The GesTIO protocol experience: safety of a standardized order set for subcutaneous insulin regimen in elderly hospitalized patients.

BACKGROUNDS: In non-critical hospitalized patients with diabetes mellitus, guidelines suggest subcutaneous insulin therapy with basal-bolus regimen, even in old and vulnerable inpatients. AIM: To evaluate safety, efficacy, and benefit on clinical management of the GesTIO protocol, a set of subcutaneous insulin administration rules, in old and vulnerable non-ICU inpatients. METHODS: Retrospective, observational study. Patients admitted to Geriatric Clinic of Padua were studied. 88 patients matched the inclusion criteria: type 2 diabetes or hospital-related hyperglycemia, ≥65 years, regular measurements of capillary glycemia, and basal-bolus subcutaneous insulin regimen managed by "GesTIO protocol" for five consecutive days. MAIN OUTCOME MEASURES: ratio of patients with blood glucose (BG) <3.9 mmol/l; number of BG per patient in target range (5-11.1 mmol/l); daily mean BG; and calls to physicians for adjusting insulin therapy. RESULTS: Mean age was 82 ± 7 years. 9.1% patients experienced mild hypoglycaemia, and no severe hypoglycaemia was reported. The median number of BG per patients in target range increased from 2.0 ± 2 to 3.0 ± 2 (p < 0.001). The daily mean BG decreased from 11.06 ± 3.03 to 9.64 ± 2.58 mmol/l (-12.8%, p < 0.005). The mean number of calls to physicians per patient decreased from 0.83 to 0.45 (p < 0.05). CONCLUSIONS: Treatment with GesTIO protocol allows a safe and effective treatment even in very old and vulnerable inpatients with a faster management insulin therapy.

Herniation of cerebellar tonsils in acromegaly: prevalence, pathogenesis and clinical impact.

Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical, laboratory and neuroimaging findings and its possible pathogenesis and clinical impact. 150 acromegaly patients (median-age 56 years, age-range 21-88, 83 females) underwent brain magnetic resonance imaging (MRI). Clinical data, laboratory and pituitary adenoma imaging findings were recorded. CTH, posterior cranial fossa area, tentorial angle, clivus, supraocciput and Twining's line length were measured in acromegaly patients and controls, who included MRI of 115 consecutive subjects with headache or transient neurological deficits (control group-1) and 24 symptomatic classic Chiari 1 malformation patients (control group-2). Acromegaly patients were interviewed for symptoms known to be related with CTH. 22/150 acromegaly patients (15 %) and 8/115 control group-1 subjects presented with CTH (p = 0.04). In acromegaly patients, CTH correlated positively with younger age and inversely with GH-receptor antagonist treatment. Control group-2 had a shorter clivus than CTH acromegaly patients (40.4 ± 3.2 mm vs 42.5 ± 3.3 mm, p < 0.05), while posterior fossa measures did not differ among acromegaly subgroups (with and without CTH) and control group-1. Headache and vision problems were more frequent in CTH acromegaly patients (p < 0.05); two acromegaly patients presented with imaging and neurological signs of syringomyelia. Despite no signs of posterior fossa underdevelopment or cranial constriction, CTH is more frequent in acromegaly patients and seems to contribute to some disabling neurological symptoms.

Insulin receptor and glucose transporters mRNA expression throughout the menstrual cycle in human endometrium: a physiological and cyclical condition of tissue insulin resistance.

