Unit of Endocrinology and Metabolism

Verona, Italy

Unit of Endocrinology and Metabolism

Verona, Italy
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Henquin J.-C.,Unit of Endocrinology and Metabolism | Dufrane D.,Endocrine Cell Therapy Unit | Gmyr V.,Institut Universitaire de France | Kerr-Conte J.,Institut Universitaire de France | Nenquin M.,Unit of Endocrinology and Metabolism
Diabetes, Obesity and Metabolism | Year: 2017

Aims: To understand better the control of insulin secretion by human β cells and to identify similarities to and differences from rodent models. Methods: Dynamic insulin secretion was measured in perifused human islets treated with pharmacological agents of known modes of action. Results: Glucokinase activation (Ro28-1675) lowered the glucose threshold for stimulation of insulin secretion to 1mmol/L (G1), augmented the response to G3-G5 but not to G8-G15, whereas tolbutamide remained active in G20, which indicates that not all KATP channels were closed by high glucose concentrations. An almost 2-fold greater response to G15 than to supramaximal tolbutamide in G3 or to KCl+diazoxide in G15 vs G3 quantified the contribution of metabolic amplification to insulin secretion. Both disruption (latrunculin-B) and stabilization (jasplakinolide) of microfilaments augmented insulin secretion without affecting metabolic amplification. Tolbutamide-induced insulin secretion was consistently greater in G10 than G3, with a threshold at 1 and maximum at 10μmol/L tolbutamide in G10, vs 10 and 25μmol/L in G3. Sulphonylurea effects were thus clearly glucose-dependent. Insulin secretion was also increased by inhibiting K channels other than KATP channels: Kv or BK channels (tetraethylammonium), TASK-1 channels (ML-365) and SK4 channels (TRAM-34). Opening KATP channels with diazoxide inhibited glucose-induced insulin secretion with half maximum inhibitory concentrations of 9.6 and 24μmol/L at G7 and G15. Blockade of L-type Ca channels (nimodipine) abolished insulin secretion, whereas a blocker of T-type Ca channels (NNC-55-0396) was ineffective at specific concentrations. Blockade of Na channels (tetrodotoxin) did not affect glucose-induced insulin secretion. Conclusions: In addition to sharing a KATP channel-dependent triggering pathway and a metabolic amplifying pathway, human and rodent β cells were found to display more similarities than differences in the control of insulin secretion. © 2017 John Wiley & Sons Ltd.

Fabris M.,Institute of Clinical Pathology | Tonutti E.,Laboratory of Immunopathology and Allergy | Panighel C.,Unit of Endocrinology and Metabolism | Blasone N.,Laboratory of Immunopathology and Allergy | And 7 more authors.
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2011

Aim of the study: B-Lymphocyte Stimulator (BLyS), a key regulator of B-cell homeostasis, was recently involved in the regulation of malignant cell survival in both hematological and non-hematological cancers. In this study we analyzed the possible role of BLyS in neuroendocrine tumors (NET). Methods: Sixty-two consecutive unselected patients with a diagnosis of NET were enrolled in the study. According to the clinical course, patients were classified in 3 subgroups: patients with evidence of persistent but stable disease (n = 19), patients in remission (n = 13) and patients with evidence of recurrent disease (progressive patients, n = 30). Patients were compared to 77 sex-matched blood donors (HBDs). BLyS and Chromogranin A (CgA) serum levels were analyzed by ELISA. Results: Overall, NET patients presented more elevated BLyS levels than HBDs (1195± 568 pg/ml vs 666±240 pg/ml; p <0.0001) and BLyS levels correlated with tumor differentiation. Patients with stable disease or in remission presented with significant lower BLyS levels than patients with disease progression (906±273 pg/ml versus 1503±637 pg/ml; p <0.0001). Patients with metastases displayed higher BLyS levels than patients without metastases (1391±724 pg/ml versus 1079±422 pg/ml; p=0.022). Of note, BLyS levels during the follow-up (after 6.6±2.8 months) demonstrated a significant increase in progressive patients (from 1576±927 pg/ml to 2003±1268 pg/ml; p=0.0107), while remained substantially unchanged in stable/remission cases (from 1103±427 pg/ml to 1060±400 pg/ml; p=0.52). In contrast, CgA in the same series showed contradictory changes. Conclusions: Elevated BLyS levels characterized patients with NET and BLyS appears as a new potential marker in the management of these neoplastic diseases. © 2011 Bentham Science Publishers.

