Nicola Sicolo

Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome.

Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.

Effects of octreotide exposure during pregnancy in acromegaly

Background  Only six women who were treated with somatostatin analogues (SSAs) throughout their pregnancies have been described so far. The influence of SSAs on the course of pregnancy and newborn outcomes remains largely unknown. Many aspects of SSAs pharmacokinetics in mother and foetus have not yet been defined.

Obesity Reduces the Expression of GLUT4 in the Endometrium of Normoinsulinemic Women Affected by the Polycystic Ovary Syndrome

Abstract: GLUT4 is the most important glucose transporter in insulin‐dependent tissues. A decrease of its expression by the adipocytes was reported in polycystic ovary syndrome (PCOS), regardless of obesity and glucose tolerance. In PCOS, abnormal menstrual cycles, abnormal insulin secretory patterns, and obesity, which are risk factors for endometrial diseases, frequently coexist. The endometrial effects of insulin are direct through specific insulin receptors. However, it is unknown whether the endometrium expresses GLUT4 and can be considered an insulin‐regulated tissue. In this study, we investigated this question, and we investigated whether obesity modulates this expression in PCOS normoinsulinemic patients. We assayed GLUT4 in the endometrial samples from 18 normoinsulinemic PCOS patients and 9 controls in the advanced follicular phase of the cycle; 10 patients were lean and 8 obese, and all were aged between 23 and 32 years. Most tissue was immediately frozen for RT‐PCR; some tissue was saved for histology and immunohistochemistry. GLUT4 mRNA expression was measured in three samples for every patient and expressed as mean ± SE of an arbitrary unit. In obese PCOS subjects, endometrial GLUT4 expression was significantly lower than in the lean ones (24.0 ± 6.8 vs. 65.2 ± 24.4; P < 0.005) and the controls (53.2 ± 10.7). Lean PCOS and control subjects showed similar values. GLUT4 immunostaining was strong in the epithelial and absent in the stromal cells. We demonstrated endometrial GLUT4 expression. The similar results in lean PCOS and control subjects suggest that endometrial GLUT4 expression is not affected by PCOS itself, whereas it is reduced by obesity in PCOS patients.

ALMS1-deficient fibroblasts over-express extra-cellular matrix components, display cell cycle delay and are resistant to apoptosis.

Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.

Increased Rate of Intracranial Saccular Aneurysms in Acromegaly: An MR Angiography Study and Review of the Literature

BACKGROUND The concurrence of intracranial aneurysms and acromegaly has been reported and debated previously. Our study in a large number of patients aimed to verify whether acromegaly patients carry a higher risk of harboring intracranial saccular aneurysms and to evaluate the possible relationship using clinical, laboratory, and imaging techniques. MATERIALS AND METHODS A total of 152 of 161 consecutive acromegaly patients (median age, 55.7 yr; 82 females) underwent neuroimaging evaluation of the circle of Willis. Clinical data (disease duration and disease control, hypertension, smoking history, diabetes and dyslipidemia, previous surgery or radiotherapy, previous or current pharmacological therapy), laboratory findings (GH and IGF-I at onset and shortly before examination), and pituitary adenoma imaging features (size and invasiveness of the cavernous sinus) were recorded. RESULTS Twenty-six patients (17.3%) harbored 40 newly diagnosed intracranial aneurysms; two other patients had previously undergone aneurysm clipping due to subarachnoid hemorrhage. Ten patients had multiple aneurysms; most of the aneurysms were located in the intracranial tract of the internal carotid artery (67.5%); no aneurysms belonged to the vertebrobasilar circulation. The presence of intracranial aneurysms correlated with GH serum values at disease onset (P < 0.05) and showed a trend to a positive correlation with poor disease control (P = 0.06); no other laboratory, clinical, and radiological findings correlated with the presence of intracranial aneurysms. CONCLUSIONS GH serum excess seems to carry an increased risk of developing intracranial aneurysms. A neuroradiological evaluation of the intracranial circulation might therefore be considered in the diagnostic work-up of patients affected with acromegaly.

