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In normal men, plasma free fatty acids (FFA) are influenced by feeding and by fasting; in addition, iv infusions of methionyl growth hormone (met-GH), so far performed during morning hours, induce an FFA rise that can be blocked by acipimox (ACX), a nicotinic acid analogue. The aims of the present study were to evaluate, in the absence of food interferences, the following aspects: i) Fasting FFA, glycerol, and insulin (IRI) in the morning and in the evening, and their response to met-GH ii) The effect of ACX and of a sustained release ACX formulation (ACX-SR) on fasting and met-GH induced lipolysis and on IRI levels. In a double blind study, 6 normal men received 50% cal at 09:30 h and 50% at 21:30 h; during placebo administrations FFA, glycerol, and IRI levels were lower at 06:30 h than at 18:30 h, and an iv met-GH infusion (160 ng/kg/min lasting 180 min) had a similar effect on FFA and on glycerol at 06:30 h and at 18:30 h. ACX-SR, administered at 21:30 h and 09:30 h, lowered FFA and glycerol in the morning as well as in the evening, and prevented met-GH induced lipolysis in the morning, but not in the evening. In another single blind study, 5 normal men received the last meal at 22:00 h, ACX 250 mg or placebo at 07:00 h and at 11:00 h and a met-GH infusion (80 ng/kg/min lasting 240 min) at 09:00 h; one month later they received the last meal at 07:30 h, ACX 250 mg or placebo at 16:30 h and at 20:30 h, and an identical met-GH infusion at 18:30 h. Again, ACX lowered FFA in the morning and in the evening, and prevented the lipolytic effect of met-GH in the morning, not in the evening. These data indicate that met-GH induces lipolysis in man, increasing both FFA and glycerol levels, and that ACX blocks these effects. In addition, in the absence of food interferences, FFA, glycerol, and IRI levels are different in the morning and in the evening. The fact that both ACX and ACX-SR prevented met-GH induced lipolysis in the morning, not in the evening, can be due to a peculiarity of ACX or to a different sensitivity of the adipose tissue to met-GH and/or other lipolytic agents (i.e. catecholamines, not evaluated in this study) in different moments of the day.

It has been suggested that growth hormone (GH) can inhibit its own release: in fact it has repeatedly been shown that an acute methionyl-GH (met-GH) infusion blocks the GH response to GH-releasing hormone (GHRH). However, met-GH infusions are accompanied by a significant increase of free fatty acids (FFA), which can block GH release. The aim of this study was to evaluate whether the inhibition of GH response to GHRH also occurs when lipolysis is pharmacologically blocked. Therefore, six normal subjects received GHRH, 50 micrograms intravenously (IV), after a 4-hour saline infusion and a 4-hour met-GH infusion (80 ng/kg/min, yielding a constant GH level of 33.6 +/- 4.63 micrograms/L), and GH release was evaluated during the following 2 hours. To prevent lipolysis, all subjects received on both occasions acipimox, an antilipolytic agent, 500 mg during the 6 hours before IV GHRH. GHRH induced a clear GH release during saline infusion (46.6 +/- 2.70 micrograms/L) and a scanty GH release during met-GH infusion (9.3 +/- 1.52 micrograms/L; P less than .01). Plasma levels of FFA, somatostatin, insulin-like growth factor I (IGF-I), and glucagon and serum insulin levels were unaffected, while blood glucose levels slightly decreased during saline infusion, but not during GH infusion. These data confirm that met-GH inhibits GHRH-induced GH release, and demonstrate that this inhibition is not mediated by FFA levels.

