Role of tissue factor in delayed bone repair induced by diabetic state in mice

Background Tissue factor (TF) is the primary activator of the extrinsic coagulation protease cascade. Although TF plays roles in various pathological states, such as thrombosis, inflammatory diseases, cancer, and atherosclerosis, its involvement in bone metabolism remains unknown. Materials and methods The present study examined the roles of TF in delayed bone repair induced by a diabetic state in mice using wild-type (WT) and low TF-expressing (LTF) male mice. A diabetic state was induced by intraperitoneal injections of streptozotocin (STZ). Results A prolonged diabetic state significantly reduced total and trabecular bone mineral densities (BMD) as well as cortical bone thickness in WT and LTF mice; these BMD parameters were similar between WT and LTF mice treated with or without STZ. The diabetic state induced in WT mice delayed the repair of the femur following injury. The diabetic state induced in LTF mice was associated with further delays in bone repair. In in vitro experiments, TF significantly decreased receptor activator of nuclear factor-κB ligand-induced osteoclast formation and osteoclastogenic gene expression in RAW264.7 cells. However, it did not affect the gene expression levels of runt-related transcription factor 2 and osterix as well as alkaline phosphatase activity in mouse primary osteoblasts. Conclusion Low TF state was associated with enhanced bone repair delay induced by diabetic state in mice. The TF-induced suppression of bone remodeling may be a contributing factor to the protective effects of TF against delayed bone repair in a diabetic state.

The Role of HbA1c as a Positive Perioperative Predictor of Surgical Site and Other Postoperative Infections: An Explorative Analysis in Patients Undergoing Minor to Major Surgery

Background Patients with diabetes mellitus type 2 (DM2) inhere impaired peripheral insulin action leading to higher perioperative morbidity and mortality rates, with hospital-acquired infections being one important complication. This post hoc, observational study aimed to analyze the impact of surgical and metabolic stress as defined by the surrogate marker hemoglobin A1c (HbA1c), in relation to self-reported DM2, on perioperative infection rates in a subcohort of the Surgical Site Infection (SSI) Trial population. Methods All patients of the SSI study were screened for HbA1c levels measured perioperatively for elective or emergency surgery and classified according to the American Diabetes Association HbA1c cutoff values. SSI and nosocomial infections, self-reported state of DM2 and type of surgery (minor, major) were assessed. Results HbA1c levels were measured in 139 of 5175 patients (2.7%) of the complete SSI study group. Seventy patients (50.4%) self-reported DM2, while 69 (49.6%) self-reported to be non-diabetic. HbA1c levels indicating pre-diabetes were found in 48 patients (34.5%) and diabetic state in 64 patients (46%). Forty-five patients of the group self-reporting no diabetes (65.2%) were previously unaware of their metabolic derangement (35 pre-diabetic and 10 diabetic). Eighteen infections were detected. Most infections (17 of 18 events) were found in patients with HbA1c levels indicating pre-/diabetic state. The odds for an infection was 3.9-fold (95% CI 1.4 to 11.3) higher for patients undergoing major compared to minor interventions. The highest percentage of infections (38.5%) was found in the group of patients with an undiagnosed pre-/diabetic state undergoing major surgery. Conclusions These results encourage investment in further studies evaluating a more generous and specific use of HbA1c screening in patients without self-reported diabetes undergoing major surgery. Trial registration Clinicaltrials.gov identifier: NCT 01790529

Rspo3 regulates the abnormal differentiation of small intestinal epithelial cells in diabetic state

Background The complications caused by diabetes mellitus (DM) are the focus of clinical treatment. However, little is known about diabetic enteropathy (DE) and its potential underlying mechanism. Methods Intestinal epithelial cells (IECs) and intestinal epithelial stem cells (IESCs) were harvested from BKS.Cg-Dock7m+/+Leprdb/JNju (DM) mice, and the expression of R-Spondin 3 (Rspo3) was detected by RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. The role of Rspo3 in the abnormal differentiation of IECs during DM was confirmed by knockdown experiments. Through miRNA expression profiling, bioinformatics analysis, and RT-qPCR, we further analyzed the differentiation-related miRNAs in the IECs from mice with DM. Results Abnormal differentiation of IECs was observed in the mice with DM. The expression of Rspo3 was upregulated in the IECs from the mice with DM. This phenomenon was associated with Rspo3 overexpression. Additionally, Rspo3 is a major determinant of Lgr5+ stem cell identity in the diabetic state. Microarray analysis, bioinformatics analysis, and luciferase reporter assays revealed that microRNA (miR)-380-5p directly targeted Rspo3. Moreover, miR-380-5p upregulation was observed to attenuate the abnormal differentiation of IECs by regulating Rspo3 expression. Conclusions Together, our results provide definitive evidence of the essential role of Rspo3 in the differentiation of IECs in DM.

Recommending encounters according to the sociodemographic characteristics of patient strata can reduce risks from type 2 diabetes

Objectives Physician encounters with patients with type 2 diabetes act as motivation for self-management and lifestyle adjustments that are indispensable for diabetes treatment. We elucidate the sociodemographic sources of variation in encounter usage and the impact of encounter usage on glucose control, which can be used to recommend encounter usage for different sociodemographic strata of patients to reduce risks from Type 2 diabetes. Data and methods We analyzed data from a multi-facility clinic in the Midwestern United States on 2124 patients with type 2 diabetes, from 95 ZIP codes. A zero-inflated Poisson model was used to estimate the effects of various ZIP-code level sociodemographic variables on the encounter usage. A multinomial logistic regression model was built to estimate the effects of physical and telephonic encounters on patients’ glucose level transitions. Results from the two models were combined in marginal effect analyses. Results and conclusions Conditional on patients’ clinical status, demographics, and insurance status, significant inequality in patient encounters exists across ZIP codes with varying sociodemographic characteristics. One additional physical encounter in a six-month period marginally increases the probability of transition from a diabetic state to a pre-diabetic state by 4.3% and from pre-diabetic to the non-diabetic state by 3.2%. Combined marginal effect analyses illustrate that a ZIP code in the lower quartile of high school graduate percentage among all ZIP codes has 1 fewer physical encounter per six months marginally compared to a ZIP code at the upper quartile, which gives 5.4% average increase in the probability of transitioning from pre-diabetic to diabetic. Our results suggest that policymakers can target particular patient groups who may have inadequate encounters to engage in diabetes care, based on their immediate environmental sociodemographic characteristics, and design programs to increase their encounters to achieve better care outcomes.

Insulin-Containing Wound Dressing Promotes Diabetic Wound Healing Through Stabilizing HIF-1α

HIF-1α is seen as a major regulator during wound healing and controls many wound healing processes, such as angiogenesis, extracellular deposition, and reepithelialization. A diabetic state plays a vicious effect on wound healing, and the destabilization of HIF-1α is a non-negligible factor. Insulin-loaded silk fibroin microparticles were prepared to release insulin by covering the wounds, and this material was proven to promote wound healing in both in vitro and in vivo studies. In this work, we found that this insulin-containing wound dressing could accelerate diabetic wound healing by promoting reepithelialization, angiogenesis, and extracellular matrix, especially collagen deposition. Meanwhile, HIF-1α was stable and accumulated in insulin-containing dressing to group wound cells, which was significantly unstable in the control group. In further studies, we showed that methylglyoxal (MGO), the main form of advanced glycation end products (AGEs), accumulated significantly and caused the destabilization of HIF-1α in the diabetic state. Insulin could alleviate the MGO-induced HIF-1α unstable state and promote HIF-1α target gene expression and its downstream biological effect such as angiogenesis and wound extracellular matrix deposition.