A mathematical model of the euglycemic hyperinsulinemic clamp

BACKGROUND: The Euglycemic Hyperinsulinemic Clamp (EHC) is the most widely used experimental procedure for the determination of insulin sensitivity, and in its usual form the patient is followed under insulinization for two hours. In the present study, sixteen subjects with BMI between 18.5 and 63.6 kg/m(2 )were studied by long-duration (five hours) EHC. RESULTS: From the results of this series and from similar reports in the literature it is clear that, in obese subjects, glucose uptake rates continue to increase if the clamp procedure is prolonged beyond the customary 2 hours. A mathematical model of the EHC, incorporating delays, was fitted to the recorded data, and the insulin resistance behaviour of obese subjects was assessed analytically. Obese subjects had significantly less effective suppression of hepatic glucose output and higher pancreatic insulin secretion than lean subjects. Tissue insulin resistance appeared to be higher in the obese group, but this difference did not reach statistical significance. CONCLUSION: The use of a mathematical model allows a greater amount of information to be recovered from clamp data, making it easier to understand the components of insulin resistance in obese vs. normal subjects

Insulin signaling in insulin resistance states and cancer: A modeling analysis

Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death

One hour post-load plasma glucose and 3 year risk of worsening fasting and 2 hour glucose tolerance in the RISC cohort

No abstract available

Obesity surgery and cancer. What are the unanswered questions?

Obesity has become a global epidemic with a soaring economic encumbrance due to its related morbidity and mortality. Amongst obesity-related conditions, cancer is indeed the most redoubtable. Bariatric surgery has been proven to be the most effective treatment for obesity and its associatedmetabolic and cardiovascular disorders. However, the understanding of whether and how bariatric surgery determines a reduction in cancer risk is limited. Obesity-related malignancies primarily include colorectal and hormone-sensitive (endometrium, breast, prostate) cancers. Additionally, esophago-gastric tumors are growing to be recognized as a new category mainly associated with post-bariatric surgery outcomes. In fact, certain types of surgical procedures have been described to induce the development and subsequent progression of pre-cancerous esophageal and gastric lesions. This emerging category is of great concern and further research is required to possibly prevent such risks. Published data has generated conflicting results. In fact, while overall cancer risk reduction was reported particularly in women, some authors showed no improvement or even increased cancer incidence. Although various studies have reported beneficial effects of surgery on risk of specific cancer development, fundamental insights into the pathogenesis of obesity-related cancer are indispensable to fully elucidate its mechanisms

The Relevance of Academic Libraries in the Twenty-First Century

The biggest challenge facing the library profession in the twenty-first century is staying relevant to its users. It is often stated that the Internet and Google have changed librarianship. This challenge, while significant, does not mean that libraries will go away. It is causing us to re-evaluate what we do, how we do it, and what role libraries have in the academy and in our culture at large. This column addresses some of the ways in which academic libraries can stay relevant throughout the twenty-first century

Role of the Gut on Glucose Homeostasis:Lesson Learned from Metabolic Surgery

Purpose of Review: Bariatric surgery was initially intended to reduce weight, and only subsequently was the remission of type two diabetes (T2D) observed as a collateral event. At the moment, the term \u201cmetabolic surgery\u201d is used to underline the fact that this type of surgery is performed specifically to treat diabetes and its metabolic complications, such as hyperlipidemia. Recent Findings: Randomized, controlled studies have recently supported the use of bariatric surgery, and in particular of Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD) as an effective treatment for decompensated T2D. The lesson learned from these randomized and many other non-randomized clinical studies is that the stomach and the small intestine play a central role in glucose homeostasis. Bypassing the duodenum and parts of the jejunum exerts a substantial effect on insulin sensitivity and secretion. In fact, with BPD, nutrient transit bypasses duodenum, the entire jejunum and a small portion of the ileum, resulting in reversal of insulin sensitivity back to normal and reduction of insulin secretion, whereas RYGB has little effect on insulin resistance but increases insulin secretion. Hypotheses concerning the mechanism of action of metabolic surgery for diabetes remission vary from theories focusing on jejunal nutrient sensing, to incretin action, to the blunted secretion of putative insulin resistance hormone(s), to changes in the microbiota. Summary: Whatever the mechanism, metabolic surgery has the undoubted merit of exposing the central role of the small intestine in insulin sensitivity and glucose homeostasis

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients An adaptive phenomenon?

