Combination of GLP-1 receptor agonists and behavioural treatment in type 2 diabetes elicits synergistic effects on body weight: A retrospective cohort study.

AIMS: Intensification of type 2 diabetes (T2DM) treatment with GLP-1 receptor agonists (GLP-1RAs) promotes weight loss. We aimed to determine the synergistic effect of behavioural programmes on body weight on top of GLP-1RA treatment. MATERIALS AND METHODS: We retrospectively analysed the time course of 328 individuals with T2DM starting GLP-1RA treatment because of insufficient metabolic control. In 29, a structured programme of elementary nutritional counselling was also implemented (elementary nutritional education [ENE]-5 group sessions), whereas 53 entered a programme of cognitive-behavioural treatment (CBT-12 group sessions). Both programmes were completed within 6 months of switching to GLP-1RAs. Data of body weight and metabolic control were followed up to 2 years as part of regular follow-up. Weight loss targets (≥10% and ≥5%) and metabolic target (HbA1c < 7%) were analysed by Cox regression model in comparison with standard care (SC, N = 244). RESULTS: Body weight remarkably decreased following both behavioural programmes, with significant differences compared with SC at 2 years (CBT, 8.5 ± 5.9% vs 6.3 ± 6.9 in ENE and only 3.1 ± 5.7 in SC; P < 0.001 and P = 0.045 vs CBT and ENE, respectively). The 10% weight loss was achieved and maintained in approximately 30% of cases during follow-up, and an additional 35% of cases lost between 5% and 10%. Data were consistent between behavioural programmes, after adjustment for confounders, including initial body weight (logreg Mantel-Cox: ENE vs SC, P < 0.01; CBT vs SC, P < 0.001). No differences in metabolic control were detected between groups. CONCLUSIONS: Initiation of GLP-1RA treatment provides an opportunity for addressing patients' needs of weight control. By producing initial weight loss, patients' motivation and self-efficacy are expected to increase and adherence to long-term lifestyle changes might be more easily attained.

Spike-Timing Dependent Plasticity in Unipolar Silicon Oxide RRAM Devices.

Resistance switching, or Resistive RAM (RRAM) devices show considerable potential for application in hardware spiking neural networks (neuro-inspired computing) by mimicking some of the behavior of biological synapses, and hence enabling non-von Neumann computer architectures. Spike-timing dependent plasticity (STDP) is one such behavior, and one example of several classes of plasticity that are being examined with the aim of finding suitable algorithms for application in many computing tasks such as coincidence detection, classification and image recognition. In previous work we have demonstrated that the neuromorphic capabilities of silicon-rich silicon oxide (SiOx) resistance switching devices extend beyond plasticity to include thresholding, spiking, and integration. We previously demonstrated such behaviors in devices operated in the unipolar mode, opening up the question of whether we could add plasticity to the list of features exhibited by our devices. Here we demonstrate clear STDP in unipolar devices. Significantly, we show that the response of our devices is broadly similar to that of biological synapses. This work further reinforces the potential of simple two-terminal RRAM devices to mimic neuronal functionality in hardware spiking neural networks.

Investigation of resistance switching in SiO x RRAM cells using a 3D multi-scale kinetic Monte Carlo simulator.

We employ an advanced three-dimensional (3D) electro-thermal simulator to explore the physics and potential of oxide-based resistive random-access memory (RRAM) cells. The physical simulation model has been developed recently, and couples a kinetic Monte Carlo study of electron and ionic transport to the self-heating phenomenon while accounting carefully for the physics of vacancy generation and recombination, and trapping mechanisms. The simulation framework successfully captures resistance switching, including the electroforming, set and reset processes, by modeling the dynamics of conductive filaments in the 3D space. This work focuses on the promising yet less studied RRAM structures based on silicon-rich silica (SiO x ) RRAMs. We explain the intrinsic nature of resistance switching of the SiO x layer, analyze the effect of self-heating on device performance, highlight the role of the initial vacancy distributions acting as precursors for switching, and also stress the importance of using 3D physics-based models to capture accurately the switching processes. The simulation work is backed by experimental studies. The simulator is useful for improving our understanding of the little-known physics of SiO x resistive memory devices, as well as other oxide-based RRAM systems (e.g. transition metal oxide RRAMs), offering design and optimization capabilities with regard to the reliability and variability of memory cells.

