The role of traditional Chinese medicine on fracture surgery, hospitalization, and total mortality risks in diabetic patients with osteoporosis.

BACKGROUND: Studies have confirmed that osteoporosis has been considered as one of the complications of diabetes, and the health hazards to patients are more obvious. This study is mainly based on the Taiwan National Health Insurance Database (TNHID). Through the analysis of TNHID, it is shown that the combined treatment of traditional Chinese medicine (TCM) medicine in patients of diabetes with osteoporosis (T2DOP) with lower related risks. METHODS: According to the study design, 3131 patients selected from TNHID who received TCM treatment were matched by 1-fold propensity score according to gender, age, and inclusion date as the control group. Cox proportional hazards analyzes were performed to compare fracture surgery, hospitalization, and all-cause mortality during a mean follow-up from 2000 to 2015. RESULTS: A total of 1055/1469/715 subjects (16.85%/23.46%/11.42%) had fracture surgery/inpatient/all-cause mortality of which 433/624/318 (13.83%/19.93%/10.16%) were in the TCM group) and 622/845/397 (19.87%/26.99%/12.68%) in the control group. Cox proportional hazards regression analysis showed that subjects in the TCM group had lower rates of fracture surgery, inpatient and all-cause mortality (adjusted HR = 0.467; 95% CI = 0.225-0.680, P<0.001; adjusted HR = 0.556; 95% CI = 0.330-0.751, P<0.001; adjusted HR = 0.704; 95% CI = 0.476-0.923, P = 0.012). Kaplan-Meier analysis showed that the cumulative risk of fracture surgery, inpatient and all-cause mortality was significantly different between the case and control groups (all log-rank p<0.001). CONCLUSION: This study provides longitudinal evidence through a cohort study of the value of integrated TCM for T2DOP. More research is needed to fully understand the clinical significance of these results.

Optimizing lipid control in Taiwanese diabetic patients: A collaborative consensus by the Diabetes Association of the Republic of China (Taiwan) and the Taiwanese Association of Diabetes Educators.

We present an in-depth analysis of dyslipidemia management strategies for patients with diabetes mellitus in Taiwan. It critically examines the disparity between established guideline recommendations and actual clinical practices, particularly in the context of evolving policies affecting statin prescriptions. The focus is on synthesizing the most recent findings concerning lipid management in patients with diabetes mellitus, with a special emphasis on establishing consensus regarding low-density lipoprotein cholesterol treatment targets. The article culminates in providing comprehensive, evidence-based recommendations tailored to the unique needs of those living with diabetes mellitus in Taiwan. It underscores the criticality of personalized care approaches, which incorporate multifaceted factors, and the integration of novel therapeutic options to enhance cardiovascular health outcomes.

Extracellular metallothionein as a therapeutic target in the early progression of type 1 diabetes.

Type 1 diabetes (T1D) is characterized by lymphocyte infiltration into the pancreatic islets of Langerhans, leading to the destruction of insulin-producing beta cells and uncontrolled hyperglycemia. In the nonobese diabetic (NOD) murine model of T1D, the onset of this infiltration starts several weeks before glucose dysregulation and overt diabetes. Recruitment of immune cells to the islets is mediated by several chemotactic cytokines, including CXCL10, while other cytokines, including SDF-1α, can confer protective effects. Global gene expression studies of the pancreas from prediabetic NOD mice and single-cell sequence analysis of human islets from prediabetic, autoantibody-positive patients showed an increased expression of metallothionein (MT), a small molecular weight, cysteine-rich metal-binding stress response protein. We have shown that beta cells can release MT into the extracellular environment, which can subsequently enhance the chemotactic response of Th1 cells to CXCL10 and interfere with the chemotactic response of Th2 cells to SDF-1α. These effects can be blocked in vitro with a monoclonal anti-MT antibody, clone UC1MT. When administered to NOD mice before the onset of diabetes, UC1MT significantly reduces the development of T1D. Manipulation of extracellular MT may be an important approach to preserving beta cell function and preventing the development of T1D.

A CRISPR Screen Identifies the E3 Ubiquitin Ligase Rfwd2 as a Negative Regulator of Glucose Uptake in Brown Adipocytes.

Brown adipose tissue activation increases energy expenditure and has been shown to improve glucose tolerance, making it a promising target for the treatment of obesity and type 2 diabetes. Brown adipocytes differentiate into cells with multilocular lipid droplets, which can efficiently absorb and oxidize glucose; however, the mechanisms regulating these processes are not completely understood. We conducted a genome-wide loss-of-function screen using a CRISPR-based approach to identify genes that promote or inhibit adipogenesis and glucose uptake in brown adipocytes. We validated genes that negatively or positively regulated these pathways and verified that the E3-ubiquitin ligase Rfwd2 suppressed brown adipocyte glucose uptake. Brown adipocytes with CRISPR-targeted Rfwd2 deletion showed an altered proteomic landscape and increased basal, as well as insulin-stimulated, glucose uptake. These data reveal the complexity of genetic regulation of brown adipogenesis and glucose metabolism.