Growth hormone (GH) induces lipolysis and an increase of free fatty acids (FFA), and FFA inhibit the GH response to arginine and to GH-releasing hormone (GHRH). The aim of this study was to evaluate the effect of the pharmacologic blockade of lipolysis on the GH response to GHRH. Eleven normal men underwent a saline infusion starting at 09:00 h, after administration of placebo or 500 mg acipimox, an antilipolytic agent; at 13:00 h (0 min) they received GHRH, 50 micrograms iv The GH response to GHRH (0 to 120 min) was significantly higher in subjects pretreated with acipimox than in subjects pretreated with placebo. In subjects receiving placebo, but not in those receiving acipimox, a progressive increase of plasma FFA levels took place, and the GH response to GHRH was inversely related to the plasma FFA levels at 0 min. These data indicate that FFA play an important role in the control of GH release, and that acipimox prevents the FFA rise induced by GH.

Objective: Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD). Patients and methods: We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NOx (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers. Results: Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NOx release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NOx incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area. Conclusions: In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers. © 2007 The Authors.

Most cases of adult GH deficiency (AGHD) result from hypothalamic-pituitary tumors or their treatment. Some experimental and clinical observations suggest that GH may possess a mitogenic potential, thus raising the question of whether it is a safe treatment in patients with a previous pituitary tumor. Few study results have been reported on this topic. All of them have inevitable methodological flaws that limit their conclusions. However, all studies report that replacement therapy with GH does not seem to increase the risk of tumor progression or recurrence, when compared to historical or matched controls. Considering the slow-growing nature of most of these benign tumors and the absence of conclusive evidence from the available studies, a continuous imaging surveillance and longer follow-up periods are nevertheless mandatory for a definite statement on the safety of GH treatment in patients with previous pituitary tumors.

Insulin resistance in acromegaly causes glucose intolerance and diabetes, but it is unknown whether it involves protein metabolism, since both insulin and growth hormone promote protein accretion. The effects of acromegaly and of its surgical cure on the insulin sensitivity of glucose and amino acid/protein metabolism were evaluated by infusing [6,6-2H2]glucose, [1-13C]leucine, and [2-15N]glutamine during a euglycemic insulin (1 mU · kg−1 · min−1) clamp in 12 acromegalic patients, six studied again 6 mo after successful adenomectomy, and eight healthy controls. Acromegalic patients, compared with postsurgical and control subjects, had higher postabsorptive glucose concentration (5.5 ± 0.3 vs. 4.9 ± 0.2 μmol/l, P < 0.05, and 5.1 ± 0.1 μmol/l) and flux (2.7 ± 0.1 vs. 2.0 ± 0.2 μmol · kg−1 · min−1, P < 0.01, and 2.2 ± 0.1 μmol · kg−1 · min−1, P < 0.05) and reduced insulin-stimulated glucose disposal (+15 ± 9 vs. +151 ± 18%, P < 0.01, and 219 ± 58%, P < 0.001 from basal). Postabsorptive leucine metabolism was similar among groups. In acromegalic and postsurgical subjects, insulin suppressed less than in controls the endogenous leucine flux (−9 ± 1 and −12 ± 2 vs. −18 ± 2%, P < 0.001 and P< 0.05), the nonoxidative leucine disposal (−4 ± 3 and −1 ± 3 vs. −18 ± 2%, P < 0.01 and P < 0.05), respectively, indexes of proteolysis and protein synthesis, and leucine oxidation (−17 ± 6% in postsurgical patients vs. −26 ± 6% in controls, P < 0.05). Within 6 mo, surgery reverses insulin resistance for glucose but not for protein metabolism. After adenomectomy, more leucine is oxidized during hyperinsulinemia.