Supervised vs. self-selected physical activity for individuals with diabetes and obesity: the Lifestyle Gym program.

The effectiveness of different programs of physical activity outside randomized studies is difficult to determine. We carried out an audit in two different units where either a supervised physical activity (PA) program or a self-selected PA program was in use in individuals with type 2 diabetes or obesity. The supervised PA cohort (n = 101) received progressive gym training (120 min, twice a week for 13 weeks) by a dedicated team, with nutritional counseling during resting periods. The self-selected PA cohort (n = 69) was enrolled in a 13-week cognitive-behavioral program (120 min/week, in groups of 12-15 individuals), chaired by an expert team. Body weight and physical fitness (6-min walk test) were measured at baseline and after 6 and 12 months. Outcome measures were attrition, weight loss ≥10 % initial body weight, 10 % increase in 6-min walk test; their association with a PA program was tested by logistic regression analysis. Attrition rate was lower in the supervised PA group (28 vs. 45 % than in the self-selected cohort, P = 0.023). After adjustment for confounders, the supervised PA program was associated with a lower risk of attrition at 1 year (odds ratio 0.45; 95 % confidence interval, 0.21-0.98) at logistic regression analysis. Body weight similarly decreased in both groups (more rapidly in the supervised PA cohort); also physical fitness improved in a similar way, and no differences in achieved targets of body weight (supervised, 31 %; self-selected, 18 %; P = 0.118) or fitness (supervised, 62 %; self-selected, 49 %; P = 0.312) were demonstrated. Different PA programs produce very similar health benefits, but an initially supervised program has lower attrition rates, which might translate into better outcomes in the long term.

Diabetes in migrants and ethnic minorities in a changing World.

On a worldwide scale, the total number of migrants exceeds 200 million and is not expected to reduce, fuelled by the economic crisis, terrorism and wars, generating increasing clinical and administrative problems to National Health Systems. Chronic non-communicable diseases (NCD), and specifically diabetes, are on the front-line, due to the high number of cases at risk, duration and cost of diseases, and availability of effective measures of prevention and treatment. We reviewed the documents of International Agencies on migration and performed a PubMed search of existing literature, focusing on the differences in the prevalence of diabetes between migrants and native people, the prevalence of NCD in migrants vs rates in the countries of origin, diabetes convergence, risk of diabetes progression and standard of care in migrants. Even in universalistic healthcare systems, differences in socioeconomic status and barriers generated by the present culture of biomedicine make high-risk ethnic minorities under-treated and not protected against inequalities. Underutilization of drugs and primary care services in specific ethnic groups are far from being money-saving, and might produce higher hospitalization rates due to disease progression and complications. Efforts should be made to favor screening and treatment programs, to adapt education programs to specific cultures, and to develop community partnerships.

Long-term weight loss maintenance for obesity: a multidisciplinary approach.

The long-term weight management of obesity remains a very difficult task, associated with a high risk of failure and weight regain. However, many people report that they have successfully managed weight loss maintenance in the long term. Several factors have been associated with better weight loss maintenance in long-term observational and randomized studies. A few pertain to the behavioral area (eg, high levels of physical activity, eating a low-calorie, low-fat diet; frequent self-monitoring of weight), a few to the cognitive component (eg, reduced disinhibition, satisfaction with results achieved, confidence in being able to lose weight without professional help), and a few to personality traits (eg, low novelty seeking) and patient-therapist interaction. Trials based on the most recent protocols of lifestyle modification, with a prolonged extended treatment after the weight loss phase, have also shown promising long-term weight loss results. These data should stimulate the adoption of a lifestyle modification-based approach for the management of obesity, featuring a nonphysician lifestyle counselor (also called "lifestyle trainer" or "healthy lifestyle practitioner") as a pivotal component of the multidisciplinary team. The obesity physicians maintain a primary role in engaging patients, in team coordination and supervision, in managing the complications associated with obesity and, in selected cases, in the decision for drug treatment or bariatric surgery, as possible more intensive, add-on interventions to lifestyle treatment.