OBJECTIVE—Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women. RESEARCH DESIGN AND METHODS—Ten glucose-normotolerant, fertile, obese women (BMI >40 kg/m2, aged 38.66 ± 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS—No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P = 0.05) and postobese women (P ≤ 0.01) as was the decrease in dehydroepiandrosterone (P ≤ 0.05 and P ≤ 0.01, respectively). CBG decreased from 51.50 ± 12.76 to 34.33 ± 7.24 mg/l (P ≤ 0.01) following BPD. FCI increased from 11.15 ± 2.85 to 18.16 ± 6.82 (P ≤ 0.05). Insulin secretion decreased (52.04 ± 16.71 vs. 30.62 ± 16.32 nmol/m−2; P ≤ 0.05), and insulin sensitivity increased by 163% (P ≤ 0.0001). Serum CBG was related to BMI (r0 = 0.708; P = 0.0001), body weight (r0 = 0.643; P = 0.0001), body fat percent (r0 = 0.462; P = 0.001), C-reactive protein (r0 = 0.619; P = 0.004), and leptin (r0 = 0.579; P = 0.007) and negatively to M value (r0 = −0.603; P = 0.005). CONCLUSIONS—After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity

The MRC1/CD68 ratio is positively associated with adipose tissue lipogenesis and with muscle mitochondrial gene expression in humans

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background]: Alternative macrophages (M2) express the cluster differentiation (CD) 206 (MCR1) at high levels. Decreased M2 in adipose tissue is known to be associated with obesity and inflammation-related metabolic disturbances. Here we aimed to investigate MCR1 relative to CD68 (total macrophages) gene expression in association with adipogenic and mitochondrial genes, which were measured in human visceral [VWAT, n = 147] and subcutaneous adipose tissue [SWAT, n = 76] and in rectus abdominis muscle (n = 23). The effects of surgery-induced weight loss were also longitudinally evaluated (n = ).[Results]: MCR1 and CD68 gene expression levels were similar in VWAT and SWAT. A higher proportion of CD206 relative to total CD68 was present in subjects with less body fat and lower fasting glucose concentrations. The ratio MCR1/CD68was positively associated with IRS1gene expression and with the expression of lipogenic genes such as ACACA, FASN and THRSP, even after adjusting for BMI. The ratio MCR1/CD68 in SWAT increased significantly after the surgery-induced weight loss (+44.7%; p = 0.005) in parallel to the expression of adipogenic genes. In addition, SWAT MCR1/CD68ratio was significantly associated with muscle mitochondrial gene expression (PPARGC1A, TFAM and MT-CO3). AT CD206 was confirmed by immunohistochemistry to be specific of macrophages, especially abundant in crown-like structures. [Conclusion]: A decreased ratio MCR1/CD68 is linked to adipose tissue and muscle mitochondrial dysfunction at least at the level of expression of adipogenic and mitochondrial genes. © 2013 moreno-navarrete et al.This work was supported by grant SAF-2009-10461 and grant PI11-00214 from the Ministerio de Economía y Competitividad, Spain.Peer Reviewe

Metabolite Changes After Metabolic Surgery Associations to Parameters Reflecting Glucose Homeostasis and Lipid Levels

Aims: To test the hypothesis that adipose tissue gene expression patterns would be affected by metabolic surgery and we aimed to identify genes and metabolic pathways as well as metabolites correlating with metabolic changes following metabolic surgery. Materials and Methods: This observational study was conducted at the Obesity Unit at the Catholic University Hospital of the Sacred Heart in Rome, Italy. Fifteen patients, of which six patients underwent Roux-en-Y gastric bypass and nine patients underwent biliopancreatic diversion, were included. The participants underwent an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Small polar metabolites were analyzed with a two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Gene expression analysis of genes related to metabolism of amino acids and fatty acids were analyzed in subcutaneous adipose tissue. All procedures were performed at study start and at follow-up (after 185.3 ± 72.9 days). Results: Twelve metabolites were significantly changed after metabolic surgery. Six metabolites were identified as 3-indoleacetic acid, 2-hydroxybutyric acid, valine, glutamic acid, 4-hydroxybenzeneacetic acid and alpha-tocopherol. The branched chain amino acids displayed a significant decrease together with a decrease in BCAT1 adipose tissue mRNA levels. Changes in the identified metabolites were associated to changes in lipid, insulin and glucose levels. Conclusions: Our study has identified metabolites and metabolic pathways that are altered by metabolic surgery and may be used as biomarkers for metabolic improvement