Effectiveness of oral semaglutide on glucose control and body weight up to 18 months: a multicenter retrospective real-world study.

AIM: Oral semaglutide, an innovative orally administered GLP-1 receptor agonist for type 2 diabetes (T2D) management was herein evaluated for its effectiveness in a multi-center retrospective real-world study. METHODS: We included new-users of oral semaglutide from 18 specialist care centres and collected retrospective data on baseline clinical characteristics. Updated values of HbA1c and body weight were analyzed using the mixed model for repeated measures. RESULTS: The study included 166 individuals with T2D, predominantly men (64.5%), with a mean age of 64.4 years and a mean diabetes duration of 10.1 years. In the majority of patients (68.3%) oral semaglutide was used as a second-line drug, mostly with metformin. At baseline, mean BMI was 28.9 kg/m2 and HbA1c was 7.5%. During the 18-month observation period, oral semaglutide demonstrated significant reductions in HbA1c, with a maximum change of - 0.9%, and 42.1% of patients achieved HbA1c values below 7.0%. Additionally, there was a substantial reduction in body weight, with an estimated change of - 3.4 kg at 18 months, and 30.3% of patients experienced a 5% or greater reduction in baseline body weight. Only 24.2% of patients reached the 14 mg dose. Subgroup analysis revealed that baseline HbA1c > 7%, persistence on drug, not being on a prior therapy with DPP-4 inhibitors, and loosing 5% or more the initial body weight were associated with greater HbA1c reductions. CONCLUSION: This study supports oral semaglutide as an effective option for T2D treatment, offering improved glucose control and weight management in a real-world setting.

Blood glucose and epicardial adipose tissue at the hospital admission as possible predictors for COVID-19 severity.

PURPOSE: To study the possible association of CT-derived quantitative epicardial adipose tissue (EAT) and glycemia at the admission, with severe outcomes in patients with COVID-19. METHODS: Two hundred and twenty-nine patients consecutively hospitalized for COVID-19 from March 1st to June 30th 2020 were studied. Non contrast chest CT scans, to confirm diagnosis of pneumonia, were performed. EAT volume (cm3) and attenuation (Hounsfield units) were measured using a CT post-processing software. The primary outcome was acute respiratory distress syndrome (ARDS) or in-hospital death. RESULTS: The primary outcome occurred in 56.8% patients. Fasting blood glucose was significantly higher in the group ARDS/death than in the group with better prognosis [114 (98-144) vs. 101 (91-118) mg/dl, p = 0.001]. EAT volume was higher in patients with vs without the primary outcome [103 (69.25; 129.75) vs. 78.95 (50.7; 100.25) cm3, p < 0.001] and it was positively correlated with glycemia, PCR, fibrinogen, P/F ratio. In the multivariable logistic regression analysis, age and EAT volume were independently associated with ARDS/death. Glycemia and EAT attenuation would appear to be factors involved in ARDS/death with a trend of statistical significance. CONCLUSIONS: Our findings suggest that both blood glucose and EAT, easily measurable and modifiable targets, could be important predisposing factors for severe Covid-19 complications.

Weight Regain and Diabetes Evolution After Sleeve Gastrectomy: a Cohort Study with over 5 Years of Follow-Up.

BACKGROUND: A number of meta-analyses have demonstrated the effectiveness of bariatric surgery in improving morbid obesity and its associated co-morbidities. The aim of the study was to evaluate at long term a cohort of obese patients with type 2 diabetes (T2DM) submitted to laparoscopic sleeve gastrectomy (LSG) analyzing the incidence of weight regain (WR) and the impact of the WR on T2DM evolution. METHODS: Seventy-eight morbid obese patients (54 females) with T2DM, aged 49.6 ± 8.7 years, weight 121.1 ± 24.4 kg, BMI 44.1 ± 7.2 kg/m2, underwent primary LSG. The trend over time of T2DM after LSG was analyzed in the different groups, subdivided on the basis of the absence or presence of WR and of its different degrees: no regain (NR), mild regain (MR), and severe regain (SR) groups. RESULTS: In the NR group, 54% show complete remission, 46% persistence, and no case of diabetes relapse; in the MR group, 59% show complete remission, 36% persistence, and 5% relapse; in the SR group, 61% show complete remission, 22% persistence, and 17% relapse. A statistically significant difference concerns the preoperative values of fasting glucose, glycosylated hemoglobin, and duration of diabetes, major in the group with diabetes relapse (respectively, p = 0.002, p = 0.001, and p < 0.0001). CONCLUSIONS: The results of this study showed no significant difference regarding the trend of diabetes remission comparing the "no regain," "mild regain," and "severe regain" groups and confirmed the importance of the duration of the illness and an early intervention towards surgical therapy.