DFATs derived from infrapatellar fat pad hold advantage on chondrogenesis and adipogenesis to evade age mediated influence.

Background: Dedifferentiated fat cells (DFATs) are highly homogeneous and multipotent compared with adipose-derived stromal cells (SCs). Infrapatellar fat pad (IFP)-SCs have advanced chondrogenic potency; however, whether IFP-DFATs could serve as better cell material remains unclear. Here, we aimed to examine the influence of age and body mass index (BMI) on the features of IFPs and IFP-derived cells (IFP-SCs and IFP-DFATs) with exploration of the clinical utilization of IFP-DFATs. Methods: We collected IFPs with isolation of paired IFP-SCs and IFP-DFATs from individuals aged 65 years and older with distinct body weights who underwent total knee replacement for osteoarthritis (OA). Flow cytometry was used to characterize the cellular immunophenotypes. Adipogenesis and chondrogenesis were performed in vitro. Real-time qPCR, western blotting, and Oil Red O or Alcian blue staining were performed to evaluate inflammation, adipogenesis, and chondrogenesis. RNA sequencing and Seahorse analyses were conducted to explore the underlying mechanisms. Results: We found that IFPs from old or normal-weight individuals with knee OA were pro-inflammatory, and that interleukin-6 (IL-6) signaling was associated with multiple immune-related molecules, whereas IFP-derived cells could escape the inflammatory properties. Aging plays an important role in diminishing the chondrogenic and adipogenic abilities of IFP-SCs; however, this effect was avoided in IFP-DFATs. Generally, IFP-DFATs presented a steady state of chondrogenesis (less influenced by age) and consistently enhanced adipogenesis compared to paired IFP-SCs in different age or BMI groups. RNA sequencing and Seahorse analysis suggested that the downregulation of eukaryotic initiation factor 2 (EIF2) signaling and enhanced mitochondrial function may contribute to the improved cellular biology of IFP-DFATs. Conclusions: Our data indicate that IFP-DFATs are superior cell material compared to IFP-SCs for cartilage differentiation and adipogenesis, particularly in advanced aging patients with knee OA. The translational potential of this article: These results provide a novel concept and supportive evidence for the use of IFP-DFATs for cell therapy or tissue engineering in patients with knee OA. Using Ingenuity Pathway Analysis (IPA) of RNA-seq data and Seahorse analysis of mitochondrial metabolic parameters, we highlighted that some molecules, signaling pathways, and mitochondrial functions are likely to be jointly coordinated to determine the enhanced biological function in IFP-DFATs.

Gender-specific impacts of thigh skinfold thickness and grip strength for predicting osteoporosis in type 2 diabetes.

BACKGROUND: Diabetes with co-existing bone fragility or osteoporosis is common in elderly patients, whereas is frequently underestimated. METHODS: We conducted dual-energy x-ray absorptiometry (DXA) with 7-site skinfold (SF) and dominant hand grip strength measurements among patients with type 2 diabetes (T2DM) to assess their gender-specific associations. A total of 103 patients with T2DM (60 females and 43 males), aged between 50 and 80 years (median 68.0 years) were enrolled and 45 non-DM females were also included to compare with T2DM females. RESULTS: Our results revealed osteoporosis was negatively correlated with grip strength in both genders, negatively correlated with lean mass solely in males and negatively correlated with fat mass (particular the gynoid fat mass and thigh SF thickness) in females. Via performing multivariable stepwise logistic regression, we identified grip strength in both genders and thigh SF thickness in females as predictors for osteoporosis. Receiver operating characteristic curve analysis further disclosed 20.5 mm female thigh skinfold thickness, 18.1 kg female grip strength and 29.0 kg male grip strength as reasonable cutoff levels for predicting osteoporosis in the Taiwanese patients with T2DM. CONCLUSIONS: Patients with T2DM presented gender-specific associations between osteoporosis, body composition and grip strength. Grip strength and thigh SF thickness might serve as predictors for detection of osteoporosis in patients with T2DM.

The efficacy and safety of combined GLP-1RA and basal insulin therapy among inadequately controlled T2D with premixed insulin therapy.

This study investigated the effect of a combination of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and basal insulin (BI) in poorly controlled type 2 diabetes mellitus previously treated with premixed insulin. The possible therapeutic benefit of the subject is mainly hoped to provide a direction for optimizing treatment options to reduce the risk of hypoglycemia and weight gain. A single-arm, open-label study was conducted. The antidiabetic regimen was switched to GLP-1 RA plus BI to replace previous treatment with premixed insulin in type 2 diabetes mellitus subjects. After 3 months of treatment modification, GLP-1 RA plus BI was compared for superior outcomes by continuous glucose monitoring system. There were 34 subjects at the beginning, 4 withdrew due to gastrointestinal discomfort, and finally 30 subjects completed the trial, of which 43% were male; the average age was 58 ± 9 years old, and the average duration of diabetes was 12 ± 6 years, the baseline glycated hemoglobin level was 8.6 ± 0.9 %. The initial insulin dose of premixed insulin was 61 ± 18 units, and the final insulin dose of GLP-1 RA + BI was 32 ± 12 units (P < .001). Time out of range (from 59%-42%), time-in-range (from 39%-56%) as well as glucose variability index including standard deviation also improved, mean magnitude of glycemic excursions, mean daily difference and continuous population in continuous glucose monitoring system, continuous overall net glycemic action (CONGA). Also noted was a decrease in body weight (from 70.9 kg-68.6 kg) and body mass index (all P values < .05). It provided important information for physicians to decide to modify therapeutic strategy as individualized needs.