Nanoscale Transformations in Metastable, Amorphous, Silicon-Rich Silica.

Electrically biasing thin films of amorphous, substoichiometric silicon oxide drives surprisingly large structural changes, apparent as density variations, oxygen movement, and ultimately, emission of superoxide ions. Results from this fundamental study are directly relevant to materials that are increasingly used in a range of technologies, and demonstrate a surprising level of field-driven local reordering of a random oxide network.

Conductance tomography of conductive filaments in intrinsic silicon-rich silica RRAM.

We present results from an imaging study of filamentary conduction in silicon suboxide resistive RAM devices. We used a conductive atomic force microscope to etch through devices while measuring current, allowing us to produce tomograms of conductive filaments. To our knowledge this is the first report of such measurements in an intrinsic resistance switching material.

A standard ballroom and Latin dance program to improve fitness and adherence to physical activity in individuals with type 2 diabetes and in obesity.

OBJECTIVE: To test the effectiveness of a dance program to improve fitness and adherence to physical activity in subjects with type 2 diabetes and obesity. RESEARCH DESIGN AND METHODS: Following a motivational interviewing session, 100 subjects with diabetes and/or obesity were enrolled either in a dance program (DP, n = 42) or in a self-selected physical activity program (SSP, n = 58), according to their preferences. Outcome measures were reduced BMI/waist circumference, improved metabolic control in type 2 diabetes (-0.3% reduction of HbA1c) and improved fitness (activity expenditure >10 MET-hour/week; 10% increase in 6-min walk test (6MWT)). Target achievement was tested at 3 and 6 months, after adjustment for baseline data (propensity score). RESULTS: Attrition was lower in DP. Both programs significantly decreased body weight (on average, -2.6 kg; P < 0.001) and waist circumference (DP, -3.2 cm; SSP, -2.2; P < 0.01) at 3 months, and the results were maintained at 6 months. In DP, the activity-related energy expenditure averaged 13.5 ± 1.8 MET-hour/week in the first three months and 14.1 ± 3.0 in the second three-month period. In SSP, activity energy expenditure was higher but highly variable in the first three-month period (16.5 ± 13.9 MET-hour/week), and decreased in the following three months (14.2 ± 12.3; P vs. first period < 0.001). At three months, no differences in target achievement were observed between groups. After six months the odds to attain the MET, 6MWT and A1c targets were all significantly associated with DP. CONCLUSION: Dance may be an effective strategy to implement physical activity in motivated subjects with type 2 diabetes or obesity (Clinical trial reg. no.NCT02021890, clinicaltrials.gov).

Physical activity support or weight loss counseling for nonalcoholic fatty liver disease?