ANGPTL4 gene E40K variation protects against obesity-associated dyslipidemia in participants with obesity.

OBJECTIVE: ANGPTL4 inhibits lipoprotein lipase in adipose tissue, regulating plasma triglycerides levels. In persons with obesity plasma ANGPTL4 levels have been positively correlated with body fat mass, TG levels and low HDL. A loss-of-function E40K mutation in ANGPTL4 prevents LPL inhibition, resulting in lower TGs and higher HDLc in the general population. Since obesity determines metabolic alterations and consequently is a major risk factor for cardiovascular disease, the aim was to explore if obesity-related metabolic abnormalities are modified by the ANGPTL4-E40K mutation. METHODS: ANGPTL4-E40K was screened in 1206 Italian participants, of which 863 (71.5%) with obesity. All subjects without diabetes underwent OGTT with calculation of indices of insulin-sensitivity. RESULTS: Participants with obesity carrying the E40K variant had significantly lower TG (p = 0.001) and higher HDLc levels (p = 0.024). Also in the whole population low TGs and high HDLc were confirmed in E40K carriers. In the obese subpopulation it was observed that almost all E40K carriers were within the lowest quartile of TGs (p = 1.1 × 10-9). E40K had no substantial effect of on glucose metabolism. Finally, none of the obese E40K carriers had T2D, and together with the favourable lipid profile, they resemble a metabolically healthy obese (MHO) phenotype, compared to 38% of E40E wild-type obese that had diabetes and/or dyslipidaemia (p = 0.0106). CONCLUSIONS: In participants with obesity the ANGPTL4-E40K variant protects against dyslipidemia. The phenotype of obese E40K carriers is that of a patient with obesity without metabolic alterations, similar to the phenotype described as metabolic healthy obesity.

Mapping ligand binding pockets in chloride ClC-1 channels through an integrated in silico and experimental approach using anthracene-9-carboxylic acid and niflumic acid.

BACKGROUND AND PURPOSE: Although chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is limited. ClC-1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC-1 blockers have been discovered, such as anthracene-9-carboxylic acid (9-AC) and niflumic acid (NFA), whereas no activator exists. The absence of a ClC-1 structure and the limited information regarding the binding pockets in CLC channels hamper the identification of improved modulators. EXPERIMENTAL APPROACH: Here we provide an in-depth characterization of drug binding pockets in ClC-1 through an integrated in silico and experimental approach. We first searched putative cavities in a homology model of ClC-1 built upon an eukaryotic CLC crystal structure, and then validated in silico data by measuring the blocking ability of 9-AC and NFA on mutant ClC-1 channels expressed in HEK 293 cells. KEY RESULTS: We identified four putative binding cavities in ClC-1. 9-AC appears to interact with residues K231, R421 and F484 within the channel pore. We also identified one preferential binding cavity for NFA and propose R421 and F484 as critical residues. CONCLUSIONS AND IMPLICATIONS: This study represents the first effort to delineate the binding sites of ClC-1. This information is fundamental to discover compounds useful in the treatment of ClC-1-associated dysfunctions and might represent a starting point for specifically targeting other CLC proteins.

The vitamin D receptor (VDR) gene rs11568820 variant is associated with type 2 diabetes and impaired insulin secretion in Italian adult subjects, and associates with increased cardio-metabolic risk in children.

