) toward the normal age- and sex-matched healthy range and to improve brachial artery blood flow [9]. These data suggest a possible therapeutic role for rhGH in reducing longterm cardiovascular disease and stroke risk by directly improving vascular morphology and function.
2. Link between VAT and impaired glucose tolerance Many viscerally obese people are also insulin resistant. When the pancreas is unable to release enough insulin to overcome the insulin resistance, impaired glucose tolerance (IGT) develops. According to the World Health Organization, IGT is a prediabetic condition in which serum glucose concentrations range between 140 and 200 mg/dL 2 h after a 75 g glucose load. IGT is more common in viscerally obese men and women. Despres et al. found that, of all fat regions, VAT is most significantly correlated with postprandial glucose levels in the IGT range (measured as glucose area under the curve during a 75 g oral glucose tolerance test) [10]. Other investigators have also found a close association between VAT and IGT [11]. The health consequences of IGT are twofold: an increased risk of CV disease and an increased risk of developing type 2 diabetes mellitus [12–14]. While the exact cause of the increased CV risk in patients with IGT is unknown, postprandial hyperglycemia itself may be responsible. Postprandial hyperglycemia appears to generate oxidative stress, increase protein glycation, increase hypercoagulability, and damage endothelial
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cells, all of which promote atherosclerosis [15]. Even after adjustment is made for insulin levels and other confounders, postprandial glucose elevation remains a significant predictor of subsequent CV events [16,17]. Loss of VAT reduces postprandial glucose levels in patients with IGT [18–24]. Fujioka et al. studied the effects of weight loss in viscerally obese women, many of whom also had IGT [25]. Weight loss, and VAT reduction in particular, resulted in a significant improvement in postprandial glucose levels. Erikkson et al. also prospectively showed that IGT subjects who had lowered their postprandial glucose levels after weight loss also had a lower risk of developing type 2 diabetes [26]. These findings were confirmed by the Diabetes Prevention Program (DPP) study, which showed that a 5–7% weight loss in IGT subjects may reduce the risk of developing type 2 diabetes by as much as 58% [27]. The growing health care burden of type 2 diabetes mellitus in the US demands that newer, more effective diabetes prevention strategies be implemented. One way to achieve diabetes prevention is to target adults who are at greatest risk for developing diabetes, such as viscerally obese adults with IGT.
3. GH, VAT reduction, and enhanced insulin sensitivity 3.1. GHD adults GHD adults have increased VAT and abnormal lipid profiles and are at increased risk of developing cardiovascular disease. GH replacement with or without diet and exercise interventions effectively reduces VAT and improves lipid abnormalities in GHD adults [28–32]. In 1989, Salomon et al. published one of the first placebo-controlled trials involving GH replacement in GHD adults. After 6 months, GH-treated subjects experienced a significant decline in total body fat mass compared to subjects receiving placebo [33]. Using computed tomography (CT) scanning, Bengtsson et al. [28] demonstrated that GH exerts its most potent lipolytic effect on VAT depots. In a recent study in which GHD patients received a fortnightly injection of depot GH, VAT declined by more than 9%, as assessed by abdominal CT scan [34], confirming similar data in GHD adults who received daily GH [35,36]. 3.2. Healthy elders Investigators at Stanford and VA Palo Alto Health Care Systems have performed several clinical trials to determine the effects of GH on body composition and a variety of metabolic indices in postmenopausal obese women. In a 12-month placebo-controlled clinical trial, Holloway and colleagues compared the effects of GH versus placebo in 27 healthy elderly women [37].
