Meta‐analysis of the association between sodium‐glucose co‐transporter‐2 inhibitors and risk of skin cancer among patients with type 2 diabetes

A slight increase in melanoma risk was observed among sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitor users in the regular reports. However, the association remains uncertain. To address this issue, we performed a systematic search of electronic databases up to May 2, 2018 and a meta‐analysis of 21 randomized controlled trials (RCTs) involving 20 308 patients. We did not find a significant increase in risk of melanoma among SGLT‐2 inhibitor users (Peto odds ratio [OR], 2.17; 95% confidence interval [CI], 0.80‐5.89; I2, 0%). Similar results were observed in the subgroup analyses according to the type of SGLT‐2 inhibitor, type of control, ages of patients, race/ethnicity, and trial durations. For non‐melanoma skin cancer risk, no significant difference was observed when all trials were combined (Peto OR, 0.70; 95% CI, 0.47‐1.07; I2, 0%), while a significantly decreased risk was observed among trials with duration <52 weeks (Peto OR, 0.12; 95% CI, 0.02‐0.59; I2, 0%). No evidence of publication bias was detected in the analyses. Current evidence from RCTs did not support a significantly increased risk of skin cancer associated with SGLT‐2 inhibitors

Identify Innovative Business Models: Can Innovative Business Models Enable Players to React to Ongoing or Unpredictable Trends?

Socioeconomic trends (such as makers, crowdsourcing, sharing economy, gamification) as well as technological trends (such as cloud computing, 3D printing technology, application, big data, TV on demand and the Internet of things) are changing the scenario and creating new opportunities, new businesses and, as a result, new players. The high level of uncertainty caused by the fast speed of innovation technology along with an enormous amount of information difficult to analyse and exploit are characterizing the current framework. On the other hand, businesses such as Netflix – with its 44,000 users and a long tail business model – show a new service based on TV on demand where innovation starts from the convergence between two different industries (TV and the Internet) and spreads on the need of new users. Quirky, with its innovative open business model, is manufacturing new products designed and developed by the community and finally produced with the use of 3D printing technology. While Google in a multi-sided model are giving their new glasses to different developers who build their own application on them, Kickstarter finds its business funders in the crowd, and pays them back with its future products, according to what the organization needs. Another element that adds complexity to the previous framework is the new customer. He or she is showing a social attitude in favour of transparency, openness, collaboration, and sharing. Every second more than 600 tweets are posted on Twitter and around 700 status updates are posted on Facebook. At the same time, people are receiving text messages, e-mails and skype or phone calls and simultaneously consuming TV,radio and print media. In this scenario characterized by trends where employees, funders, customers and partners do not play a stable role but work together with a sort of “platform organization” to create a product or service completely customized for different market niches, how can an organization set up an innovative business model in a defined trend? Is it possible to identify a sort of framework, able to inspire new business models, with an examination of trends? In this article we will use a mix of different approaches to inspire new business model

Shrinkage estimation for robust and efficient screening of single-SNP association from case-control genome-wide association studies

Population-based case-control design has become one of the most popular approaches for conducting genome-wide association scans for rare diseases like cancer. In this article, we propose a novel method for improving the power of the widely used single-single-nucleotide polymorphism (SNP) two-degrees-of-freedom (2 d.f.) association test for case-control studies by exploiting the common assumption of Hardy-Weinberg Equilibrium (HWE) for the underlying population. A key feature of the method is that it can relax the assumed model constraints via a completely data-adaptive shrinkage estimation approach so that the number of false-positive results due to the departure of HWE is controlled. The method is computationally simple and is easily scalable to association tests involving hundreds of thousands or millions of genetic markers. Simulation studies as well as an application involving data from a real genome-wide association study illustrate that the proposed method is very robust for large-scale association studies and can improve the power for detecting susceptibility SNPs with recessive effects, when compared to existing methods. Implications of the general estimation strategy beyond the simple 2 d.f. association test are discussed. Genet. Epidemiol . 33:740–750, 2009. Published 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64559/1/20428_ftp.pd

Metabolomics Applied to Diabetes Research: Moving From Information to Knowledge

Type 2 diabetes is caused by a complex set ofinteractions between genetic and environmentalfactors. Recent work has shown that human type2 diabetes is a constellation of disorders associ-ated with polymorphisms in a wide array of genes, with each individual gene accounting for 1 % of disease risk (1). Moreover, type 2 diabetes involves dysfunction of multiple organ systems, including impaired insulin action in muscle and adipose, defective control of hepatic glu-cose production, and insulin deficiency caused by loss of -cell mass and function (2). This complexity presents challenges for a full understanding of the molecular path-ways that contribute to the development of this major disease. Progress in this area may be aided by the recent advent of technologies for comprehensive metabolic anal-ysis, sometimes termed “metabolomics. ” Herein, we sum-marize key metabolomics methodologies, including nuclear magnetic resonance (NMR) and mass spectrome

In Vivo Conditional Pax4 Overexpression in Mature Islet β-Cells Prevents Stress-Induced Hyperglycemia in Mice

OBJECTIVE To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129 W) in β-cells. RESEARCH DESIGN AND METHODS Glucose homeostasis and β-cell death and proliferation were assessed in Pax4- or Pax4R129 W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and β-cell markers were studied by immunohistochemistry and quantitative RT-PCR. RESULTS Pax4 but not Pax4R129 W protected animals against streptozotocin-induced hyperglycemia and isolated islets from cytokine-mediated β-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1β transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129 W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. CONCLUSIONS Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-κB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of β-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression

The Association of Cardiometabolic, Diet and Lifestyle Parameters With Plasma Glucagon-like Peptide-1: An IMI DIRECT Study

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.Context: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. Objective: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. Methods: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. Results: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. Conclusion: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE - At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS - A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/ 191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS - The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 1

Role of Histone Acetylation in the Stimulatory Effect of Valproic Acid on Vascular Endothelial Tissue-Type Plasminogen Activator Expression

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