Effect of Acute Reduction of Free Fatty Acids by Acipimox
Effect of Acute Reduction of Free Fatty Acids by Acipimox
Background: In type 1 diabetes mellitus (DM1), high GH basal levels and exaggerated responses to several stimuli have been described. Acipimox is an antilipolytic drug that produces an acute reduction of free fatty acids (FFA). The aim of this study was to evaluate the effect of the reduction of plasma FFA with acipimox, alone or in combination with GHRH, on GH secretion in DM1.
Methods: Six type 1 diabetic patients were studied (three women, three men), mean age of 30 ± 2·1 years, body mass index (BMI) 23·1 ± 1·5 kg /m. As a control group, six normal healthy subjects of similar age, sex and weight were studied. Each patient and control received GHRH [1 µg/kg intravenously (i.v.) at min 180], acipimox (250 mg orally at min 0 and 120) and GHRH plus acipimox on three separated days. Subjects served as their own control. Blood samples were taken at appropriate intervals for determination of GH, FFA and glucose.
Result: In control subjects, the GH area under the curve (AUC; µg/l x 120 min) was for acipimox-treated 1339 ± 292 and 1528 ± 330 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 3031 ± 669, significantly greater than the response after acipimox alone (P < 0·05) or GHRH alone (P < 0·05). In diabetic patients, the GH AUC was for acipimox-treated 2516 ± 606 and 1821 ± 311 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 7311 ± 1154, significantly greater than the response after acipimox alone (P < 0·05) or GHRH alone (P < 0·05). The GH response after acipimox was increased in diabetic when compared with normal (P < 0·05), with a GH AUC of 1339 ± 292 and 2515 ± 606 for normal subjects and diabetic patients, respectively. The GH response after acipimox plus GHRH was increased in diabetic when compared with normal (P < 0·05), with a GH AUC of 3031 ± 669 and 7311 ± 1154 for normal subjects and diabetic patients, respectively. The administration of acipimox induced a FFA reduction during the entire test.
Conclusions: Reduction of free fatty acids with acipimox is a stimulus for GH secretion in DM1. The combined administration of GHRH plus acipimox induces a markedly increased GH secretion in type 1 diabetic patients when compared with normal subjects. These data suggest that patients with DM1 exhibit a greater GH secretory capacity than control subjects, despite the fact that endogenous FFA levels seems to exert a greater inhibitory effect on GH secretion in these patients.
Growth hormone (GH) secretion is mainly dependent on the interaction between GHRH, Ghrelin, the recently isolated endogenous ligand of the GH-secretagogues (GHS)-receptor and somatostatin (Cuttler et al., 1996; Giustina & Veldhuis, 1998; Dieguez & Casanueva, 2000). In addition several neurotransmitters, peripheral hormones and metabolic signals influence GH secretion (Cutler et al., 1996; Giustina & Veldhuis, 1998).
In type 1 diabetes mellitus (DM1), high GH basal levels and exaggerated responses to several stimuli have been described. In normal subjects, hyperglycaemia inhibits pituitary GH response to provocative stimuli. However, DM1 patients, despite elevated blood glucose levels, show exaggerated GH responses to several physiological and pharmacological provocative tests (Hansen, 1970; Lorenzi et al., 1980; Krassowski et al., 1988; Almqvist et al., 1999), and they have mean 24-h GH levels higher than those of normal subjects (Asplin et al., 1989; Edge et al., 1990).
Abnormal GH secretion has been suggested as a causative factor in the development of the microangiopathic complications of diabetes (Lorenzi et al., 1980; Salardi et al., 1986; Edge et al., 1990; Blankestijn et al., 1993). Abnormal GH secretion may contribute to the altered metabolic control of diabetes, although chronic effects of elevated GH levels on the metabolism and control of diabetes are unknown (Hansen et al., 1970; Lorenzi et al., 1980; Krassowski et al., 1988; Asplin et al., 1989; Edge et al., 1990; Miller et al., 1992; Carroll et al., 2000).
Diabetes is associated with a generalized impairment in lipid metabolism and with increased plasma free fatty acid (FFA) levels (Basu et al., 2001; Boden et al., 2001), although others have found normal baseline plasma FFA in diabetic patients (Coiro et al., 1999). A classic feedback relationship has been postulated between GH and the FFA. GH has a direct lipolytic effect on adipose tissue, leading to the release of glycerol, FFA and ketone bodies (Vance, 1993). Pharmacological reduction of FFA is associated with GH release (Dieguez & Casanueva, 1995). Acipimox is an antilipolytic drug that blocks lipolysis, is devoid of side-effects and produces an acute reduction of FFA (Pontiroli et al., 1990, 1991).