Gentile S.,2nd University | Agrusta M.,Cava Of Tirreni And Amalfi Coast Hospital | Guarino G.,2nd University | Carbone L.,2nd University | And 3 more authors.
Acta Diabetologica | Year: 2011

Only few insulin-treated (IT) people with diabetes mellitus (DM) reach the target due to poor compliance and/or to sedentary lifestyle and/or to inadequate treatment regimen. The latter may be also brought about by often overlooked factors including insulin injection into altered skin areas, often brought about by incorrect habits, namely needle reutilization or poor compliance to the suggestion to continuously rotate skin injection areas. The aim of our study was to evaluate the rate of skin lesions within the sites commonly used for insulin injection in our IT DM patients and to verify whether a short-acting insulin analogue yielded different metabolic effects when injected in altered vs. normal skin areas. One hundred and eighty well-trained IT people with type 1 and type 2 DM (64 ± 15 years of age) consecutively referring to our unit underwent a standard clinical examination involving an accurate skin inspection protocol meant at looking for any alterations eventually affecting all possible injection sites, including bruising, multiple needle pricks and lipodystrophic nodules (LN). They were also tested for HPLC HbA1c determination and asked to fill in a standard questionnaire on injection habits. Furthermore, seven male, T1DM glulisine-glargine basal-bolus-treated patients in this group were randomly injected 10 IU glulisine into either normal skin (NS) or an LN by a nurse before a standard, 405 kcal breakfast, for blood glucose and free insulin determination at 0, 30, 45, 60, 75, 90, 120 and 150 min. More lesions were found in people over sixty (P < 0.01) and in women (P < 0.05). A higher prevalence of HbA1c >7.5% was found in patients with lesions (with an O.R. of 3.74) and further confirmed by data obtained from head-to-head comparison of insulin injection into an LN and NS. In fact, injection into an LN proved to impair and slow down insulin absorption, resulting in a higher absolute value and a larger variability of blood glucose levels than those observed by utilizing NS. This suggests us to pay more attention to all aspects of patient-team relationship to try and obtain good metabolic control in all people with diabetes and even more in the elderly. © 2010 Springer-Verlag.

Costanzo P.,University of Naples Federico II | Costanzo P.,University of Hull | Cleland J.G.,University of Hull | Atkin S.L.,Unit of Endocrinology and Metabolism | And 2 more authors.
Current Treatment Options in Cardiovascular Medicine | Year: 2012

Opinion statement: Although carotid intima-media thickness (IMT) has been broadly used as a tool to evaluate cardiovascular risk, its role as a surrogate endpoint is still debated. The main issue is the fact that no study has ever been powered to show a relationship between changes in carotid IMT during follow-up and cardiovascular events. A meta-analysis of existing clinical studies was performed to investigate this relationship but it failed to demonstrate a predictive role of regression in carotid IMT for cardiovascular events. The reasons for the lack of a clear evidence for a predictive role of IMT progression are unknown but are likely multifactorial. Firstly, it may depend on the fact that this index is not a pure atherosclerosis index. Second, carotid atherosclerosis does not always reflect coronary atherosclerosis. Furthermore, methodologic problems related to intra- and interobserver variability make this index not adequately reproducible when tracking the progression of carotid atherosclerosis. A further meta-analysis based on individual patient data, instead of published data, has been planned to better address the predictive role of IMT. Lastly, in the future, the variability of ultrasound measurements of carotid IMT are likely to be reduced by further development of automatic calculation of this index by magnetic resonance imaging. © 2011 Springer Science+Business Media, LLC.

Cicero A.F.G.,University of Bologna | Magni P.,University of Milan | More M.,Unit of Endocrinology and Metabolism | Ruscica M.,University of Milan | And 4 more authors.
International Journal of Endocrinology | Year: 2011

We evaluated the association of the sex hormone pattern and the serum level of the main adipokines to metabolic syndrome (MS) and its components in 199 pharmacologically untreated subjects. Men and women included in the age-class subgroups were matched for body mass index, waist circumference, blood pressure, heart rate, fasting plasma glucose, and plasma lipids. Men without MS had significantly lower leptin/adiponectin ratio than men with MS. Women without MS had lower leptin and leptin/adiponectin ratio than women with MS but had significantly higher adiponectin, estrone, and dehydroepiandrosterone levels. In men, the leptin/adiponectin ratio is the main factor associated to MS diagnosis (OR: 3.36, 95 CI 1.40-8.08), while in women adiponectin alone appears to be a protective factor (OR: 0.87, 95 CI 0.79-0.95). In conclusion, in a sample of pharmacologically untreated subjects, leptin/adiponectin ratio seems to be the factor more strongly associated to MS and its components. Copyright © 2011 Arrigo F. G. Cicero et al.

Bacchi E.,University of Verona | Negri C.,Unit of Endocrinology and Metabolism | Tarperi C.,University of Verona | Baraldo A.,University of Verona | And 8 more authors.
Acta Diabetologica | Year: 2014