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Skinfold thickness measurements in GH-treated women not taking estrogen revealed a 2.7 kg decline in total body fat mass and a 9.3% decline in percent fat at 6 months. In contrast, no change in VAT was observed in the placebo group. After 2 months, women taking both GH and estrogen experienced a non-significant trend toward decreased fat mass [37]. 3.3. Obese adults Abdominally obese adults without pituitary pathology also have low serum GH concentrations [38]. Viscerally obese adults have significantly lower integrated 24-h GH concentrations compared with non-viscerally obese young adult controls [39]. This association between visceral obesity and an apparent ‘‘underproduction’’ of GH has prompted investigators to study the effects of GH on body composition and metabolism in viscerally obese adults. Studies involving viscerally obese adult men have demonstrated that VAT quantity, as measured by CT scan or magnetic resonance imaging (MRI), diminishes by at least 10– 20% after 6 months of standard-dose GH treatment [40,41]. Although 1 week of treatment with low doses of GH (2.5 or 3.3 lg/kg/d; average weight 107 kg) stimulates lipolysis in viscerally obese men [42], a similar dose (0.4 mg/d) of GH, when given for 8 months, did not actually alter fat mass in a group of obese men [43]. We examined the effects of GH and/or recombinant human insulin-like growth factor I (IGF-I) on body composition in elderly women undergoing weight loss through diet and exercise. Thirty-four postmenopausal women, aged 59–79 years, were included in this placebo-controlled, double-blind trial [44]. Using dual X-ray absorptiometry to assess regional and whole body fat mass, we determined that GH, either alone or combined with IGF-I, augmented the loss of central, or truncal, fat as well as peripheral fat in these women on a diet-plus-exercise regimen (Fig. 1). In viscerally obese adult women, however, the effects of GH are variable. Estrogen may attenuate the effect of GH in premenopausal and estrogen-replete postmenopausal women [45]. These women often exhibit lower IGF-I levels and a less pronounced reduction in body fat compared to men in response to a given dose of GH. Munzer et al. showed that elderly women treated with GH alone (without estrogen) experienced a reduction in waist circumference as well as a decrease in total abdominal area as measured by MRI [40]. However, this study failed to reveal any reduction in MRI-measured visceral fat area in women treated with GH with or without estrogen. One explanation for this finding may be that IGF-I levels were quite low in this group of GHtreated women, indicating that an inadequate GH dose might have been used.
Fig. 1. Mean (±SE) limb and truncal fat in postmenopausal women at baseline and following growth hormone (GH) and insulin-like growth factor I (IGF-I) given alone or in combination versus placebo for 12 weeks. *P < 0.01 versus baseline; P < 0.05 GH plus IGF-I versus IGF-I plus placebo; §P < 0.01 GH plus IGF-I versus placebo. (Reproduced with permission from [44].)
Other studies involving GH-treated obese women have demonstrated a significant reduction in body fat as measured by hydrodensitometry [46]. Richelsen et al. demonstrated a 5% reduction in VAT area as measured by CT scan in abdominally obese women treated with rhGH for only 5 weeks [47]. In a randomized, double-blind, placebo-controlled study, Franco and colleagues treated 40 middle-aged, abdominally obese postmenopausal women with GH for 12 months. VAT decreased in GH-treated patients who maintained a stable weight. Moreover, insulin sensitivity increased in GH-treated subjects, and this improvement correlated with a reduction in hepatic fat content [48].
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3.4. Effects of rhGH in viscerally obese, insulin-resistant adults Johannsson et al. examined the effects of GH in viscerally obese, insulin-resistant men with normal glucose tolerance [41]. Thirty men between the ages of 48 and 66 were treated with GH in a double-blind, placebo-controlled trial. During the first 6 months of the study, subjects receiving GH lost 18.1% of VAT as measured by CT scan. In addition, while overall glucose levels did not change during the study, an interesting paradoxical effect on short-term versus long-term insulin sensitivity was observed in GH-treated subjects. GH-treated subjects developed a transient decrease in insulin sensitivity during the first 6 weeks of therapy. However, after 9 months of rhGH treatment, the glucose disposal rate (GDR), a measure of tissue insulin sensitivity, increased by 1.2 ± 0.7 mg/kg per minute compared to baseline, indicating that insulin sensitivity increases with long-term GH administration. Similar results have been observed in adults with documented GH deficiency and insulin resistance, in whom endogenous insulin sensitivity improved following prolonged GH administration. Using the modified insulin suppression test (MIST) to measure insulin sensitivity, Hwu and colleagues demonstrated that 12 months of GH improves morning steady-state plasma glucose (SSPG) in GHD adults compared to untreated GH-deficient controls [49]. This improvement was also associated with a reduction in total body and visceral fat.