The aim of this study was to evaluate whether increased GH secretion in type DM1 could be due to an impairment of the inhibitory effect exerted by circulating FFA.
Background: In type 1 diabetes mellitus (DM1), high GH basal levels and exaggerated responses to several stimuli have been described. Acipimox is an antilipolytic drug that produces an acute reduction of free fatty acids (FFA). The aim of this study was to evaluate the effect of the reduction of plasma FFA with acipimox, alone or in combination with GHRH, on GH secretion in DM1.
Methods: Six type 1 diabetic patients were studied (three women, three men), mean age of 30 ± 2·1 years, body mass index (BMI) 23·1 ± 1·5 kg /m. As a control group, six normal healthy subjects of similar age, sex and weight were studied. Each patient and control received GHRH [1 µg/kg intravenously (i.v.) at min 180], acipimox (250 mg orally at min 0 and 120) and GHRH plus acipimox on three separated days. Subjects served as their own control. Blood samples were taken at appropriate intervals for determination of GH, FFA and glucose.
Result: In control subjects, the GH area under the curve (AUC; µg/l x 120 min) was for acipimox-treated 1339 ± 292 and 1528 ± 330 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 3031 ± 669, significantly greater than the response after acipimox alone (P < 0·05) or GHRH alone (P < 0·05). In diabetic patients, the GH AUC was for acipimox-treated 2516 ± 606 and 1821 ± 311 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 7311 ± 1154, significantly greater than the response after acipimox alone (P < 0·05) or GHRH alone (P < 0·05). The GH response after acipimox was increased in diabetic when compared with normal (P < 0·05), with a GH AUC of 1339 ± 292 and 2515 ± 606 for normal subjects and diabetic patients, respectively. The GH response after acipimox plus GHRH was increased in diabetic when compared with normal (P < 0·05), with a GH AUC of 3031 ± 669 and 7311 ± 1154 for normal subjects and diabetic patients, respectively. The administration of acipimox induced a FFA reduction during the entire test.
Conclusions: Reduction of free fatty acids with acipimox is a stimulus for GH secretion in DM1. The combined administration of GHRH plus acipimox induces a markedly increased GH secretion in type 1 diabetic patients when compared with normal subjects. These data suggest that patients with DM1 exhibit a greater GH secretory capacity than control subjects, despite the fact that endogenous FFA levels seems to exert a greater inhibitory effect on GH secretion in these patients.
Growth hormone (GH) secretion is mainly dependent on the interaction between GHRH, Ghrelin, the recently isolated endogenous ligand of the GH-secretagogues (GHS)-receptor and somatostatin (Cuttler et al., 1996; Giustina & Veldhuis, 1998; Dieguez & Casanueva, 2000). In addition several neurotransmitters, peripheral hormones and metabolic signals influence GH secretion (Cutler et al., 1996; Giustina & Veldhuis, 1998).
In type 1 diabetes mellitus (DM1), high GH basal levels and exaggerated responses to several stimuli have been described. In normal subjects, hyperglycaemia inhibits pituitary GH response to provocative stimuli. However, DM1 patients, despite elevated blood glucose levels, show exaggerated GH responses to several physiological and pharmacological provocative tests (Hansen, 1970; Lorenzi et al., 1980; Krassowski et al., 1988; Almqvist et al., 1999), and they have mean 24-h GH levels higher than those of normal subjects (Asplin et al., 1989; Edge et al., 1990).
Abnormal GH secretion has been suggested as a causative factor in the development of the microangiopathic complications of diabetes (Lorenzi et al., 1980; Salardi et al., 1986; Edge et al., 1990; Blankestijn et al., 1993). Abnormal GH secretion may contribute to the altered metabolic control of diabetes, although chronic effects of elevated GH levels on the metabolism and control of diabetes are unknown (Hansen et al., 1970; Lorenzi et al., 1980; Krassowski et al., 1988; Asplin et al., 1989; Edge et al., 1990; Miller et al., 1992; Carroll et al., 2000).
Diabetes is associated with a generalized impairment in lipid metabolism and with increased plasma free fatty acid (FFA) levels (Basu et al., 2001; Boden et al., 2001), although others have found normal baseline plasma FFA in diabetic patients (Coiro et al., 1999). A classic feedback relationship has been postulated between GH and the FFA. GH has a direct lipolytic effect on adipose tissue, leading to the release of glycerol, FFA and ketone bodies (Vance, 1993). Pharmacological reduction of FFA is associated with GH release (Dieguez & Casanueva, 1995). Acipimox is an antilipolytic drug that blocks lipolysis, is devoid of side-effects and produces an acute reduction of FFA (Pontiroli et al., 1990, 1991).
The aim of this study was to evaluate whether increased GH secretion in type DM1 could be due to an impairment of the inhibitory effect exerted by circulating FFA.