Obese Type 2 Diabetes Patients Research Articles

Effect of intermittent fasting on lipid biokinetics in obese and overweight patients with type 2 diabetes mellitus: prospective observational study

BackgroundIntermittent fasting (IF) is a commonly used dietary practice that alternates between periods of unrestricted dietary consumption and abstinence from caloric intake. IF reduces caloric intake along with metabolic switch from utilization of glucose to fatty acids and ketones and resulting in reduction in adiposity and subsequently insulin resistance. Thus, it has been hypothesized that IF regimens can improve body composition in obese and overweight individuals.AimTo assess the effect of IF on lipid biokinetics in obese and overweight patients with type 2 diabetes (T2D).Patients and methodsThirty overweight or obese T2D patients were recruited from the diabetes outpatient clinics at the Specialized Medical Hospital, Mansoura University. Patients were subjected to time restricted fasting for 16 h (from dawn to sunset) during Ramadan. Anthropometric data were measured for participants before and 3 weeks after Ramadan fasting. Fasting plasma glucose (FPG), HbA1c, lipid profile, leptin, beta hydroxybutyrate (βHB) and high sensitive CRP levels were measured 1 week before and 3 weeks after Ramadan fasting.Results30 diabetic patients were recruited with a mean age of 54.3 ± 7.2 years. 24 (80%) were females. Obesity was diagnosed in 27 cases (90%). The median diabetes duration was 10 years. The study showed a statistically significant decrease in post-fasting body weight (BW), Body mass index (BMI), waist circumference (WC) & hip circumference (HC). There was a statistically significant decrease of post-fasting low density lipoprotein (LDL-C), Total cholesterol (TC), and leptin. The study also showed a statistically significant increase of post-fasting high density lipoprotein (HDL-C) and βHB. No significant change was found in post-fasting levels of HbA1c, FPG, triglycerides (TG) or high sensitive CRP. Post-fasting leptin was positively correlated with post-fasting BW, BMI, WC, and HC. Post-fasting βHB was positively correlated with post-fasting TG, HbA1c, and LDL-C. Leptin levels change (pre vs post fasting) was positively correlated with the change in LDL-C levels.ConclusionIF reduced leptin and increased β-hydroxybutyrate levels. IF is an effective tool for losing weight and visceral fat and improving lipid profile in obese and overweight patients with T2D.

Efficacy and safety profile of Glucagon-Like Peptide-1 Receptor Agonist in obese Type-2 diabetes patients from a private institution in Karachi.

To assess the effectiveness of GLP-1RAs in managing obese T2DM patients. This prospective cohort analysis was conducted at Medicell Institute of Diabetes, Karachi, Pakistan; from July 2019 to July 2021. A total of 97 obese individuals >16 years of age with T2DM and IGT were initially enrolled, and 81 patients who showed up for the follow-up were prescribed one of the three GLP-1RAs available in Pakistan. Out of 81 patients who showed up for the follow-up visit, 43 had received Liraglutide, 25 were taking Dulaglutide, and 13 had been prescribed IDegLira supplemented with oral hypoglycemic medications ± insulin. The mean age of the enrolled patients was 49.21(12.44) years, and there was female predominance (55.6%). Overall, there was a significant weight and BMI reduction among the patients treated with either of the GLP-1RAs (P<.01). Furthermore, significant glycemic control was observed in all three groups after the treatment. The Dulaglutide group demonstrated a more significant reduction of HbA1c compared to Liraglutide group, which showed more pronounced weight and BMI reduction. Nevertheless, this class of medications was well-tolerated, with nausea being the most often reported side effect. GLP-1RAs showed favorable weight and HbA1c reduction among patients of all three treatment groups.

The Depletion of Carbohydrate Metabolic Genes in the Gut Microbiome Contributes to the Transition From Central Obesity to Type 2 Diabetes.