BACKGROUND AND AIMS: 1α,25-dihydroxyvitamin-D3, the biologically active vitamin D, plays a central role in several metabolic pathways through the binding to the vitamin D receptor (VDR). VDR has been shown to be involved in cardiovascular diseases, cancer, autoimmunity and type 2 diabetes mellitus (T2DM). Several polymorphisms in the VDR gene have been described. Among these, the rs11568820 G-to-A nucleotide substitution was found to be functional, modulating the transcription of the VDR gene. Objective of this study was to perform an association study between rs11568820 polymorphism and T2DM in a cohort of Italian adults with T2DM and in non-diabetic controls. To add further insight into the role of VDR gene we explored whether this association begins early in life in overweight/obese children, or becomes manifest only in adulthood. METHODS AND RESULTS: As many as 1788 adults and 878 children were genotyped for the rs11568820 polymorphism. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin-resistance and secretion were also calculated. The AA genotype was significantly more frequent in adults with T2DM compared to controls (7.5% vs. 4.6%, P = 0.037), and conferred a higher risk of T2DM (ORHom = 1.69C.I. = [1.13-2.53], P = 0.011). In the adult cohort, rs11568820 was also associated with reduced indices of ß-cell insulin secretion. In children, the AA genotype was associated with 2 h high-normal glucose, a marker of cardio-metabolic risk. CONCLUSIONS: Our study demonstrates for the first time that VDR gene AA carriers have higher risk of T2DM and impaired insulin secretion. In children, the association between AA homozygous and high-normal 2h glucose suggests that mild alterations associated with this genotype may appear early in life.

Assessing the association between 25-OH vitamin D levels and ROMA score in a population of obese women.

The “Risk of Malignancy Algorithm” (ROMA) combines the diagnostic power of the CA125 and HE4 markers with menopausal status to predict the risk for developing epithelial ovarian cancer (EOC). The aim of this study was to evaluate the association between 25-OH vitamin D levels and ROMA score in obese women. One hundred and eighteen patients with a Body Mass Index (BMI) > 30 kg/m2 (Group 1) and 80 women with a BMI less than 25 kg / m² (Group 2) were studied. The 25-OH vitamin D was quantified with LUMIPULSE® G 1200. As a threshold value, identified by ROC curve analysis, 20.2 ng/ mL (sensitivity 73.3%, specificity 84%) was chosen corresponding to the limit between sufficient and insufficient 25-OH vitamin D according to the World Health Organization (WHO). Low 25-OH vitamin D levels were observed in 64% of obese women and in 11% of normal-weight women (p less than 0.001). ROMA score above 13% was detected only in obese women (19%). An association between low levels of 25-OH vitamin D and ROMA score was observed. Indeed, 64% of obese women with ROMA score >13% had concomitant insufficient levels of 25-OH vitamin D, while only 36% of obese women with ROMA score >13% had sufficient 25-OH vitamin D levels (p less than 0.0001). This study suggests that the deficiency of 25- OH vitamin D in obese women has a possible correlation with high ROMA score.

The "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes": Study protocol.

BACKGROUND AND AIMS: The rate of mortality in diabetic patients, especially of cardiovascular origin, is about twice as much that of nondiabetic individuals. Thus, the pathogenic factors shaping the risk of mortality in such patients must be unraveled in order to target intensive prevention and treatment strategies. The "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes" is aimed at identifying new molecular promoters of mortality and major vascular events in patients with type 2 diabetes mellitus (T2DM). METHODS/DESIGN: The "SUMMER study in diabetes" is an observational, prospective, and collaborative study conducted on at least 5000 consecutive patients with T2DM, recruited from several diabetes clinics of Central-Southern Italy and followed up for a minimum of 5 years. The primary outcome is all-cause mortality; the secondary outcomes are cardiovascular mortality, acute myocardial infarction, stroke, and dialysis. A biobank will be created for genomic, transcriptomic, and metabolomic analysis, in order to unravel new molecular predictors of mortality and vascular morbidity. DISCUSSION: The "SUMMER study in diabetes" is aimed at identifying new molecular promoters of mortality and major vascular events in patients with T2DM. These novel pathogenic factors will most likely be instrumental in unraveling new pathways underlying such dramatic events. In addition, they will also be used as additional markers to increase the performance of the already existing risk-scoring models for predicting the above-mentioned outcomes in T2DM, as well as for setting up new preventive and treatment strategies, possibly tailored to specific pathogenic backgrounds. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02311244; URL https://clinicaltrials.gov/ct2/show/NCT02311244?term=SUMMER&rank=5.