AIM: To determine the clinical effectiveness of intense psychological support to physical activity (PA) in nonalcoholic fatty liver disease (NAFLD), compared with cognitive-behavioral treatment (CBT). METHODS: Twenty-two NAFLD cases received support to exercise, tailored to their motivational needs (PA group). The effects on body weight, physical fitness [6-min walk test, VO2max and the PA-rating (PA-R) questionnaire] and body fat (fatty liver indices and visceral adiposity index) were compared with data obtained in 44 NAFLD subjects enrolled in a CBT program for weight loss, after adjustment for propensity score, calculated on baseline data. Measurements were performed at baseline, at 4-mo and one-year follow-up. Changes in anthropometric, biochemical and PA parameters were tested by repeated measurement ANOVA. Outcome results were tested by logistic regression analysis. RESULTS: At the end of the intensive program, BMI was less significantly reduced in the PA group (-1.09 ± 1.68 kg/m(2) vs -2.04 ± 1.42 kg/m(2) in the CBT group, P = 0.019) and the difference was maintained at 1-year follow-up (-0.73 ± 1.63 vs -1.95 ± 1.88, P = 0.012) (ANOVA, P = 0.005). PA-R was similar at baseline, when only 14% of cases in PA and 36% in CBT (P = 0.120) recorded values ≥ 3. At 4 mo, a PA-R ≥ 3 was registered in 91% of PA and 46% of CBT, respectively (P < 0.001) and PA-R ≥ 5 (up to 3 h/wk of moderate-to-heavy intensity physical activity) was registered in 41% of PA and only 9% of CBT group (P < 0.007). The 6-min walk test increased by 139 ± 26 m in PA and by only 43 ± 38 m in CBT (P < 0.001) and VO2max by 8.2 ± 3.8 mL/kg per minute and 3.3 ± 2.7 mL/kg per minute, respectively (P < 0.002). After adjustment for propensity, weight loss > 7% was significantly associated with CBT group at one year (OR = 6.21; 95%CI: 1.23-31.30), whereas PA-R > 3 was associated with PA group (10.31; 2.02-52.63). Liver enzymes decreased to values within normal limits in 36% of PA cases and 61% of CBT (P < 0.070). Estimated liver fat (Kotronen index) fell below the fatty liver threshold in 36% of PA and 34% and CBT cases at one-year (not different). Also the fatty liver index and the visceral adiposity index improved to a similar extent. CONCLUSION: Intensive psychological counseling for PA produces hepatic effects not different from standard CBT, improving physical fitness and liver fat independent of weight loss. Strategies promoting exercise are worth and effective in motivated patients, particularly in lean NAFLD patients where large weight loss cannot be systematically pursued.

Insulin resistance: mechanism and implications for carcinogenesis and hepatocellular carcinoma in NASH.

INTRODUCTION: The effects of insulin resistance in human diseases are of paramount importance. Since the original proposal by the WHO indicating insulin resistance as the common substrate of the metabolic syndrome, large data are now available on its significance in cardiovascular diseases, nonalcoholic fatty liver disease and cancer risk. MATERIALS AND METHODS: We reviewed the evidence linking hyperinsulinemia to insulin resistance and ultimately to increased cancer risk. Insulin resistance, by reducing substrate flux along the PI3-K pathway, is followed by compensatory hyperinsulinemia, considered a potential stimulus for cancerogenesis along the MAP-K pathway. Adaptive mechanisms of fat storage, promoted by insulin resistance, chronically maintained in an obesiogenic environment, may lead to oxidative stress and inflammation and modify the immune responses, further increasing the carcinogenic potential. The increased cancer risk associated with obesity, type 2 diabetes and nonalcoholic fatty liver may thus be fueled by hyperinsulinemia. Insulin secretagogs and insulin treatment, by raising circulating insulin levels, further increase cancer risk, whereas insulin sensitizers are associated with decreased cancer risk (all sites) and specifically decrease hepatocellular carcinoma. Likewise, drugs related to the incretin system, which are weight neutral or even reduce whole-body and hepatic fat, improve insulin sensitivity and potentially reduce the cancer risk. CONCLUSION: New diabetes treatments might thus help decrease the future burden of diabetes-associated cancer and particularly of hepatocellular carcinoma.

Physical activity for the prevention and treatment of metabolic disorders.

Metabolic syndrome and its various features (obesity, hypertension, dyslipidemia, diabetes, and nonalcoholic fatty liver disease) are increasing worldwide and constitute a severe risk for the sustainability of the present universal Italian health care system. Lifestyle interventions should be the first therapeutic strategy to prevent/treat metabolic diseases, far before pharmacologic treatment. The role of diet and weight loss has been fully ascertained, whereas the role of physical activity is frequently overlooked both by physicians and by patients. Physical activity has favorable effects on all components of the metabolic syndrome and on the resulting cardiovascular risk, the cornerstone in the development of cardiometabolic diseases. The quantity and the frequency of physical activity necessary to produce beneficial effects has not been defined as yet, but brisk walking is considered particularly appropriate, as it can be practiced by a large number of individuals, without any additional cost, and has a low rate of injury. The effects of exercise and leisure time physical activity extend from prevention to treatment of the various components of the metabolic syndrome, as well as to mood and quality of life. Any effort should be done to favor adherence to protocols of physical activity in the community.