Plasma and urine free L-Carnitine in human diabetes mellitus

SummaryL-carnitine is essential for the transport of long-chain fatty acids into mitochondria and their oxidation. Recently, a relationship between plasma free fatty acids (FFA) and L-carnitine metabolism has been observed. Plasma free L-carnitine (FC), FFA, triglycerides, cholesterol, blood glucose concentration and daily excretion of FC were determined in 20 diabetic patients as well as in 18 control subjects. Both in male diabetics and in male controls, plasma FC was significantly higher than in females. Mean plasma FC was found to be significantly reduced in diabetics (21 ± 2vs 35 ± 2 Μmol/1 in non-diabetic subjects; p<0.005). Daily urinary excretion of FC was clearly lower in diabetic patients than in controls (172 ± 34vs 403 ± 38 Μmol/24 h; p<0.001). The reduced plasma FC in diabetes mellitus may be due to redistribution between circulating free and esterified carnitine and to increased utilization of FC for synthesis of acylcarnitine in tissues.

Characterization of the IGF system in 15 patients with Alström syndrome

Background  Alström syndrome (ALMS) is a rare recessively inherited progressive disease (OMIM 203800). Among its diverse spectrum of clinical features are phenotypes associated with deficiencies of the GH/IGF‐I axis, including short stature, obesity, insulin resistance, hypertriglyceridaemia and heart failure.

Acromegalic cardiopathy: A left ventricular scintigraphic study

In order to study “acromegalic cardiomyopathy”, cardiac function was examined, using gated radionuclide ventriculography, in 18 acromegalic patients and 21 control subjects with no clinical evidence of cardiac involvement. In these acromegalic subjects, while the Ejection Fraction (EF) did not appear to be significantly different, the Peak Filling Rate (PFR) was reduced while the Time to Peak Filling Rate (TPFR) resulted significantly greater than in control subjects. These findings indicate that chronic growth hormone (GH) hypersecretion, as observed in acromegaly, deteriorate the cardiac ventricular relaxation (diastolic phase) while it has no influence on contractility (systolic phase).

Acromegalic cardiomyopathy. An echocardiography study

Eighteen acromegalic patients (A) and 18 controls without clinical evidence of cardiac involvement and/or endocrine disease (C), matched for sex, age, body surface area, and blood pressure (BP), were investigated by M-mode (2-D derived) echocardiography, to clarify the prevalence and the possible determinants of left ventricular hypertrophy (LVH). Seven patients in each group were hypertensive (BP > 160/95 mmHg). Left ventricular mass (LVM) was 183.1 ± 60.0 g/m2 in A and 130 ± 25.9 g/m2 in C. ALVM above 140 g/m2 (that is the upper normal range in our laboratory) was found in 15/18 A and 2/18 C. The LVH was concentric (h/r > 0.45) in 12/15 A and 1/2 C. Systolic function indexes (% FS, end-systolic stress/end-systolic volume), cardiac index and total peripheral resistance index (as determined by echo) were within the normal range and similar in both groups. No correlationwas found between LVM and BP, LVM and GH plasma levels, LVM and Sm-C levels. A significant correlation was found between LVM and duration of the disease (r 0.44; p<0.05). Our data confirm that LVH is an early and frequent finding in acromegaly. Its prevalence is not entirely accounted for by such factors as body size, BP or increased cardiac output. Metabolic factors may play a major role, and a long lasting exposition to increased GH levels seems the most relevant determinant of LVH.

In vivo studies on 5-hydroxytryptamine and insulin secretion in dogs and in man

Summary5-Hydroxytryptamine (5-HT) effects on the insulin secretion of anaesthetized dogs and of humans were studied. From our investigations the following conclusions can be drawn: 5-HT when injected at a dose of 4.30 mg into the pancreatic artery, elicits a sharp rise of insulin concentration in pancreatico-duodenal vein; on the contrary, 21.50 mg of 5-HT is unable to modify insulin release. The infusion in fasting man of small amounts of 5-HT (∼ 0.50 μg/kg/min) during 1 h, does not alter blood glucose nor plasma insulin levels; a similar infusion, however, increases insulin response after oral glucose load. The results obtained in dogs are in agreement with the idea that 5-HT may modulate insulin release from the pancreas. The results in man suggest that enteramine released by the intestine may increase insulin secretion induced by the ingestion of glucose, through a fine interplay with other gut-factors.