Axis II disorders, body image and childhood abuse in bariatric surgery candidates.

BACKGROUND AND AIMS: Psychiatric disorders are common in obese patients and they are often considered contraindications for bariatric surgery. In this patients Axis I profile has been widely investigated, while only few studies on Axis II profile are reported. Aim of the study was to examine the prevalence of Axis II psychopathology, to describe the typical body image and to evaluate the prevalence of childhood abuse in bariatric surgery candidates. MATERIALS AND METHODS: A total of 102 consecutive obese patients (77 females) were evaluated by the Structured Clinical Interview for DSM IV which assessed Axis I Disorders. After the exclusion of Axis I Disorders, 50 patients (36 females, BMI: 44.68 ± 9.48 Kg/m2, age: 44.5 ± 11.7 years) were enrolled. All 50 patients received a psychiatric assessment including the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II); the Body Uneasiness Test, part a (BUT-A), which assesses body image disorders; the Childhood Trauma Questionnaire (CTQ) as a screening test of childhood maltreatment histories. RESULTS: Nineteen patients (38%) were affected by Axis II disorders. Cluster C disorders, including avoidant, dependent and obsessive-compulsive personality disorders, represented the most common diagnosis (24%). Moreover, 34 patients (68%) showed body image disorders (BID), with a GSI score ≥1.2 and 24 (48%) referred an abuse during childhood. Patients with Axis II disorder or a body image uneasiness or a history of maltreatment during childhood, showed higher BMI in adulthood. CONCLUSIONS: Psychiatric comorbidities in obese patients were not only represented by depression or anxiety (Axis I disorders), but also by personality disorders (Axis II), body image disorders and childhood abuse. The identification of these conditions could improve outcomes of bariatric surgery and represent an indication for a most important psychiatric support before, during and after surgery.

Is type 2 diabetes really resolved after laparoscopic sleeve gastrectomy? Glucose variability studied by continuous glucose monitoring.

The study was carried out on type 2 diabetic obese patients who underwent laparoscopic sleeve gastrectomy (LSG). Patients underwent regular glycemic controls throughout 3 years and all patients were defined cured from diabetes according to conventional criteria defined as normalization of fasting glucose levels and glycated hemoglobin in absence of antidiabetic therapy. After 3 years of follow-up, Continuous Glucose Monitoring (CGM) was performed in each patient to better clarify the remission of diabetes. In this study, we found that the diabetes resolution after LSG occurred in 40% of patients; in the other 60%, even if they showed a normal fasting glycemia and A1c, patients spent a lot of time in hyperglycemia. During the oral glucose tolerance test (OGTT), we found that 2 h postload glucose determinations revealed overt diabetes only in a small group of patients and might be insufficient to exclude the diagnosis of diabetes in the other patients who spent a lot of time in hyperglycemia, even if they showed a normal glycemia (<140 mg/dL) at 120 minutes OGTT. These interesting data could help clinicians to better individualize patients in which diabetes is not resolved and who could need more attention in order to prevent chronic complications of diabetes.

TSH levels are associated with vitamin D status and seasonality in an adult population of euthyroid adults.