The expression of insulin receptor (IR), together with that of glucose transporters 1 and 4 (GLUT1-4) and of Insulin Growth Factor-I and -II (IGF-I,-II) in the endometrium of healthy and young women in both phases of menstrual cycle was assessed. Sixteen out of 20 healthy and normal menstruating volunteers were studied. Endometrial samplings were performed in every subject, twice in the same cycle, during the follicular and luteal phase respectively. The mRNA expression of IR, GLUT1-4, IGF-I and -II were evaluated by real-time quantitative RT-PCR and immunostaining reactions. Our results indicate that IR, GLUT1-4, IGF-I and -II mRNAs were expressed in both phases of the endometrial cycle: GLUT4 and IGF-I mRNA expression were significantly higher in the follicular phase and localized at the epithelial and stromal cell level, respectively, whereas IR, GLUT1 and IGF-II mRNA expression were mostly present in the secretory phase and mainly localized at the stromal level. An inverse tendency of IR and GLUT4 mRNA expression was respectively observed from follicular to luteal phase. In conclusion our data suggest that IR, glucose transporters and IGFs are significantly and differently expressed at the endometrial level throughout the menstrual cycle and that human endometrium cyclically undergoes through a transitory condition from normal to an insulin-resistance state.

The progression from obesity to type 2 diabetes in Alström syndrome.

BACKGROUND: Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia, and alterations of glucose metabolism that often lead to the development of type 2 diabetes at a young age. OBJECTIVE: To study the relationship between weight and metabolism in a group of ALMS patients and matched controls. RESEARCH DESIGN AND METHODS: Fifteen ALMS patients (eight males, seven females; aged 3-51) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic oral glucose tolerance test (OGTT) conditions were measured. Furthermore, anthropometric and body composition data were obtained from an international group of 27 ALMS patients (13 males, 14 females, age range: 4-29 yr). RESULTS: In ALMS we observed an inverse correlation between age and standard deviation scores for height, weight, and body mass index. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, whereas insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index, HOMA%ß-cell and insulinogenic index in ALMS, but unlike the insulin-resistance indices, the ß-cell function indices showed a significant reduction with age. CONCLUSIONS: In ALMS the progression from the early onset obesity toward the impaired fasting glucose or impaired glucose tolerance and overt diabetes is mostly because of a progressive failure of ß-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.

Ambulatory arterial stiffness indexes in acromegaly.

OBJECTIVE: Acromegaly is associated with increased cardiovascular morbidity and mortality and with specific heart and vascular abnormalities. The aim of our study was to investigate arterial stiffness using the ambulatory arterial stiffness index (AASI) and symmetric AASI (Sym-AASI), two indexes derived from 24-h ambulatory blood pressure monitoring (ABPM), in a group of normotensive and hypertensive patients with active acromegaly, compared with normotensive controls (NOR-CTR) or hypertensive controls (HYP-CTR). SUBJECTS AND METHODS: Ninety-six consecutive patients with active acromegaly (46 males, mean age 49±14 years) underwent 24-h ABPM and evaluation of cardiovascular risk factors. Based on ABPM measurement, acromegalic patients were divided into 64 normotensive (normotensive acromegalic patients (NOR-ACRO)) and 32 hypertensive (hypertensive acromegalic patients (HYP-ACRO)) patients, and were compared with 35 normotensive (NOR-CTR) and 34 hypertensive (HYP-CTR) age-, sex,- and ABPM-matched control subjects. RESULTS: The AASI and Sym-AASI indexes were significantly higher in acromegalic patients than in controls, either in the normotensive (NOR-ACRO vs NOR-CTR, P<0.0001 for AASI and P=0.005 for Sym-AASI) or in the hypertensive (HYP-ACRO vs HYP-CTR, P=0.01 for AASI and P=0.01 for Sym-AASI) group. Multiple logistic regression analysis showed a significant association of the highest AASI tertile with serum IGF1 (P=0.034) in the whole acromegalic group. CONCLUSION: AASIs are increased in acromegaly, independent of blood pressure (BP) elevation, and may have an important role in predicting cardiovascular risk in this disease.

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.

