Opposite sorting of tissue factor in human umbilical vein endothelial cells and Madin-Darby canine kidney epithelial cells

Tissue factor (TF) is a 48-kD transmembrane glycoprotein that triggers the extrinsic pathway of blood coagulation by interacting with the plasma coagulation factor VII (FVII). TF is also a true receptor in that a cellular signal is generated when activated FVII (FVIIa) binds to TF. For both of these functions, the cellular surface distribution of TF is important, since FVII is primarily available on the apical side of vascular endothelial cells and on the basolateral side of epithelial cells lining the internal and external surfaces. We show that in endothelial cells, TF (both antigen and procoagulant activity) is sorted to the apical surface, whereas in wild-type and stably transfected Madin-Darby canine kidney epithelial cells (MDCK), which form tight junctions and express TF constitutively, TF antigen is on the basolateral surface. No significant clotting activity is detectable on this surface. Truncated TF (cytoplasmic tail residues 246 to 263 deleted) is sorted as wild-type in MDCK cells.     

Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study

Introduction  

Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI).     

Obesity and Type 2 Diabetes: What Can Be Unified and What Needs to Be Individualized?

OBJECTIVE

This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care.

RESEARCH DESIGN AND METHODS

An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6–7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data.

RESULTS

The writing group unanimously supported the summary and recommendations as representing the working group''s majority or unanimous opinions.

CONCLUSIONS

The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to β-cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on β-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost-effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management.Most patients with type 2 diabetes are obese, and the global epidemic of obesity largely explains the dramatic increase in the incidence and prevalence of type 2 diabetes over the past 20 years. Currently, over a third (34%) of U.S. adults are obese (defined as BMI >30 kg/m²), and over 11% of people aged ≥20 years have diabetes (1), a prevalence projected to increase to 21% by 2050 (2). However, the precise mechanisms linking the two conditions remain unclear, as does our understanding of interindividual differences. Improved understanding will help advance identification and development of effective treatment options.Excess weight is an established risk factor for type 2 diabetes, yet most obese individuals do not develop type 2 diabetes. Recent studies have identified “links” between obesity and type 2 diabetes involving proinflammatory cytokines (tumor necrosis factor and interleukin-6), insulin resistance, deranged fatty acid metabolism, and cellular processes such as mitochondrial dysfunction and endoplasmic reticulum stress. These interactions are complex, with the relative importance of each unclearly defined. Further genetic studies may elucidate additional common pathophysiological pathways for obesity and diabetes and identify promising new treatment targets. As physicians frequently prescribe glucose-lowering medications associated with weight gain, trade-offs between glycemic control and body weight with current therapeutic options need more consideration. This issue is particularly pressing given accumulating evidence that even modest weight reduction—whether through lifestyle/behavioral interventions, obesity medications, or bariatric surgery—can improve glycemic control and reduce diabetes risk.These intriguing, but still largely unexplored, connections between obesity and type 2 diabetes suggested the timely need to convene a group of scientific experts in the fields to more closely examine underlying pathophysiology and treatment options for patients with type 2 diabetes addressing issues of excess weight and glycemic control simultaneously. Participants in the January 2011 conference (Supplementary Data) were tasked with examining what is known about the relationship between obesity and type 2 diabetes and the heterogeneity of these conditions, what needs to be learned, and how to direct future research in these areas to advance effective interventions and improve patient care. What follows summarizes the major issues addressed and the outcomes of the discussion.     

Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass

Aims/hypothesis  

Glucagon-like peptide-1 (GLP-1) receptors are highly overexpressed in benign insulinomas, permitting in vivo tumour visualisation with GLP-1 receptor scanning. The present study sought to evaluate the GLP-1 receptor status in vitro in other pancreatic disorders leading to hyperinsulinaemic hypoglycaemia, specifically after gastric bypass surgery.