A circannual periodicity in thyrotropin (TSH) secretion has been reported but the causes of these phenomenon are still undefined. Vitamin D exerts a direct influence on pituitary axes including the hypothalamus-pituitary-thyroid axis. Aims of the present study were to investigate the presence of a seasonal variability of TSH secretion and to study the association between vitamin D status and TSH levels in a population of euthyroid adults. For this purpose, we recruited 294 euthyroid adults (M/F 133/161, 48.5 ± 12.4 years). Study participants underwent clinical examination and routine biochemistry assessment. Vitamin D deficiency was diagnosed for serum 25(OH) vitamin D <25 nmol/l. Significantly higher TSH levels were found in subjects who underwent blood sampling during the Autumn-Winter compared with individuals evaluated in Spring-Summer (2.3 ± 1.3 vs. 1.8 ± 1.1 µIU/ml, p = 0.03). Vitamin D deficiency was strongly associated with higher TSH levels (p = 0.01) after adjusting for sex, age, and sample's season. Although vitamin D deficiency was also associated with metabolic syndrome and its components, the association between TSH levels and vitamin D status persisted also considering these confounders. These data reveal the occurrence of seasonal variability of serum TSH concentration in euthyroid subjects and provide evidence for the first time that an association exists between vitamin D status and serum TSH levels.

Peripheral nociceptor sensitization mediates allodynia in patients with distal symmetric polyneuropathy.

Patients with painful neuropathy frequently complain of pain in response to normally non-painful brushing, namely dynamic mechanical allodynia. Despite many animal studies suggesting that allodynia arises when the spontaneous firing in damaged nociceptive afferents sensitise second-order nociceptive neurons to Aß-fibre input, no studies have sought to confirm this mechanism by investigating Aß-fibre sparing in human patients with allodynia. In this study we compared data from Aß-fibre-mediated nerve conduction studies and nociceptive-fibre-mediated laser-evoked potentials (LEPs) in 200 patients with distal symmetric polyneuropathy (114 with neuropathic pain, 86 without). Of the 114 patients with painful neuropathy studied, 44 suffered from allodynia. Whereas no statistical difference was found in nerve conduction study data between patients with and without allodynia, LEP amplitudes were larger in patients with allodynia than in those without (P < 0.01 by Mann-Whitney U test). The lack of difference in NCS data between patients with and without allodynia suggest that this type of pain, rather than arising through second-order nociceptive neuron sensitization to Aß-fibre input, might reflect a reduced mechanical threshold in sensitised intraepidermal nociceptive nerve terminals.

Costs of treatment and complications of adult type 1 diabetes.

BACKGROUND AND AIMS: Costs associated with diabetes represent a large burden for patients and the health-care system. However, few studies examined the costs for diabetes treatment in adults with type 1 diabetes (T1DM). This analysis was aimed to assess the costs of treatment associated with T1DM among adults in Italy from the national health-care system perspective. METHODS AND RESULTS: Data were collected using a questionnaire assessing resource consumption retrospectively (drugs, visits, diagnostics, hospitalisations and self-monitoring of blood glucose (SMBG)). One-year costs were calculated for the 12 months preceding the survey. Cost estimation, referred to 2006, was carried out using univariate and multivariate Poisson regression models. Fifty-eight centres enrolled 1193 patients (49.5% women; aged between 18 and 55 years, average diabetes duration was 16.1 ± 9.8 years). The average annual cost for an adult patient with TDM1 was € 2450 (95% confidence interval (CI): 2358-2544). Insulin therapy and SMBG accounted together for 71.2% of total costs (35.6% and 35.6%, respectively); the remainder was shared by hospitalisations (18%), visits (4.0%), diagnostics (3.9%) and other drugs (2.9%). Univariate analyses showed that the presence of complications was associated with excess of costs, mainly related to the hospitalisation and drugs. Multivariate analyses confirmed these results showing that the presence of micro-vascular plus macrovascular complications doubles the cost of treatment. CONCLUSION: Strategies of care for T1DM that can improve disease management and prevent or delay the onset of complications could represent the most important tool to reduce costs in the long term while improving clinical outcomes and quality of life.

Laparoscopic gastric sleeve and micronutrients supplementation: our experience.