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. METHODS AND FINDINGS: We report a case study on the effects of octreotide on uterine artery blood flow, octreotide concentrations in biological fluids of mother and newborn, and somatostatin (SST) receptor expression and binding at the level of the maternal-foetal barrier tissues in an acromegalic woman treated with short-acting octreotide throughout her pregnancy. An acute decrease in uterine artery blood flow was observed after octreotide injections, without affecting the pregnancy course, delivery, or foetal development. Octreotide concentrations were high in maternal serum and colostrum and lower in umbilical cord serum, amniotic fluid, and newborn serum. All SST receptor subtypes can be expressed in placental tissue but their binding profile was weak both in the placenta and umbilical cord. The child was healthy and developed normally up to age 6 from an anthropometric, metabolic, and endocrine point of view. We reviewed all published reports on pregnancy SSA exposure and outcomes were compared to a time-matched group of acromegalic women not exposed to SSA. No significant effect on the mother or foetus was observed. CONCLUSIONS: Short-acting octreotide appears not to affect the function of the maternal-foetal barrier or foetal development, except for the occurrence of acute, reversible, and clinically irrelevant haemodynamic changes. These data support the feasibility and safety of treatment with short-acting octreotide in acromegalic women during pregnancy and excludes major matters of concern about the effects of this medication on pregnancy itself and its outcome.

Sudden death due to aortic rupture in acromegaly.

Acromegaly, when left untreated, is associated with premature mortality which is chiefly related to cardiovascular complications. We report on a 50-year-old acromegalic woman, resistant to therapy, who died suddenly because of thoracic aortic rupture and massive bleeding into the left pleural space. The postmortem examination disclosed, nearby the point of rupture, a pulmonary abscess as well as extensive intrinsic alteration of arteries originating from the aortic arch and aorta itself, which featured microscopic cystic medial necrosis. We discussed how these aspects could be related to long-term exposition to growth hormone excess. In particular, this case gives further evidence of vascular system frailty in acromegaly.

Risk factors of falls in elderly population in acute care hospitals and nursing homes in north Italy: a retrospective study.

A retrospective comparative study was conducted in Italy to determine whether the risk of accidental falls is the same in acute care hospitals as in nursing homes. Accidental falls were significantly related to women older than 80 years and to a hospital stay 10 days or longer, with an increased risk related to stroke, arterial hypertension, and a Norton Scale score greater than 15. Prevention strategies need to be based on the context and specific intrinsic and extrinsic factors influencing the risk of falls in elderly patients.

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. PATIENTS AND MEASUREMENTS: To characterize the IGF system in ALMS, we evaluated a subset of 15 young adults with ALMS for hepatic, renal and thyroid function. Glycaemic and hormone measurements such as insulin, GH, FSH, LH, testosterone and 17-beta-oestradiol were clinically assessed. In addition, we measured IGF-I, IGF-II, IGF binding-protein-3 (IGFBP-3) and acid labile subunit (ALS - the subunits that constitute the main somatomedin complex in the circulation), and IGFBP-1 and IGFBP-2 (known to influence the bioavailability of the IGFs). RESULTS: A significantly lower height was observed in ALMS patients compared to age-matched controls. ALMS patients were clinically obese (by weight and body mass index (BMI) standards) and leptin levels correlated with BMI. Renal and hepatic dysfunction was implicated in some patients by increased values of blood urea nitrogen (BUN) and creatinine, and transaminases, respectively. One-third of the patients presented with fasting hyperglycaemia and 80% were hyperinsulinaemic. TSH was slightly increased in 20% of patients. Baseline FSH and LH in females were within the normal range, while half of the males had abnormally low testosterone values. Male patients with hypogonadism showed significantly lower testosterone, oestrogen and ALS levels. Baseline GH values were not found to be increased. ALS and IGFBP-1 were significantly reduced and IGFBP-2 was markedly increased in ALMS patients compared to age-matched controls. The IGFs and IGFBPs were not significantly different between males and females affected with ALMS. No significant association was observed between IGFs or IGFBPs levels and weight, height, BMI, glycaemia, hyperinsulinaemia and testosterone levels. However, we found a significant association of gamma-glutamyltransferase (GGT) with IGFBP-2. IGF-I levels were significantly associated with LH in female patients. CONCLUSIONS: In summary, the reduction of ALS and the increase of IGFBP-2 points to a growth hormone deficiency (GHD) condition in ALMS. However, further tests, including GH dynamics, are needed to determine whether, or to what degree disturbances in the GH/IGF axis contribute to the relatively short stature.