Obesity, especially central obesity, is a strong risk factor for developing type 2 diabetes (T2D). However, the mechanism underlying the progression from central obesity to T2D remains unknown. Therefore, we analyzed the gut microbial profiles of central obese individuals with or without T2D from a Chinese population. Here we reported both the microbial compositional and gene functional alterations during the progression from central obesity to T2D. Several opportunistic pathogens were enriched in obese T2D patients. We also characterized thousands of genes involved in sugar and amino acid metabolism whose abundance were significantly depleted in obese T2D group. Moreover, the abundance of those genes was negatively associated with plasma glycemia level and percentage of individuals with impaired plasma glucose status. Therefore, our study indicates that the abundance of those depleted genes can be used as a potential biomarker to identify central obese individuals with high risks of developing T2D.

Daily transient coating of the intestine leads to weight loss and improved glucose tolerance

IntroductionRoux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis. MethodsSprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry. ResultsAt 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ± 3.8 mg/dl vs. 99.1 ± 2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption. ConclusionWe demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.

Long-Term Effectiveness and Safety of Once Weekly Dulaglutide as Add-on to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes

Aim of this monocentric retrospective observational study was to evaluate the 18-month effectiveness and safety of once weekly 1.5 mg GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) as add-on to metformin (MET) or MET plus conventional insulin secretagogues (SFU/glinide) in a study cohort with excess body weight (BW) and type 2 diabetes (T2D). Comparative efficacy versus once daily 1.2/1.8 mg liraglutide (LIRA) in a study sample naïve to GLP-1 RAs, matching for age, gender, BMI, T2D duration, cardiovascular comorbidities and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate-severe gastrointestinal AEs after a median follow-up of 6 (3 to 8) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant median HbA1c reduction of -0.9 (-1.50 to -0.20) % with respect to baseline values (p<0.001), which remained stable during 18 months of follow-up. These results were accompanied by a moderate BW loss sustained over time, with a median reduction of -1.16 (-4,29 to 0.45) % at 6 months and -1.47 (-4.2 to 0.72) % at 18 months (p=0.048). At univariate Spearman analysis, a negative correlation between baseline BMI and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity (BMI ≥ 30kg/m2) against drug discontinuation was confirmed by an exploratory logistic regression analysis, while adjusting for confounders [OR 0.211 (95%CI 0.058–0.771), p=0.019]. Neither gender, nor age, nor T2D duration, nor concomitant SUF/glinide use, nor shifting to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in form of HbA1c reduction ≥ 0.5% [OR 2.961 (95%CI 1.394–6.290), p=0.005] or BW loss ≥ 5% [OR 2.571 (95%CI 1.171–5.644), p=0.019]. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and BW in real word scenarios (1). With the advantage of once weekly administration, at 18-month follow-up, a significant larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p=0.033). Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial glycometabolic responses to DU on a background of MET or MET plus SFU/glinide are durable, especially in presence of obesity and greater HbA1c impairment.(1) Ref: Mirabelli et al. IJERPH. 2019;17(1):207.

Trajectory of Glycated Hemoglobin Over Time Among Obese Type 2 Diabetes Patients on U-100 Basal-Bolus Insulin Regimen Using Real-World Data