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3.5. GH plus antidiabetic drugs GH is generally well tolerated and is effective in promoting VAT loss. Although GH may transiently exacerbate insulin resistance, prolonged GH administration might help to prevent diabetes in viscerally obese adults with IGT. If prospective studies demonstrate this outcome, the long-term savings in health care dollars accrued through diabetes prevention may offset the short-term cost of this drug. In addition, the co-administration of an insulin sensitizer with GH might counteract the transient rise in insulin resistance that sometimes occurs with GH. If this is prospectively shown to occur, then GH could be safely used to treat visceral obesity and its associated metabolic complications not only in adults with IGT but also in those with frank diabetes mellitus and other disorders of glucose metabolism. Herrmann et al. studied 25 middle-aged men with the metabolic syndrome using metformin (850 mg bid) with or without GH (9.5 lg/kg/d) for 18 months in a doubleblind, placebo-controlled trial [50]. Their results showed no significant differences between GH- and placebotreated groups in BMI, total body fat, or waist circumference. At 6 months, the group receiving GH plus metformin demonstrated a transient increase in fasting plasma glucose. At 18 months, the glucose disposal rate increased by 20% in patients receiving GH plus metformin, while it decreased by 11% in the metformin alone group. In summary, it did not appear that adding metformin mitigated the diabetogenic potential of GH, but there was a trend to suggest that combined
Fig. 2. Computed tomography scan in a subject who received combined treatment with growth hormone (GH) and pioglitazone. At baseline (left), visceral adipose tissue (VAT) area and subcutaneous (SC) fat area at L 4–5 were 180 and 568 cm2, respectively. After 40 weeks of treatment with GH and pioglitazone, these values declined to 120 cm2 (33%) and 534 cm2 (6%), respectively.
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treatment was more effective at increasing glucose disposal than metformin alone. Long-term administration of thiazolidinediones (TZDs) or GH have been shown to reduce VAT and improve insulin sensitivity in insulin-resistant adults. However, GH is rarely administered to individuals with abnormal glucose metabolism because of its short-term insulin-antagonizing effects. Since adults with increased VAT and IGT are at risk for developing diabetes, and VAT reduction can lower this risk, we studied the effects of GH (8 lg/kg/d) and the TZD pioglitazone (30 mg/d) on VAT and insulin sensitivity in viscerally obese adults with IGT in a double-blind, placebo-controlled trial [51]. Subjects received double placebo (n = 16), GH + pioglitazone placebo (n = 16), GH placebo + pioglitazone, or GH + pioglitazone (n = 15) for 40 weeks. Significant declines in VAT were observed in both groups receiving GH, with a trend toward greater VAT loss in the group that also received pioglitazone (Fig. 2). Fasting plasma glucose increased transiently (week 12) in the group receiving GH alone but remained unchanged in patients receiving GH plus pioglitazone. Steady-state plasma glucose, an index of insulin resistance, was unchanged in patients treated with GH alone but was approximately 15% lower in the group receiving GH plus pioglitazone. Thus, 40 weeks of GH with or without pioglitazone reduced VAT, while the addition of pioglitazone to GH prevented the short-term diabetogenic effects of GH and actually improved insulin sensitivity over time.
4. Conclusion GH therapy decreases VAT in subjects with adult GH deficiency and in GH-replete viscerally obese adults. It is generally agreed that adults with GHD and visceral obesity should be given GH replacement therapy. The use of GH, with or without insulin sensitizers, represents a novel, albeit expensive, adjunct to diet and exercise in GH-replete obese individuals who are striving to reduce their cardiovascular risk.
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