Patient education in peritoneal dialysis: an observational study in Italy.

This observational study describes the characteristics of the education programmes used in Italian PD-centres, evaluating a possible relationship between programmes and peritonitis rates. The survey involved 150 non-paediatric public dialysis centres in Italy. The data were collected by a questionnaire and evaluated with SPSS software. Descriptive statistics of synthesis were calculated, Kruskal-Wallis, Wilcoxon's test were used to verify the differences in the replies, and association between variables was tested with Pearson correlation and Pearson's chi2 test. 120 dialysis centres took part in the survey and reported a median incidence of peritonitis of 1/29 months. Training occurs in all the centres, while pre-dialysis education, home visits and re-training take place in 38.3%, 50% and 44.2% respectively. A lower peritonitis rates proves to be correlated to these activities rather than to presence of specialised personnel, to ratio nurses-patients or training time.

Clinical and diagnostic aspects of cystic insulinoma.

Cystic endocrine tumors of the pancreas rarely occur, and only a few cases of cystic insulinoma have been reported to date. Diagnosis of insulinoma could be difficult if the functional activity is incomplete, possibly leading to blunted symptoms of hypoglycemia and failure in the laboratory to provide evidence of hyperinsulinemia. We report a clinical case of cystic insulinoma confirmed by histological examination after surgery, characterized by a high intracystic insulin concentration despite normal blood basal levels of the hormone. New diagnostic findings from dynamic tests and cystic fluid examination have been carefully focused on.

Late potentials and ventricular arrhythmias in acromegaly.

BACKGROUND: Sudden death and increased prevalence of ventricular arrhythmias have already been described in acromegaly. Although late potentials (LPs) have been proved to be a new technique in detecting patients at risk for ventricular tachyarrhythmias its use in acromegaly is still unknown. METHODS: We studied 70 acromegalic patients [32 males, 38 females; age 49+/-12 years (mean+/-S.D.)] and 70 control subjects age- and sex-matched [(35 males and 35 females; 46+/-12 years (mean+/-S.D.)]. Besides hormonal tests, we performed the following cardiovascular investigations: ECG, 24-h ECG Holter monitoring, echocardiography, and signal-averaged ECG (SAECG) time-domain analysis. RESULTS: LPs occurrence was significantly higher in acromegalic patients as compared to the control group (22.9% vs. 2.9%; p=0.001). A greater duration of disease in patients with positive LPs compared to negative ones was pointed out (18 vs. 12 years; p=0.024). In the group of acromegalic patients with positive LPs we observed a significant association with premature ventricular complexes (PVCs) detected by means of 24-h Holter ECG recording (13 out of 15 patients: 86.7%; p=0.024). The positivity or negativity of LPs proved to be significantly associated with Lown scale PVC trends recorded by 24-h Holter ECG (p=0.014). In the group of patients with left ventricular hypertrophy a significant and pathological worsening of SAECG signals (QRS, LAS, RMS) was documented. CONCLUSIONS: We observed a higher prevalence of LPs in acromegaly which significantly correlated with Lown scale of PVCs.

New Alström syndrome phenotypes based on the evaluation of 182 cases.