Introduction: There is a consistent increase in prevalence of obese type 2 diabetes (T2D) patients, many of whom require insulin treatment. As endogenous insulin secretion dwindles and progressively increasing body weight worsens insulin resistance, exogenous insulin doses can be quite high. This presents unique disease management challenges to patients, treating physicians, and the health systems. These challenges could lead to therapeutic inertia and result in poor glycemic control (continuous increase or persistently high glycated hemoglobin [A1c]). Therefore, examining the A1c trajectory over a significant period could detect the existence and magnitude of therapeutic inertia. Further segmenting the patients based on their A1c trajectory over time would help formulate management strategies with tailored interventions to targeted patient segments with signs of therapeutic inertia. Objective: To segment obese patients with T2D on U-100 basal-bolus regimen based on A1c trajectory over a 3-year period. Methods: Adults with ≥2 T2D claims who were on U-100 basal-bolus regimen and with body mass index ≥30 kg/m2 or diagnosis codes for obesity during the identification period (APR2014-SEP2015) in the Veterans Health Administration database were included. The study period was OCT2013-SEP2018 and patients were required to have continuous enrollment for ≥6 months pre- and ≥3 years post-index periods. We captured the A1c pattern at 6-month intervals over a 3-year period. Only patients with A1c in at least 4 of the 6 time periods were included. A longitudinal unsupervised trajectory clustering method using the traj R package was implemented. Twenty-four features of A1c trajectory were examined followed by feature reduction using factor analysis. Based on the selected features, K-means clustering was used to identify patient segments based on the A1c trajectory. We extended the approach by repeating the same process as above among patient cluster with stable A1c trajectory to detect further A1c patterns. Results: A total of 45,520 patients were included. Four patient clusters were identified based on distinct patterns of A1c trajectory. The first cluster has descending A1c over time (N=8,325; 18.3%) while the second one has ascending A1c over time (N=8,123; 17.8%). Among patients with stable A1c trajectory, two more clusters were identified: stable high (N=10,654; 23.4%) with persistently high A1c around 9.0% and stable low (N=18,378; 40.4%) with persistently low A1c around 7.2%. Conclusions: By applying an unsupervised machine learning algorithm on A1c trajectory over time, this study identified over 40% of obese T2D patients on basal-bolus regimen belong to segments with poor A1c control during a three-year period, suggesting the significant existence of therapeutic inertia. Further research is planned to identify various forms of therapeutic inertia associated with these segments.

The Effects of Cabergoline on Vascular Indices in Overweight and Obese Type 2 Diabetes Patients

Introduction: Type 2 diabetes (T2D) and obesity often coexist and are associated with increased cardiovascular complications.&#x0D; Objective: This study aims to determine the effects of cabergoline, a dopamine agonist on fasting blood glucose (FBG), glycated hemoglobin (HbA1c), lipid profile, blood pressure (BP) and arterial stiffness in overweight and obese T2D patients.&#x0D; Methods: Fifty-eight T2D patients were randomized to cabergoline 0.5 mg biweekly or control groups for 12 weeks. BP and arterial stiffness were recorded at baseline before starting study medication and repeated after 12 weeks. Pulse wave velocity (PWV) and central augmentation index (AIx) were used to assess arterial stiffness. Other parameters measured were anthropometric measurements, FBG, HbA1c and lipid profile. Changes in these parameters after 12 weeks compared to baseline were calculated for each group, and compared between the two groups.&#x0D; Results: Twenty-eight and twenty-six patients from cabergoline and control groups completed the treatment respectively. After 12 weeks, weight and diastolic BP were increased for both groups while body mass index (BMI) and waist circumference (WC) were increased in cabergoline group. PWV and AIx were not significantly different either within or between group comparisons. There were no significant differences in mean changes in all parameters between the two groups.&#x0D; Conclusion: Weight and diastolic BP were elevated in both groups while BMI and WC were increased in cabergoline group. Compared to control, cabergoline treatment at 0.5 mg biweekly in overweight and obese T2D patients for 12 weeks did not improve BP and arterial stiffness.

Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes.

Aims and methods: The aim of this monocentric retrospective observational study was to evaluate the 18-month safety and effectiveness of GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) 1.5 mg/once weekly as an add-on to metformin (MET) or MET plus conventional insulin secretagogues in a study cohort with excess body weight and type 2 diabetes (T2D). Comparative efficacy versus liraglutide (LIRA) 1.2–1.8 mg/once daily in a study sample naïve to GLP-1 RAs, frequency matching for age, gender, T2D duration, degree of glycemic impairment, cardiovascular comorbidities, and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Results: Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate–severe gastrointestinal AEs after a mean follow-up of 6 (4 standard deviations (SD)) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant mean HbA1c reduction of −0.85% (1.17 SD) with respect to baseline values (p < 0.001), which remained stable during 18 months follow-up. These results were accompanied by a moderate weight loss sustained over time, with a mean reduction of −2.0% (4.3 SD) at 6 months and −1.3% (4.8 SD) at 18 months (p = 0.091). At univariate analysis, a negative correlation between baseline body mass index (BMI) and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity against drug discontinuation was confirmed by logistic regression analysis. Neither gender, nor age, nor T2D duration, nor concomitant conventional insulin secretagogue use, nor switching to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in terms of HbA1c reduction ≥ 0.5% or body weight loss ≥ 5%. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and body weight in real-world experiences. With the advantage of once-weekly administration, at 18-month follow-up, a significantly larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p = 0.033). Conclusions: Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial responses to DU on a background of MET or MET plus insulin secretagogues are durable, especially in the presence of obesity and greater HbA1c impairment.

