98 research outputs found
Management of diabetes across the course of disease: minimizing obesity-associated complications
Obesity increases the risk for developing type 2 diabetes mellitus (T2DM) and this in turn correlates with an elevated probability of long-term diabetes complications once diabetes is established. Interventions aimed at lowering weight via changes in diet and lifestyle have repeatedly been shown to improve glycemic control in patients with T2DM and even to reverse early disease. Weight gain, a potential side effect of treatment for patients with T2DM, is also an important concern, and it has been noted that weight increases associated with antidiabetes therapy may blunt cardiovascular risk reductions achieved by decreasing blood glucose. Among older agents, metformin and acarbose have the lowest risk for weight gain, while sulfonylureas, meglitinides, and thiazolidinediones are all associated with weight increases. Clinical trial results have also consistently demonstrated that treatment with glucagon-like peptide-1 receptor agonists and amylin lowers weight, and that dipeptidyl peptidase-4 inhibitors are weight neutral in patients with T2DM. Conventional human insulin formulations are known to increase weight in patients with T2DM. However, some insulin analogs, particularly insulin detemir, have lower liability for this adverse event. The use of both pharmacologic and surgical therapies aimed at treating obesity rather than lowering blood glucose have the potential to improve glycemic control and even resolve T2DM in some patients
B Cell Activation in Insulin Resistance and Obesity
Our group has demonstrated that inflammatory diseases such as type 2 diabetes (DM), inflammatory bowel disease (IBD), and periodontal disease (PD) are associated with altered B cell function that may contribute to disease pathogenesis. B cells were found to be highly activated with characteristics of inflammatory cells. Obesity is a pre-disease state for cardiovascular disease and type 2 diabetes and
is considered a state of chronic inflammation. Therefore, we sought to better characterize B cell function and phenotype in obese patients. We demonstrate that (Toll-like receptor) TLR4 and CD36 expression by B cells is elevated in obese subjects, suggesting increased sensing of lipopolysaccharide (LPS) and other TLR ligands. These ligands may be of microbial, from translocation from a leaky gut, or host origin. To better assess microbial ligand burden and host response in the bloodstream, we measured LPS binding protein (LBP), bacterial/permeability increasing protein (BPI), and high mobility group box 1 (HMGB1). Thus far, our data demonstrate an increase in LBP in DM and obesity indicating increased responses to TLR ligands in the blood. Interestingly, B cells responded to certain types of LPS by phosphorylating extracellular-signal-regulated kinases (ERK) 1/2. A better understanding of the immunological state of obesity and the microbial and endogenous TLR ligands that may be activating B cells will help identify novel therapeutics to reduce the risk of more dangerous conditions, such as cardiovascular disease
Diabetic Ketoacidosis Post Bariatric Surgery
In patients with type 2 diabetes, bariatric surgery can lead to significant improvements in glycemic control and diabetes remission. We present a case of a Hispanic female with type 2 diabetes phenotype who underwent bariatric surgery and post-operatively stopped her insulin therapy due to multiple reasons, including decreased oral intake and concern for hypoglycemia. Ultimately, she developed diabetic ketoacidosis. She does not fit into the classical type 2 diabetes or type 1 diabetes definition but into the heterogeneous subgroup of diabetes called ketosis-prone diabetes
14-color flow cytometry to determine the contribution of mitochondrial mass to differences in glycolytic capacity in human immune cell subsets
Mitochondrial metabolism controls immune cell function, but comprehensive tools to assess human primary immune cell metabolic capacity remain rudimentary. We previously demonstrated that CD19+ B cells rely more heavily on anaerobic glycolysis (i.e. are more glycolytic) than CD4+ T cells. Furthermore, both PBMCs and CD4+ T cells from subjects with type 2 diabetes (T2D) are more glycolytic than their counterparts from BMI-matched non-T2D controls. The contribution of mitochondrial mass, an indicator of non-glycolytic metabolism, to the various metabolic phenotypes is untested. To assess the contribution of immune cell subset identity and mitochondrial mass to the enhanced glycolytic capacity of resting B cells and PBMCs from T2D subjects, we designed a 13-color panel based on standard immune cell subset markers and chemokine receptors, and included MitoTracker Green FM (MTG), which quantitatively indicates mitochondrial mass. We used this novel panel to phenotype 63 total samples from BMI-matched subjects in three groups: non-T2D, pre-T2D, and fulminant T2D, as defined by American Diabetes Association guidelines. The panel was built in several iterations to accommodate spillover of MTG fluorescence into neighboring channels and includes, besides MTG and live-dead discriminator, the following surface markers: CD4, CD8, CD19, CD45RA, CD25, CD127, CD14, CCR4, CCR5, CCR6, CXCR3, and CD161. The PBMC samples were run on a 4-laser BD FACSARIA II SORP with pre-established panel-specific PMT voltages tracked using 6-peak Ultrarainbow beads. To normalize MTG fluorescence intensity and thus minimize batch effects, each of 5 total batches included a reference donor PBMC sample that was frozen in multiple aliquots from one blood draw. Using this approach, we quantified the percentages of immune cell populations (CD19+ B cells, CD8+ naïve and memory/effector T cells, and CD4+ cells including Tregs and populations enriched in Th1, Th2 and Th17) along with the relative mitochondrial mass in each subset. We found that CD19+ B cells in PBMCs from both ND and T2D subjects had significantly less mitochondrial mass than CD4+ cells, supporting the demonstration that B cells are more glycolytic than CD4+ T cells. Of all the CD4+ T cell subsets, Th17 cells consistently had the lowest mitochondrial mass, consistent with the interpretation that Th17s are more dependent on glycolysis than previously appreciated. Our results validate the utility of our 13-color panel to simultaneously quantify relative mitochondrial mass in numerous immune cell subsets and thereby provide a new tool to explore metabolism in human primary cells
Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline
OBJECTIVE: To formulate clinical practice guidelines for the pharmacological management of obesity. PARTICIPANTS: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. This guideline was co-sponsored by the European Society of Endocrinology and The Obesity Society. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the European Society of Endocrinology, and The Obesity Society reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize some of the supporting evidence. CONCLUSIONS: Weight loss is a pathway to health improvement for patients with obesity-associated risk factors and comorbidities. Medications approved for chronic weight management can be useful adjuncts to lifestyle change for patients who have been unsuccessful with diet and exercise alone. Many medications commonly prescribed for diabetes, depression, and other chronic diseases have weight effects, either to promote weight gain or produce weight loss. Knowledgeable prescribing of medications, choosing whenever possible those with favorable weight profiles, can aid in the prevention and management of obesity and thus improve health
Effect of Bariatric Weight Loss on the Adipose Lipolytic Transcriptome in Obese Humans
Insulin Status and Vascular Responses to Weight Loss in Obesity
ObjectivesThe aim of this study was to determine whether the effects of weight loss on arterial function are differentially modified by insulin status.BackgroundClinical studies suggest that plasma insulin levels may predict the extent of cardiovascular benefit achieved with weight loss in obese individuals, but mechanisms are currently unknown.MethodsWe prospectively followed 208 overweight or obese patients (body mass index [BMI] ≥25 kg/m2) receiving medical/dietary (48%) or bariatric surgical (52%) weight-loss treatment during a median period of 11.7 months (interquartile range: 4.6 to 13 months). We measured plasma metabolic parameters and vascular endothelial function using ultrasound at baseline and following weight-loss intervention and stratified analyses by median plasma insulin levels.ResultsPatients age 45 ± 1 years, with BMI 45 ± 9 kg/m2, experienced 14 ± 14% weight loss during the study period. In individuals with higher baseline plasma insulin levels (above median >12 μIU/ml; n = 99), ≥10% weight loss (compared with <10%) significantly improved brachial artery macrovascular flow-mediated vasodilation and microvascular reactive hyperemia (p < 0.05 for all). By contrast, vascular function did not change significantly in the lower insulin group (≤12 μIU/ml; n = 109) despite a similar degree of weight loss. In analyses using a 5% weight loss cut point, only microvascular responses improved in the higher insulin group (p = 0.02).ConclusionsInsulin status is an important determinant of the positive effect of weight reduction on vascular function with hyperinsulinemic patients deriving the greatest benefit. Integrated improvement in both microvascular and macrovascular function was associated with ≥10% weight loss. Reversal of insulin resistance and endothelial dysfunction may represent key therapeutic targets for cardiovascular risk reduction in obesity
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Aspiration therapy for the treatment of obesity: 4-year results of a multicenter randomized controlled trial.
BackgroundThe AspireAssist is the first Food and Drug Administration-approved endoluminal device indicated for treatment of class II and III obesity.ObjectivesWe earlier reported 1-year results of the PATHWAY study. Here, we report 4-year outcomes.SettingUnited States-based, 10-center, randomized controlled trial involving 171 participants with the treatment arm receiving Aspiration Therapy (AT) plus Lifestyle Therapy and the control arm receiving Lifestyle Therapy (2:1 randomization).MethodsAT participants were permitted to continue in the study for an additional year up to a maximum of 5 years providing they maintained at least 10% total weight loss (TWL) from baseline at each year end. For AT participants who continued the study, 5 medical monitoring visits were provided at weeks 60, 68, 76, 90, and 104 and thereafter once every 13 weeks up to week 260. Exclusion criteria were a history of eating disorder or evidence of eating disorder on a validated questionnaire. Follow-up weight, quality of life, and co-morbidities were compared with the baseline levels. In addition, rates of serious adverse event, persistent fistula, withdrawal, and A-tube replacement were reported. All analyses were performed using a per-protocol analysis.ResultsOf the 82 AT participants who completed 1 year, 58 continued to this phase of the trial. Mean baseline body mass index of these 58 patients was 41.6 ± 4.5 kg/m2. At the end of first year (at the beginning of the follow-up study), these 58 patients had a body mass index of 34.1 ± 5.4 kg/m2 and had achieved an 18.3 ± 8.0% TWL. On a per protocol basis, patients experienced 14.2%, 15.3%, 16.6%, and 18.7% TWL at 1, 2, 3, and 4 years, respectively (P < .01 for all). Forty of 58 patients (69%) achieved at least 10% TWL at 4 years or at time of study withdrawal. Improvements in quality of life scores and select cardiometabolic parameters were also maintained through 4 years. There were 2 serious adverse events reported in the second through fourth years, both of which resolved with removal or replacement of the A tube. Two persistent fistulas required surgical repair, representing approximately 2% of all tube removals. There were no clinically significant metabolic or electrolytes disorders observed, nor any evidence for development of any eating disorders.ConclusionsThe results of this midterm study have shown that AT is a safe, effective, and durable weight loss alternative for people with class II and III obesity and who are willing to commit to using the therapy and adhere to adjustments in eating behavior
WNT5A-JNK regulation of vascular insulin resistance in human obesity
Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (pWNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p
Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation
Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes
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