BACKGROUND: Alström syndrome is a recessively inherited genetic disorder characterized by congenital retinal dystrophy that leads to blindness, hearing impairment, childhood obesity, insulin resistance, and type 2 diabetes mellitus. We provide new details on cardiologic, hepatic, gastrointestinal, urologic, pulmonary, and neurobehavioral phenotypes in Alström syndrome and describe the histopathologic findings in 5 individuals. METHODS: We obtained data on 182 patients from clinical examinations, medical record reviews, standardized questionnaires, and personal interviews with physicians and parents. RESULTS: Dilated cardiomyopathy occurred in 60% of patients. Age at onset was either during infancy, often before vision disturbances were noted, or in adolescence or adulthood. There is a risk of recurrence of infantile cardiomyopathy. Hyperinsulinemia (92%) developed in early childhood and progressed to type 2 diabetes mellitus in 82% of those older than 16 years. Hypertriglyceridemia (54%) precipitated pancreatitis in 8 patients. Urologic dysfunction and gastrointestinal disturbances occurred in 48% and 35% of patients, respectively. Fifty-three percent of patients had persistent pulmonary symptoms. Neurologic symptoms in 20% of patients included clonic tic and absence seizures. Developmental motor or language delays were observed in 46% of patients. Fibrotic infiltrations of multiple organs, that is, kidney, heart, liver, lung, urinary bladder, gonads, and pancreas, were observed. CONCLUSIONS: The wide-ranging and complex spectrum of phenotypes reported herein broadens those previously described for Alström syndrome. These findings will aid physicians in making an early and accurate diagnosis and will help effect appropriate monitoring and treatment.

Somatostatin analogs in vitro effects in a growth hormone-releasing hormone-secreting bronchial carcinoid.

A 29-yr-old woman presented with acromegaly, pituitary gland enlargement, and an isolated pulmonary mass of 3.3 cm in diameter, which displayed a very high tracer uptake after OctreoScan. Plasma GHRH levels were markedly elevated. The patient underwent left lung upper lobectomy, and histopathology disclosed a bronchial atypical carcinoid. The tissue was examined for somatostatin (SRIH) receptor subtypes (SSTRs) 1-5 expression by RT-PCR. Cultured tumor cells were treated with SRIH, lanreotide (BIM-23014), or SRIH analogs selective for SSTR2 (BIM-23120), SSTR5 (BIM-23206), or SSTR1 (BIM-23926). GHRH was measured in the medium after 6 h, and cell viability was assessed after 48 h. RT-PCR analysis showed expression of SSTR1, -2, and -5. GHRH secretion was significantly reduced by SRIH (-50%), Lan (-35%), as well as by the SSTR2, SSTR5, and SSTR1 selective agonists (-55, -75, and -20%, respectively), whereas cell viability was not affected. Our data show SSTR expression in a GHRH-secreting bronchial carcinoid and provide evidence that, in vitro, selective SSTR activation differently inhibit ectopic GHRH secretion. These findings suggest that SSTR-specific SRIH analogs may be useful in the medical therapy of GHRH-secreting bronchial carcinoids.

Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients.

Glucose transporter 4 (GLUT4) seems to be involved in the mechanism of insulin resistance in polycystic ovary syndrome (PCOS) patients (PCOSs) in both muscular and adipose tissue. The observation that insulin stimulates glucose oxidation in endometrial cells led us to investigate the presence of GLUT4 in this tissue and whether a defect of GLUT4 is present at the endometrial level in PCOSs. We also investigated whether body weight influences GLUT4 expression in this syndrome. GLUT4 mRNA content was examined by real-time quantitative RT-PCR and immunostaining reaction in the endometrial tissue of nine normal subjects, nine lean and eight obese hyperinsulinemic (h-INS), and eight lean and 10 obese normoinsulinemic (n-INS) PCOSs. GLUT4 mRNA and its positive immunostaining reaction were present in epithelial cell level in the endometrium of both normal and PCOS subjects. Significantly higher levels of GLUT4 were observed in normal and lean n-INS PCOSs in comparison with other groups. In both n-INS and h-INS obese PCOSs, GLUT4 was significantly lower than in lean subjects. However, obese n-INS and lean h-INS PCOSs showed a similar low GLUT4 expression, whereas obese h-INS PCOSs showed the lowest expression when compared with other groups. In conclusion, our data demonstrate that GLUT4 is present in the endometrium of normal and PCOS subjects and that hyperinsulinism and obesity seem to have a negative effect on endometrial GLUT4 expression in PCOS.