The efficacy of once-daily liraglutide as an add-on to oral antidiabetic agents on weight reduction and glycemic control in obese patients with inadequately controlled type 2 diabetes: a retrospective analysis in relation to liraglutide dose escalation within a 7-month treatment period

This study aimed to evaluate the efficacy of once-daily liraglutide as an add-on to oral antidiabetics (OADs) on glycemic control and body weight in obese patients with inadequately controlled type 2 diabetes (T2D). A total of 27 obese T2D patients who received 7 months (0.6 mg/day for the first month, 1.2 mg/day for 3 months, and 1.8 mg/day for 3 months) of liraglutide treatment as an add-on to OADs were included. Data on body weight (kg), fasting plasma glucose (FPG, mg/dL), postprandial glucose (PPG, mg/dL), and HbA1c (%), were recorded. Liraglutide doses of 1.2 mg/day and 1.8 mg/day were associated with significant decreases in body weight (by 8.0% and 11.9%, respectively, p < 0.01 for each) and HbA1c (by 20.0 and 26.5%, respectively, p < 0.01), while all liraglutide doses yielded significant reductions in FPG (p ranging from < 0.001 to < 0.01) and PPG (p ranging from < 0.001 to < 0.01). Glycemic parameters showed a significant reduction from the 1.2 mg/day dose to the 1.8 mg/day dose (p < 0.01 for each), whereas no further reduction in body weight was noted. Our findings indicate favorable efficacy of liraglutide as an add-on to OADs in weight reduction and improving glycemic parameters in obese patients with inadequately controlled T2D. Once-daily liraglutide treatment was associated with significant weight loss and improved HbA1c levels only at 1.2-mg and 1.8-mg doses, while a 1.8-mg dose compared with a 1.2-mg dose seemed to enable a further improvement in glycemic control but not in weight loss.

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.

Comparing the Efficacy and Safety of Glucagon-Like Peptide 1 Receptor Agonists with Sodium-Glucose Cotransporter 2 Inhibitors for Obese Type 2 Diabetes Patients Uncontrolled on Metformin: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Introduction To conduct the first meta-analysis of randomized controlled trials (RCTs) comparing glucagon-like peptide 1 receptor agonists (GLP-1RAs) with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) for obese type 2 diabetes (T2D) patients uncontrolled on metformin. Methods We searched Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Ovid, and Web of Science from inception to May 14, 2020, without language restrictions for eligible RCTs. The primary outcome is the mean change from baseline in glycated haemoglobin (HbA1c). Results Totally, 3 RCTs enrolled 2066 patients were identified. Compared with SGLT-2is, treatment with GLP-1RAs achieved significant reduced HbA1c by 0.40% (95% CI: −0.54, −0.25; p < 0.00001), fasting blood glucose (FBG) by 0.17 mmol/L (95% CI: −0.31, −0.04; p=0.01), and postprandial blood glucose (PBG) by 0.32 mmol/L (95% CI: −0.49, −0.14; p=0.0003) for obese T2D patients uncontrolled on metformin. The significant benefit of weight loss was seen in semaglutide (MD: −0.75; 95% CI: −1.18, −0.31; p < 0.0007). No significant difference was detected between GLP-1RAs and SGLT-2is in overall adverse events (RR: 1.03; 95% CI: 0.98, 1.09; p=0.76), but gastrointestinal events showed higher occurrence in GLP-1RAs groups compared with SGLT-2is (RR: 1.62; 95% CI: 1.37, 1.93; p < 0.00001). Subgroup analyses revealed that follow-up time did not statistically influence glycemic control. Conclusion GLP-1RAs are superior to SGLT-2is for obese T2D patients uncontrolled on metformin in glycemic control without an increase in adverse events except for a higher occurrence in gastrointestinal events. Future large longer-term follow-up clinical trials are needed to provide more evidence about the sustainable effects and safety of GLP-1RAs compared with SGLT-2is.

