Growth hormone secretion in polytransfused prepubertal patients with homozygous beta-thalassemia. Effect of long-term recombinant GH (recGH) therapy.

Growth was monitored in 133 male and 150 female North Sardinian prepubertal patients with homozygous beta-thalassemia in order to ascertain the incidence of GH deficiency (GHD) and the effects of long-term recombinant GH (recGH) treatment on growth velocity and bone maturation. A significant reduction in growth velocity and a fall in IGF-I levels was observed in 19 male and 16 female patients (12.3%). Their peak GH responses to GHRH (5.45+/-0.78 and 4.99+/-0.86 ng/ml) and clonidine administration (4.21+/-0.32 and 4.15+/-0.27 ng/ml in males and females, respectively) were markedly reduced with respect to control subjects (p<0.01). No statistically significant correlation was found between chronological age, number of blood units received, plasma ferritin levels and plasma IGF-I levels as well as with peak GH response to stimulation. Thalassemic patients with GHD had plasma ferritin levels (1382.44+/-160.34 and 1255.23+/-139.81 ng/ml in males and females, respectively) significantly lower than those recorded in the other patients (2848.94+/-283.61 and 3077.82+/-220.51 ng/ml). Patients with GHD were treated with recGH for an average period of 59 months (range 26-124). Treatment was able to restore growth and to increase significantly plasma IGF-I levels. Growth velocity at the end of the first yr of treatment was 6.78+/-1.21 and 6.11+/-0.85 cm/yr in males and females, respectively. Growth velocity values and plasma IGF-I levels remained significantly higher than basal values throughout the period of treatment. However, treatment was unable to normalize bone maturation since bone age values were always reduced with respect to chronological age. No incidence of side effects was observed. These data indicate that GHD, when present, is one but not the sole cause of delayed bone maturation and height deficiency in thalassemia.

Evaluation of serum leptin levels and thyroid function in morbidly obese patients treated with bariatric surgery.

Biliopancreatic diversion (BPD), a gastrectomy with a long ROUX en Y reconstruction, reduces intestinal absorption by delaying the mixing of food and biliopancreatic juices, and induces persistent weight loss in obese patients unresponsive to medical treatments. The levels of leptin (a plasma protein synthesised in human adipose tissue) are increased in obese subjects and significantly decrease after a major weight loss. A possible role of thyroid hormones in regulating adipose tissue metabolism in humans has been proposed, but it is not universally accepted and the relationship between thyroid function and leptin levels has not yet been clearly defined. We studied serum leptin, TSH, fT4 and fT3 levels in 38 obese patients (26 women and 12 men), before and 12 months after BPD. There was a significant post-surgical decrease in BMI and circulating leptin levels in all of the treated subjects, but thyroid function did not seem to be affected (TSH and fT4 levels were unchanged). However, fT3 levels significantly decreased after surgery. Our data suggest that BPD-induced malabsorption has no direct effect on thyroid function, but possibly reduces the peripheral conversion of thyroxine to T3. Further studies seem to be necessary to clarify the clinical relevance of these observations.

Association of Trp64Arg beta 3-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population.

OBJECTIVE: To evaluate the possible association of three candidate gene polymorphisms with essential hypertension in the genetically homogeneous Sardinian population. SUBJECTS AND METHODS: We studied 494 unrelated, nondiabetic subjects, 213 (43.2%) with essential hypertension. All subjects underwent a 75 g oral glucose tolerance test with determination of glycemia and insulinemia and serum lipids. The polymorphisms evaluated comprised Trp64Arg of the beta 3-adrenergic receptor, Gly40Ser of the glucagon receptor gene and the insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene. RESULTS: Among the overall population studied, 48 (9.7%) were heterozygous carriers of the Trp64Arg polymorphism. The frequency of the Trp64Arg variant was significantly higher in hypertensives (13.6%) than normotensives (6.8%; chi 2 5.73, P = 0.017). The 48 subjects with the Trp64Arg variant had significantly higher (P < 0.049) serum triglyceride levels than the 446 with the Trp64Trp variant, while no significant differences were observed, either fasting or during the 75 g oral glucose tolerance test, in glycemia and insulinemia. No differences were found between hypertensive and normotensive subjects for ACE gene insertion/deletion polymorphism nor in the frequency of the Gly40Ser coding change in exon 2 of the glucagon receptor gene. CONCLUSIONS: Our results are consistent with the thesis that the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is associated more often with the condition of high blood pressure than with normal blood pressure.

Reduction of albumin excretion rate in normotensive microalbuminuric type 2 diabetic patients during long-term simvastatin treatment.