Context: Hypokalemic periodic paralysis (HypoPP) is a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs, which spontaneously resolve within several hours or days. Primary HypoPP is genetically determined, while secondary acquired HypoPP has been described in association with thyreotoxycosis, hyperaldosteronism, kidney diseases, diuretics and liquorice abuse, gastrointestinal potassium loss, or cysplatinum therapy. Objective: To report a case of HypoPP associated with GH deficiency. Patient: A 33 yr-old man with hypopituitarism and diabetes insipidus secondary to pituitary stalk-localized sarcoidosis, and documented HypoPP episodes. Clinical Presentation: Neurologic exam outside HypoPP episodes was normal. Needle electromyography was normal without myotonia or other spontaneous electric activity. Muscle biopsy documented a vacuolar myopathy with tubular aggregates. However, genetic analysis ruled out common mutations of the voltage-gated calcium channel observed in primary HypoPP. Common causes of secondary HypoPP were also ruled out. The patient was diagnosed with severe GH deficiency with modest fasting hyperinsulinemia and insulin resistance and started on GH replacement therapy, an α-glucosidase inhibitor (acarbose) and a diet low in simple carbohydrates. Conclusions: GH replacement therapy, acarbose and a diet low in simple carbohydrates resulted in the complete long-term (>2 yr) remission of HypoPP episodes. This is consistent with the hypothesis that the hyperinsulinemia associated to GH deficiency may trigger HypoPP episodes by increasing Na+/K+ ATPase activity and K+ transport into the intracellular compartment with subsequent hypokalemia.

Myotonic distrophy (MyD), the most common adult form of muscular dystrophy, is often complicated by diabetes. MyD is dominantly inherited and is due to heterozygosity for a tri-nucleotide repeat expansion mutation in a protein kinase gene which was suggested to induce derangement of RNA metabolism able to reduce insulin receptor expression. To test whether the abnormal RNA metabolism or a specific malfunction of protein kinase gene induces defective energy metabolism and insuline resistance prior to the onset of diabetes, we studied 10 MyD patients (2 glucose intolerant) and 10 matched healthy subjects, by means of (a) dual X-ray energy absorption, (b) euglycemic-hyperinsulinemic clamp ( 1 mU/Kg/min) combined with primed-continuous infusion of [6,6-d2]-glucose and [1-13C]-leucine, (c) indirect calorimetry, and (d) oral glucose tolerance test (OGTT) to explore insulin-dependent glucose, lipid and protein metabolism. MyD reduced Jean body mass (LBM: 36 ± 3 vs 46 ± 3 Kg; P < 0.02) and increased fat mass. Nevertheless, resting energy expenditure (33.4 ± 0.9 vs 33.8 ± 1.5 kcal/kg/day; P = 0.83), insulin-stimulated glucose metabolism [7.22 ± 0.22 vs 8.48 ± 0.80 mg/(kg LBM · min); P = 0.49], and lipid metabolism in the postabsortive and clamp conditions were comparable to normals. Proinsulin concentrations were increased in MyD patients (P = 0.01) and the intact proinsulin/insulin ratio (23 ± 4 vs 10 ± 1%; P < 0.01) was twofold higher in MyD. Circulating proinsulin levels also failed to be normally regulated during suppressing (clamp) or stimulating (OGTT) conditions. Markers of proteolysis (ELF: endogenous leucine flux) in the postabsorptive [203 ± 15 vs 146 ± 9 μmol/(kg LBM · h); P < 0.02] and insulin-stimulated conditions (ELF suppression during the insulin clamp: 11 ± 3 vs 18 ± 2%; P < 0.05) were higher in MyD than in normals and they were associated to reduced plasma insulin-like growth factor (IGF-1: 125 ± 18 vs 212 ± 8 ng/ml; P < 0.03) and increased plasma α-tumor necrosis factor receptor-2 (TNFR-2: 1919 ± 212 vs 1401 ± 172 pg/ml, P = 0.04). In summary, in MyD, energy metabolism was preserved but the severe loss of LBM was associated with abnormal postabsorptive and insulin-stimulated regulation of protein breakdown. Insulin resistance with respect to glucose metabolism was lacking, and a higher risk to develop type 2 diabetes is more likely due to abnormal insulin secretion. The combination of reduced circulating IGF-1 levels and increased TNF system activity may be responsible for the increased protein breakdown which is involved in muscle wasting in MyD