Sleeve gastrectomy and Roux-en-Y gastric bypass in the treatment of type 2 diabetes. Two-year results from a Swedish multicenter randomized controlled trial.

Obesity is a world-wide epidemic and it is a risk factor for type 2 diabetes (T2D). Few randomized controlled studies have compared the 2 most common surgical procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in the treatment of obese patients with T2D. To compare diabetes remission rates (glycosylated hemoglobin ≤6.0%, without diabetes medications) in obese T2D patients (body mass index, 35-50) undergoing RYGB or SG. Three University Hospital clinics and 1 Regional Hospital in Sweden. Forty-nine patients with T2D were included. Twenty-five were randomized to RYGB and 24 to SG. There was no difference between groups regarding patient characteristics, duration of T2D, overall usage of antidiabetic medications, or glycosylated hemoglobin levels. All patients (100%) completed 1-year follow-up and 47 (95.9%) 2-year follow-up. Remission of T2D was not significantly different between the RYGB and SG, reaching 44% and 46% (n = 25 and n = 24, respectively, P = .897, power = .80) at 1 year, and 48% and 55% (n = 25 and n =22, respectively, P = .654) at 2 years of follow-up. Similarly, mean glycosylated hemoglobin was improved in both groups at 1 and 2 years, with no significant differences between the groups (RYGB baseline versus1yr; mean ± standard deviation: 7.9 ± 1.5 versus 5.8 ± .6%, P < .0001; versus 2 yr: 5.9 ± .7%, P < .0001; SG baseline versus 1 yr: 8.2 ± 1.9 versus 5.9 ± .7%, P < .0001; versus 2 yr: 5.9 ± 1.1%, P<.0001). Total weight loss was not different but percentage excess weight loss was higher after RYGB compared with SG both at 1 and 2 years; mean ± standard deviation: 78 ± 22 versus 60 ± 22%, and 76 ± 24 versus 54 ± 21%, respectively (P < .01 for both). Waist circumference also decreased significantly more in the RYGB group. Despite superior excess weight loss after RYGB, T2D remission rates did not differ significantly between RYGB and SG after 2 years. Long-term follow-up data are needed to define the role of SG in the treatment of patients with obesity and T2D.

Distinct Dysfunctional States of Circulating Innate-Like T Cells in Metabolic Disease.

The immune system plays a significant role in controlling systemic metabolism. Innate-like T (ILT) cells in particular, such as mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells and γδ T cell receptor expressing cells, have been reported to promote metabolic homeostasis. However, these different ILT cell subsets have, to date, been generally studied in isolation. Here we conducted a pilot study assessing the phenotype and function of circulating MAIT, iNKT, and Vδ2+ T cells in a small cohort of 10 people with obesity and type 2 diabetes (T2D), 10 people with obesity but no diabetes, and 12 healthy individuals. We conducted phenotypic analysis by flow cytometry ex vivo, and then functional analysis after in vitro stimulation using either PMA/ionomycin or synthetic agonists, or precursors thereof, for each of the cell-types; use of the latter may provide important knowledge for the development of novel therapeutics aimed at activating human ILT cells. The results of our pilot study, conducted on circulating cells, show clear dysfunction of all three ILT cell subsets in obese and obese T2D patients, as compared to healthy controls. Importantly, while both iNKT and Vδ2+ T cell dysfunctions were characterized by diminished IL-2 and interferon-γ production, the distinct dysfunctional state of MAIT cells was instead defined by skewed subset composition, heightened sensitivity to T cell receptor engagement and unchanged production of all measured cytokines.