Factors contributing to the reduced cardiorespiratory fitness typical of sedentary subjects with type 2 diabetes are still largely unknown. In this study, we assessed the relationships between cardiorespiratory fitness and abdominal and skeletal muscle fat content in 39 untrained type 2 diabetes subjects, 27 males and 12 females (mean ± SD age 56.5 ± 7.3 year, BMI 29.4 ± 4.7 kg/m2). Peak oxygen uptake (VO2peak) and ventilatory threshold (VO2VT) were assessed by maximal cycle ergometer exercise test, insulin sensitivity by euglycemic-hyperinsulinemic clamp, and body composition by dual-energy X-ray absorptiometry. Magnetic resonance imaging was used to evaluate visceral, total subcutaneous (SAT), superficial (SSAT) and deep sub-depots of subcutaneous abdominal adipose tissue, and sagittal abdominal diameter (SAD), as well as femoral quadriceps skeletal muscle fat content. In univariate analysis, both VO2peak and VO 2VT were inversely associated with BMI, total fat mass, SAT, SSAT, and sagittal abdominal diameter. VO2peak was also inversely associated with skeletal muscle fat content. A significant direct association was observed between VO2VT and insulin sensitivity. No associations between cardiorespiratory fitness parameters and metabolic profile data were found. In multivariable regression analysis, after adjusting for age and gender, VO2peak was independently predicted by higher HDL cholesterol, and lower SAD and skeletal muscle fat content (R2 = 0.64, p < 0.001), whereas VO2VT was predicted only by sagittal abdominal diameter (R2 = 0.48, p = 0.025). In conclusion, in untrained type 2 diabetes subjects, peak oxygen uptake is associated with sagittal abdominal diameter, skeletal muscle fat content, and HDL cholesterol levels. Future research should target these features in prospective intervention studies. © Springer-Verlag 2013.

Negri C.,Unit of Endocrinology and Metabolism | Bacchi E.,University of Verona | Morgante S.,Unita Locale Socio Sanitaria ULSS | Soave D.,Unita Locale Socio Sanitaria ULSS | And 8 more authors.
Diabetes Care | Year: 2010

OBJECTIVE - To evaluate the impact of an exercise program organized into supervised walking groups in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS - Fifty-nine diabetic subjects were randomized to a control group receiving standard lifestyle recommendations or an intervention group assigned to three supervised walking sessions per week and counseling. Changes in metabolic features, weight, 6-min walk test, prescription of antidiabetic medications, and overall physical activity were assessed. RESULTS - Functional capacity and overall physical activity were higher in the intervention group, whereas metabolic changes were not different between groups after 4 months. However, in subjects who attended at least 50% of scheduled walking sessions, changes in A1C and fasting glucose were greater than in control subjects. Discontinuation or reduction of antidiabetic drugs occurred in 33% of these patients versus 5% of control subjects (P < 0.05). CONCLUSIONS - Supervised walking may be beneficial in diabetic subjects, but metabolic improvement requires adequate compliance. © 2010 by the American Diabetes Association.

PubMed | Unit of Endocrinology and Metabolism, University of Munster and University of Modena and Reggio Emilia
Type: Journal Article | Journal: European thyroid journal | Year: 2014

Thyroidectomized patients need variable doses of levothyroxine (LT4) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated.We hypothesized that genetic variants of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to thyroid hormone feedback.We retrospectively analyzed 84 thyroidectomized patients with no residual thyroid function and undetectable thyroglobulin levels. Patients were evaluated under LT4 resulting in TSH levels detectable but <0.5 IU/ml. The two SNPs rs3134105 and rs3110040 were identified as informative markers of the TRHR gene. Genotyping was performed using high-resolution melting technology. Genotype distribution was compared between the patients and 99 euthyroid controls.The selected SNPs were in linkage disequilibrium and only rs3134105 was further considered. A significant difference between the three possible genotypes for rs3134105 was found for TSH (p = 0.04) and free thyroxine (fT4)/TSH ratio (p = 0.02). Moreover, despite similar serum concentrations of free triiodothyronine (fT3) and fT4, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (p = 0.01) as well as higher fT3/TSH (p = 0.01) and fT4/TSH ratios (p < 0.01).We demonstrated an association between serum TSH levels and discrete alleles of the TRHR gene in totally thyroidectomized patients under LT4 therapy. Therefore, the TRHR gene seems to be a determinant of hypothalamo-pituitary sensitivity to LT4.

Nenquin M.,Unit of Endocrinology and Metabolism | Henquin J.-C.,Unit of Endocrinology and Metabolism
Diabetes, Obesity and Metabolism | Year: 2016

Amplification of insulin secretion by cyclic AMP involves activation of protein kinase A (PKA) and Epac2 in pancreatic β cells. Recent hypotheses suggest that sulphonylurea receptor-1 (SUR1), the regulatory subunit of ATP-sensitive potassium channels, is implicated in Epac2 effects and that direct activation of Epac2 by hypoglycaemic sulphonylureas contributes to the stimulation of insulin secretion by these drugs. In the present experiments, using islets from Sur1KO mice, we show that dibutyryl-cAMP and membrane-permeant selective activators of Epac or PKA normally amplify insulin secretion in β cells lacking SUR1. In contrast to Epac activator, sulphonylureas (glibenclamide and tolbutamide) did not increase insulin secretion in Sur1KO islets, as would be expected if they were activating Epac2 directly. Furthermore, glibenclamide and tolbutamide did not augment the amplification of insulin secretion produced by Epac activator or dibutyryl-cAMP. Collectively, the results show that SUR1 is dispensable for amplification of insulin secretion by Epac2 activation and that direct activation of Epac2 is unimportant for the action of therapeutic concentrations of sulphonylureas in β cells. © 2015 John Wiley & Sons Ltd.

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