Background. Laparoscopic gastric sleeve (LGS) has been recently introduced as a stand-alone, restrictive bariatric surgery. Theoretically, LGS attenuates micronutrients deficiencies and associated complications that were typically observed following malabsorptive procedures. The aim of this study was to assess some micronutrients and mineral deficiencies in patients undergoing LGS. Methods. In the period between July 2008 and April 2010, 138 obese patients (110 females and 28 males) with mean BMI 44.4 kg/m(2) ± 6.5, mean age 43.9 ± 10.9 years were enrolled and underwent LGS. Patients were followed up with routine laboratory tests and anthropometric measurements and assessed for nutritional status, as regards vitamin B12, folic acid, iron, hemoglobin, calcium, and vitamin D, every three months throughout 12 months. Results. 12 months after sleeve, patients did not show iron deficiency and/or anemia; plasma calcium levels were in the normal range without supplementation from the sixth month after the operation. Vitamin B12 and folic acid were adequately supplemented for all the follow-up period. Vitamin D was in suboptimal levels, despite daily multivitamin supplementation. Conclusion. In this study, we showed that LGS is an effective surgery for the management of morbid obesity. An adequate supplementation is important to avoid micronutrients deficiencies and greater weight loss does not require higher dosage of multivitamins.

Estimation of the binding free energy by Linear Interaction Energy models.

Since Hansch's extra thermodynamic multi-parameter approach, originally coined as Linear Free Energy Relationship, great efforts in medicinal chemistry have been made to properly estimate the binding free energy. Despite the often small amount, its value is however very critical in determining a successful binding. As a result, its correct estimation may provide a guide for a prospective rational drug design. The calculation of the absolute binding free energies is however a very challenging task as it requires a rigorous treatment of a number of physical terms that are both very time demanding and to some extent not immediately interpretable. In view of this, the introduction of some numerical approximations has permitted to develop the so called Linear Interaction Energy method that, at present, constitutes the best compromise among accuracy, speed of computation and easy interpretation. The initially developed Linear Interaction Energy method was subsequently revisited and several important improvements have been made. Significant examples are the Extended Linear Response, the surface generalized Born LIE, the molecular mechanics generalized Born surface area, the linear interaction energy in continuum electrostatics as well as its quantum mechanics variant. Principles and selected applications of these methods will be herein reviewed.

New strategies in the chemotherapy of leukemia: eradicating cancer stem cells in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the Philadelphia-positive chromosome deriving from a translocation between chromosomes 22 and 9. The oncogenic product of this aberrant chromosome is the constitutively active tyrosine kinase BCR-ABL that is responsible for leukemic cell growth, proliferation and survival driven by the dysregulation of a large array of signal transduction pathways. Inhibition of BCR-ABL with tyrosine kinase inhibitors proved to be an efficient therapy of CML in the chronic phase. Unfortunately, the impressive success of BCR-ABL inhibitors as front-line therapy in CML has been tempered by problems of disease persistence or relapse arising from different mechanisms, including mutations in the kinase domain of the enzyme BCRABL and mechanisms independent from BCR-ABL activity. Growing evidence has also suggested a pivotal role of persistent leukemic cancer stem cells, characterized by high self-renewal and pluripotency, in CML maintenance and/or relapse. The present review deals with the most recent advances in this challenging field and focuses on the development of new drugs and therapeutic approaches to eradicate the subtle and dangerous leukemic stem cells responsible for maintaining and sustaining tumor growth.

Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases.

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

First-phase insulin secretion, insulin sensitivity, ghrelin, GLP-1, and PYY changes 72 h after sleeve gastrectomy in obese diabetic patients: the gastric hypothesis.