Circulating Follistatin and Activin A and Their Regulation by Insulin in Obesity and Type 2 Diabetes

Circulating follistatin (Fst) binds activin A and thereby regulates biological functions such as muscle growth and β-cell survival. However, Fst and activin A's implication in metabolic regulation is unclear. To investigate circulating Fst and activin A in obesity and type 2 diabetes (T2D) and determine their association with metabolic parameters. Further, to examine regulation of Fst and activin A by insulin and the influence of obesity and T2D hereon. Plasma Fst and activin A levels were analyzed in obese T2D patients (N = 10) closely matched to glucose-tolerant lean (N = 12) and obese (N = 10) individuals in the fasted state and following a 4-h hyperinsulinemic-euglycemic clamp (40 mU·m-2·min-1) combined with indirect calorimetry. Circulating Fst was ~30% higher in patients with T2D compared with both lean and obese nondiabetic individuals (P < .001), while plasma activin A was unaltered. In the total cohort, fasting plasma Fst correlated positively with fasting plasma glucose, serum insulin and C-peptide levels, homeostasis model assessment of insulin resistance, and hepatic and adipose tissue insulin resistance after adjusting for age, gender and group (all r > 0.47; P < .05). However, in the individual groups these correlations only achieved significance in patients with T2D (not plasma glucose). Acute hyperinsulinemia at euglycemia reduced circulating Fst by ~30% (P < .001) and this response was intact in patients with T2D. Insulin inhibited FST expression in human hepatocytes after 2 h and even further after 48 h. Elevated circulating Fst, but not activin A, is strongly associated with measures of insulin resistance in patients with T2D. However, the ability of insulin to suppress circulating Fst is preserved in T2D.

Oral hypoglycemic drugs: An overview

The aim of this study was to evaluate safety and efficacy of oral hypoglycemic agents in obese Type-2 diabetic patients. The objectives are to compare fasting and postprandial blood sugar (PPBS) levels, to compare body mass index in all the groups and to identify glycosylated hemoglobin levels and adverse drug reaction in all the groups. Diabetes mellitus is one of the world’s major diseases. It currently affects an estimated143 million people worldwide and the number is growing rapidly. In the India, about 1-5% population suffer from diabetes or related complication. So there is need to cure this disease. Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral anti hyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors. Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type 1, which must be injected or inhaled. Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include agents which increase the amount of insulin secreted by the pancreas, agents which increase the sensitivity of target organs to insulin , and agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract. Keywords: hypoglycemic, blood suger, insulin, diabetes mellitus, pancreas

GLP-1 Limits Adipocyte Inflammation and Its Low Circulating Pre-Operative Concentrations Predict Worse Type 2 Diabetes Remission after Bariatric Surgery in Obese Patients.

Objective: Glucagon-like peptide (GLP)-1 has been proposed as a key candidate in glucose improvements after bariatric surgery. Our aim was to explore the role of GLP-1 in surgically-induced type 2 diabetes (T2D) improvement and its capacity to regulate human adipocyte inflammation. Methods: Basal circulating concentrations of GLP-1 as well as during an oral glucose tolerance test (OGTT) were measured in lean and obese volunteers with and without T2D (n = 93). In addition, GLP-1 levels were determined before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 77). The impact of GLP-1 on inflammation signalling pathways was also evaluated. Results: We show that the reduced (p < 0.05) circulating levels of GLP-1 in obese T2D patients increased (p < 0.05) after RYGB. The area under the curve was significantly lower in obese patients with (p < 0.01) and without (p < 0.05) T2D compared to lean volunteers while obese patients with T2D exhibited decreased GLP-1 levels at baseline (p < 0.05) and 120 min (p < 0.01) after the OGTT. Importantly, higher (p < 0.05) pre-operative GLP-1 concentrations were found in patients with T2D remission after RYGB. We also revealed that exendin-4, a GLP-1 agonist, downregulated the expression of inflammation-related genes (IL1B, IL6, IL8, TNF) and, conversely, upregulated the mRNA levels of ADIPOQ in human visceral adipocytes. Furthermore, exendin-4 blocked (p < 0.05) LPS-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Conclusions: Our data indicate that GLP-1 may contribute to glycemic control and exert a role in T2D remission after RYGB. GLP-1 is also involved in limiting inflammation in human visceral adipocytes.