OBJECTIVE: To study the long-term effects of simvastatin on urinary albumin excretion rate (AER) in normotensive microalbuminuric type 2 diabetic patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: A total of 19 normotensive microalbuminuric hypercholesterolemic type 2 diabetic patients entered a double-blind crossover study for 2 years, receiving either simvastatin (20 mg/day) or placebo (each treatment for 1 year). RESULTS: Simvastatin significantly decreased plasma cholesterol (total and LDL) after 52 weeks of treatment. A concomitant significant decrease of AER (25% from basal) with no significant changes in creatinine clearance was observed during the same period. CONCLUSIONS: Our data are in keeping with the hypothesis that simvastatin might be used as an additional means to preserve renal function in microalbuminuric hypercholesterolemic type 2 diabetic patients.

Glucagon receptor Gly40Ser amino acid variant in Sardinian hypertensive non-insulin-dependent diabetic patients. Sardinian Diabetic Genetic Study Group (SDGSG).

A significantly different prevalence in the Gly40Ser variant of the glucagon receptor gene in a small group of essential hypertensive patients compared with normotensive probands was described in a Caucasian population. It has been postulated that this variant may exacerbate the antinatriuretic effect of high plasma insulin levels commonly seen in hypertensive subjects, leading to volume expansion and rise in blood pressure level. The aim of this study was to evaluate the prevalence of the Gly40Ser variant in a population of 404 non-insulin-dependent diabetic patients of Sardinian origin. No association of the Gly40Ser variant with hypertension was seen in this large population.

Physiological and genetic characterization of the Gly40Ser mutation in the glucagon receptor gene in the Sardinian population. The Sardinian Diabetes Genetic Study Group.

A Gly40Ser amino acid substitution in the glucagon receptor gene has been associated with non-insulin-dependent diabetes mellitus (NIDDM), but the questions raised about its physiological implications have not been resolved. The aim of this study was to determine the frequency of the Gly40Ser mutation in different regions of Sardinia and to investigate the physiological implications of the mutation in glucose and insulin homeostasis. We studied a population of 691 subjects selected on the basis of their Sardinian origin. Only heterozygous subjects were found, 21 of 574 (3.6%) in NIDDM patients and 5 of 117 in non-diabetic subjects (4.2%). In northern Sardinia 3.4% of the NIDDM patients were carriers of the Gly40Ser substitution, 1.4% in central Sardinia, while 7.6% carried the substitution in the Southern part. No significant differences were found between hypertensive and normotensive subjects with respect to the presence of Gly40Ser. Ten subjects with Gly40Ser were carefully matched for diabetic state, BMI, age, sex, and geographical origin with 10 patients with Gly40, and a glucagon infusion test was performed using 1, 3, 9 and 27 ng glucagon kg-1.min-1 for 30 min. Blood for determination of glucose, glucagon, and insulin concentrations was drawn at 15-min intervals from the Controlateral arm. Plasma glucagon increased dose-dependently during the infusion with no significant difference between the two groups. Carriers of Gly40Ser had a significantly lower (p < 0.02) increase in plasma glucose concentration in response to glucagon infusion compared to Gly40 homozygous subjects at all times, while the plasma insulin increase was not significantly different at any time. In conclusion, our results indicate that the Gly40Ser variation is not associated with NIDDM in the Sardinian population and that its frequency varies in different parts of Sardinia. Moreover in vivo Gly40Ser plays a physiological role in the glucose homeostasis under glucagon control both in NIDDM and non-diabetic subjects. This latter result suggests that this amino acid substitution in the glucagon receptor may lead to a decreased blood glucose concentration because of the reduced stimulation of liver glucose output via the glucagon receptor.

Lipoprotein(a): identification of subjects with a superbinding capacity for fibrinogen.

We have previously shown that the binding of lipoprotein(a) [Lp(a)] to immobilized fibrinogen involves the domain located in kringles IV-5 to IV-8, but not kringle IV-10. In extending those studies to subjects living in Chicago and in the island of Sardinia, we found that about 6% of them had an Lp(a) with Bmax values of 27.7+/-6.0 fmol, which were about 5-8-fold higher than those of controls (3.4+/-2.8 fmol) and in the range of those observed for free apo(a) derived from the Lp(a) of controls (36.6+/-2.9 fmol). This superbinding phenotype was unaffected by age, sex, type of lipid disorder and hypolipidemic agents, and also had a familial incidence. We are currently exploring the hypothesis that this fibrinogen superbinding phenotype is due to conformational changes of apolipoprotein(a) [apo(a)] resulting from the lipid content and composition of the Lp(a) particle and/or sequence anomalies in the kringle domain IV-5 to IV-8.