Preliminary study about the possible glycemic clinical advantage in using a fixed combination of Berberis aristata and Silybum marianum standardized extracts versus only Berberis aristata in patients with type 2 diabetes.

BACKGROUND: Berberine is an isoquinoline alkaloid widely used to improve the glucidic and lipidic profiles of patients with hypercholesterolemia, metabolic syndrome, and type 2 diabetes. The limitation of berberine seems to be its poor oral bioavailability, which is affected by the presence, in enterocytes, of P-glycoprotein - an active adenosine triphosphate (ATP)-consuming efflux protein that extrudes berberine into the intestinal lumen, thus limiting its absorption. According to some authors, silymarin, derived from Silybum marianum, could be considered a P-glycoprotein antagonist. AIM: The study aimed to evaluate the role played by a possible P-glycoprotein antagonist (silymarin), when added to a product containing Berberis aristata extract, in terms of benefits to patients with type 2 diabetes. METHODS: The study enrolled 69 patients with type 2 diabetes in suboptimal glycemic control who were treated with diet, hypoglycemic drugs, and in cases of concomitant alterations of the lipid profile, hypolipidemic agents. The patients received an add-on therapy consisting of either a standardized extract of Berberis aristata (titrated in 85% berberine) corresponding to 1,000 mg/day of berberine, or Berberol®, a fixed combination containing the same standardized extract of Berberis aristata plus a standardized extract of Silybum marianum (titrated as >60% in silymarin), for a total intake of 1,000 mg/day of berberine and 210 mg/day of silymarin. RESULTS: Both treatments similarly improved fasting glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and liver enzyme levels, whereas glycosylated hemoglobin (HbA1c) values were reduced to a greater extent by the fixed combination. CONCLUSION: The association of berberine and silymarin demonstrated to be more effective than berberine alone in reducing HbA1c, when administered at the same dose and in the form of standardized extracts in type 2 diabetic patients.

Interactions between lipoproteins and platelet membranes in obesity.

The aim was to investigate low-density lipoprotein (LDL) composition and Na(+)/K(+) adenosine triphosphatase (ATPase) and Ca(2+) ATPase activities and membrane fluidity measured by 1-(4-trimethylaminophenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) in platelets from obese patients and controls in order to identify, if any, platelet membrane's chemical-physical and/or functional modifications associated with compositional modification of circulating lipoproteins. Moreover, we studied the in vitro effect on both platelet transmembrane cationic transport and fluidity, by incubating LDL from 30 obese subjects with platelets from 30 control subjects. The analysis of the chemical composition of LDL from obese patients showed a significant increase in the percent content of total cholesterol (TC) and triglycerides (TGs) and in the mean levels of lipid hydroperoxides compared to controls' LDL. Platelet Na(+)/K(+) ATPase and Ca(2+) ATPase activities showed, respectively, a significant decrease and increase in patients compared to controls; minor significant, respectively, decreases and increases are shown also in control platelets incubated with LDL from obese patients. Anisotropy tested with TMA-DPH probe was significantly increased both in platelets from obese patients and in control platelets incubated with LDL from obese patients compared to control platelets. This study highlights that obesity induces remarkable modifications both in lipoproteins and platelets. Both platelet hyperfunction and quantitative/qualitative alterations in plasma lipoproteins, as well as an altered interaction between circulating lipoproteins and platelets, might play a relevant role in the increased prevalence of the early atherosclerotic lesions development in obese subjects. The present data point out that obesity might represent a major potentially modifiable risk factor for the onset of numerous complications, in particular cardiovascular ones.