Sera of Obese Type 2 Diabetic Patients Undergoing Metabolic Surgery Instead of Conventional Treatment Exert Beneficial Effects on Beta Cell Survival and Function: Results of a Randomized Clinical Study.

Pancreatic beta cells are highly sensitive to oxidative and endoplasmic reticulum (ER) stress, commonly occurring in type 2 diabetes (T2D) and obesity. We aimed at investigating cellular responses of human beta cells exposed to sera from obese T2D patients treated differently, namely by conventional therapy or laparoscopic sleeve gastrectomy (LSG). Serum samples from obese T2D men randomized to conventional treatment or LSG were taken at baseline and 6months later. After exposing 1.1B4 cells to study patients' sera, the following were assessed: cellular viability and proliferation (by MTT and xCELLigence assays), reactive oxygen species (ROS) production (with DCFH-DA), and expression of ER stress markers, oxidative- or autophagy-related proteins and insulin (by real-time PCR and Western blot). At 6-month follow-up, patients undergoing LSG achieved an adequate glycemic control, whereas conventionally treated patients did not. As compared to 1.1B4 cells incubated with baseline sera (control), cells exposed to sera from LSG-treated participants exhibited (i) increased viability and proliferation (p < 0.05); (ii) diminished levels of ROS and p53 (p < 0.05); (iii) enhanced protein expression of autophagy-related SIRT1 and p62/SQSTM1 (p < 0.05); (iv) significantly decreased transcript levels of ER stress markers (p < 0.05); and (v) augmented insulin expression (p < 0.05). Conversely, the 6-month conventional therapy appeared not to impact on circulating redox status. Moreover, 1.1B4 cells exposed to sera from conventionally treated patients experienced mild ER stress. Circulating factors in patients with improved diabetes after metabolic surgery exerted favorable effects on beta cell function and survival.

Metabolic surgery ameliorates cardiovascular risk in obese diabetic patients: Influence of different surgical procedures

BackgroundIn recent years, bariatric surgery was found to have therapeutic potential for the treatment of type 2 diabetes (T2D) in severely obese patients (body mass index [BMI] ≥35 kg/m2) and to reduce cardiovascular disease (CVD) risk and mortality. However, the benefit of CVD risk reduction after metabolic surgery in nonseverely obese T2D patients (BMI <35 kg/m2) remained to be proven. ObjectiveTo evaluate the CVD risk after metabolic surgery in T2D patients using The UK Prospective Diabetes Study score. SettingTertiary referral general hospital, Taiwan, Republic of China. MethodsOutcomes of 392 patients (235 women and 147 men) who had undergone sleeve gastrectomy (87) or gastric bypass (305) for treatment of T2D with 1-year follow-up were assessed. Data were prospectively collected for study, and cerebral and coronary heart disease risk was calculated by using The UK Prospective Diabetes Study risk engine. Outcomes of patients who had undergone different surgical procedures were assessed. ResultsOne year after surgery, weight and glycemic control with complete and partial remission of T2D were significant in most of the patients. The 10-year coronary heart disease risk and fatal coronary heart disease risk were also reduced from 8.8% to 4.6% and from 4.6% to 2.1%, respectively (both P < .001). Similar CVD risk reduction was seen in both patients with BMI ≥35 and BMI <35. Multivariable analysis confirmed that surgical procedure of sleeve gastrectomy was a negative independent predictor of CVD risk reduction after metabolic surgery. ConclusionThe present study confirms the efficacy of metabolic surgery for the T2D treatment and reduction of CVD risk up to 50% 1 year after surgery. Gastric bypass surgery has more power on CVD risk reduction than sleeve gastrectomy.