BACKGROUND: The aim of this study was to evaluate the possible role of sleeve gastrectomy (SG) per se in the reversibility of diabetes. METHODS: Insulin secretion and peripheral insulin sensitivity using the intravenous glucose tolerance test (IVGTT) were assessed in 18 obese type 2 diabetic patients and in 10 nondiabetic obese patients before and 3 days after SG, before any food intake and any weight change occurrence. At the same time, ghrelin, GLP-1, and PYY levels were determined. RESULTS: In diabetic patients who had the disease less than 10.5 years, the first phase of insulin secretion promptly improved after SG. The early insulin area under the curve (AUC) significantly increased at the postoperative IVGTT, indicating an increased glucose-induced insulin secretion. The second phase of insulin secretion (late AUC) significantly decreased after SG in all groups, indicating an improved insulin peripheral sensitivity. In all groups, pre- and postoperatively, intravenous glucose stimulation determined a decrease in ghrelin values and an increase in GLP-1 and PYY values. However, in the group of patients with disease duration >10.5 years, the differences were not significant except for the late insulin AUC. Postoperative basal and intravenous glucose-stimulated ghrelin levels were lower than preoperative levels in all groups of patients. Basal and intravenous stimulated GLP-1 and PYY postoperative values were higher than preoperative levels in all groups. CONCLUSIONS: Restoration of the first phase of insulin secretion and improved insulin sensitivity in diabetic obese patients immediately after SG, before any food passage through the gastrointestinal tract and before any weight loss, seem to be related to ghrelin, GLP-1, and PYY hormonal changes of possible gastric origin and was neither meal- nor weight-change-related. Duration of the disease up to 10.5 years seems to be a major cut off in the pathophysiological changes induced by SG. A "gastric" hypothesis may be put forward to explain the antidiabetes effect of SG.

BCR-ABL inhibitors in chronic myeloid leukemia: process chemistry and biochemical profile.

Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, called BCR-ABL, expressed by an oncogene resulting from a reciprocal translocation between chromosome 9 and chromosome 22, coded as (t[9,22][q34;q11]). Inhibition of BCR-ABL with tyrosine kinase inhibitors (TKI) proved to be an efficient targeted therapy of Philadelphia-positive (Ph+) CML in the chronic phase. This review mainly addresses the synthetic pathways and process chemistry leading to the large scale preparation for pre-clinical demands and clinical supply of the three TKIs approved for Ph+ CML, i.e., imatinib, dasatinib and nilotinib and three more investigational drugs, i.e., bosutinib, ponatinib and bafetinib. Recent progress on the biochemical profiling of the six examined TKIs has been also reported.

Metabolic syndrome in subjects at high risk for type 2 diabetes: the genetic, physiopathology and evolution of type 2 diabetes (GENFIEV) study.

BACKGROUND AND AIM: We evaluated the relationship between insulin resistance (IR) and insulin secretion with the metabolic syndrome (MS) in 885 subjects (377 men/508 women, age 49±11 years, BMI 29±5.2kgm(-2)) at risk of diabetes enrolled in the genetics, pathophysiology and evolution of type 2 diabetes (GENFIEV) study. METHODS AND RESULTS: All subjects underwent a 75-g oral glucose tolerance test (OGTT) for the estimation of plasma levels of glucose and C-peptide, as well as fasting insulin and lipid profile. IR was arbitrarily defined as HOMA-IR value above the 75th centile of normal glucose tolerance (NGT) subjects. Overall MS prevalence (National Cholesterol Treatment Panel-Adult Treatment Panel (NCEP-ATPIII) criteria) was 33%, 19% in subjects with NGT, 42% in impaired fasting glucose (IFG), 34% in impaired glucose tolerance (IGT), 74% in IFG+IGT subjects, and 56% in newly diagnosed diabetic patients. Prevalence was slightly higher with IDF criteria. MS prevalence was >50% in subjects with 2h glucose >7.8mmoll(-1), independently of fasting plasma glucose. IR prevalence was higher in subjects with MS than in those without (63% vs. 23%; p<0.0001) and increased from 54% to 73% and 88% in the presence of three, four or five traits, respectively. IR occurred in 42% of subjects with non-diabetic alterations of glucose homeostasis, being the highest in those with IFG+IGT (IFG+IGT 53%, IFG 45%, IGT 38%; p<0.0001). Individuals with MS were more IR irrespective of glucose tolerance (p<0.0001) with no difference in insulinogenic index. Hypertriglyceridaemia (OR: 3.38; Confidence Interval, CI: 2.294.99), abdominal obesity (3.26; CI: 2.18-4.89), hyperglycaemia (3.02; CI: 1.80-5.07) and hypertension (1.69; CI: 1.12-2.55) were all associated with IR. CONCLUSIONS: These results show that in subjects with altered glucose tolerance (in particular IFG+IGT) MS prevalence is high and is generally associated to IR. Some combinations of traits of MS may significantly contribute to identify subjects with IR.