Westernized Diet–Induced Insulin Resistance in Mice Is Associated with Focal Duodenal Hyperplasia

Westernized diet (WD; high fat and sugar) induces an insulin resistant state associated with obesity and type 2 diabetes (T2D). Duodenal exclusion surgery in obese T2D patients implicates the duodenum as a key GI region involved in insulin resistance. To identify adaptive changes of pathophysiological relevance, detailed analyses of the GI tract was undertaken following exposure of mice to WD. Metabolic indices and stereological characteristics of the whole gut, mucosal surface and transcriptome were investigated in C57BI/6J male mice fed either chow (lean) or WD (60% fat; 20% sugar) for 7 or 13 weeks (10 mice/cohort). Compared to lean, WD gained more weight and had higher plasma glucose, insulin and total cholesterol (Table) with differences greater at 13 vs. 7 weeks. Unlike other intestinal segments, focal hyperplasia was observed in the duodenum with increased weight and surface area (∼40%). The hyperplastic duodenum was characterized by increased chromogranin-A staining of enteroendocrine (EE) cells. Transcriptomic analysis revealed differences between WD and lean groups (both 7 and 13 weeks) with enrichment for genes involved in lipid and glucose metabolism. Exposure to WD induces adaptive responses in duodenal mucosa, EE cell population, and transcriptome. These findings suggest a potential role of the duodenum in insulin resistance and may explain the insulin-sensitizing effect of duodenal exclusion. Disclosure S. Ghosh: Consultant; Self; Fractyl Laboratories, Inc. F. Rubino: Advisory Panel; Self; Fractyl Laboratories, Inc.. Consultant; Self; Fractyl Laboratories, Inc., Ethicon US, LLC.. Speaker's Bureau; Self; Ethicon US, LLC.. Consultant; Self; Medtronic. Advisory Panel; Self; GI Dynamics Inc.. Consultant; Self; GI Dynamics Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Ethicon US, LLC.. P. Wismann: None. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. H. Rajagopalan: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Board Member; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc. D. Maggs: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Spouse/Partner; Gelesis. Employee; Spouse/Partner; Gelesis.

COMPARATIVE STUDY OF ORAL HYPOGLYCEMIC AGENTS IN TYPE-2 DIABETES OBESE PATIENTS

Objectives: The aim of this study was to evaluate safety and efficacy of oral hypoglycemic agents in obese Type-2 diabetic patients. The objectives are to compare fasting and postprandial blood sugar (PPBS) levels, to compare body mass index (BMI) in all the groups, and to identify glycosylated hemoglobin levels and adverse drug reactions (if present) in all the groups.Method: This is a prospective observational study conducted in care diabetic center over a period of 1 year. All the patients those are receiving only oral hypoglycemic agents continuously over a period of 3 months and BMI ≥30 were enrolled. The patients receiving insulin were excluded. Patients were followed over a period of 3 months and were reviewed on visit basis (every 30 days). All the necessary information was collected into the data collection form that includes demographic details (age, gender, etc.), past medication history, current treatment charts, and their relevant laboratory reports (fasting blood sugar levels [mg/dl], PPBS levels [mg/dl], glycosylated hemoglobin A1c [HbA1c] (%), and BMI [kg/m2]). Results: A total of 395 patients were recruited into the study and the drugs received by the population were found to be metformin+sulfonylureas (33%), metformin+pioglitazone (26%), and metformin+dipeptidyl peptidase inhibitors (DPI) (23%). A significant reduction in HbA1c was seen in all groups of patients. Adverse drug reactions observed were hypoglycemia, pedal edema, and itching distributed to drugs metformin+DPI, respectively. A significant reduction in BMI was seen in patients receiving DPI and BMI was found to be increased in other groups of patients.Conclusion: Overall, three classes of drugs were found to have similar efficacy. Sulfonylureas were commonly associated with hypoglycemia when compared to other drugs and weight reduction observed in dipeptidyl peptidase inhibitors.