LncRNA HOTAIR impairs the prognosis of papillary thyroid cancer via regulating cellular malignancy and epigenetically suppressing DLX1.

PURPOSE: Papillary thyroid cancer (PTC) is the most common endocrine malignancy with a fast-growing incidence in recent decades. HOTAIR as a long non-coding RNA has been shown to be highly expressed in papillary thyroid cancer tissues with only a limited understanding of its functional roles and downstream regulatory mechanisms in papillary thyroid cancer cells. METHODS: We applied three thyroid cancer cell lines (MDA-T32, MDA-T41 and K1) to investigate the phenotypic influence after gain or loss of HOTAIR. The Cancer Genome Atlas (TCGA) database were utilised to select candidate genes possibly regulated by HOTAIR with validation in the cellular system and immunohistochemical (IHC) staining of PTC tissues. RESULTS: We observed HOTAIR was highly expressed in MDA-T32 cells but presents significantly decreased levels in MDA-T41 and K1 cells. HOTAIR knockdown in MDA-T32 cells significantly suppressed proliferation, colony formation, migration with cell cycle retardation at G1 phase. On the contrary, HOTAIR overexpression in MDA-T41 cells dramatically enhanced proliferation, colony formation, migration with cell cycle driven toward S and G2/M phases. Similar phenotypic effects were also observed as overexpressing HOTAIR in K1 cells. To explore novel HOTAIR downstream mechanisms, we analyzed TCGA transcriptome in PTC tissues and found DLX1 negatively correlated to HOTAIR, and its lower expression associated with reduced progression free survival. We further validated DLX1 gene was epigenetically suppressed by HOTAIR via performing chromatin immunoprecipitation. Moreover, IHC staining shows a significantly stepwise decrease of DLX1 protein from normal thyroid tissues to stage III PTC tissues. CONCLUSIONS: Our study pointed out that HOTAIR is a key regulator of cellular malignancy and its epigenetic suppression on DLX1 serves as a novel biomarker to evaluate the PTC disease progression.

Association of dipeptidyl peptidase-4 inhibitor use and the risk of asthma development among type 2 diabetes patients.

BACKGROUND: Numerous studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4i) may regulate immunological pathways implicated in asthma. The association between DPP-4i use and risk of asthma development is limited, however. AIM: We aimed to evaluate if DPP-4i treatment in individuals with type 2 diabetes mellitus (T2DM) is associated with a lower risk and severity of asthma. METHODS: We performed a population-based retrospective cohort study using the Longitudinal National Health Insurance Research database between 2008 and 2015. After one-to-four propensity score matching from 1,914,201 patients with defined criteria, we enrolled 3001 patients who were on DPP-4i (DPP-4i group) for a diagnosis of T2DM but without a diagnosis of asthma for further analysis. Cox proportional hazards regression analysis was performed to estimate and compare the risk of developing and severity of asthma, including no acute exacerbations event (No-AE), acute exacerbations (AEs), status asthmaticus (Status), and required endotracheal intubation (ET-tube intubated), between the two groups. RESULTS: The participants had a mean age of 66.05 ± 17.23 years and the mean follow-up time was 4.96 ± 4.39 years. The risk of asthma development was significantly lower in the DPP-4i group than in the non-DPP-4i group [adjusted hazard ratio (HR) = 0.65; 95% confidence interval (CI) = 0.29-0.83; p < 0.001], with a class effect. This trend was observed for severity of asthma as No-AE (HR = 0.55; 95% CI = 0.24-0.70; p < 0.001), AE (HR = 0.57; 95% CI = 0.26-0.73; p < 0.001), and Status (HR = 0.78; 95% CI = 0.35-0.99; p = 0.047), but not in ET-tube intubated cases (HR = 0.96; 95% CI = 0.43-1.22; p = 0.258). CONCLUSION: The use of DPP-4i decreased the risk and severity of asthma with a class effect among No-AE, AE, status of asthma events, but not in ET-tube intubated events. Our report suggests that DPP-4i may play a role in attenuating the impact of asthma on incidence in the future and on more severe forms of disease exacerbation in T2DM patients.

Dipeptidyl peptidase-4 inhibitors attenuates osteoporosis in patients with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan.

BACKGROUND: Patients with diabetes have a relatively high risk of fracture due to osteoporosis. However, the risk of osteoporosis associated with the use of oral hypoglycemic drugs and dipeptidyl peptidase-4 inhibitor (DPP-4i) by patients with diabetes is unclear. This study aimed to explore the effect of DPP-4i on the risk of osteoporosis in Taiwanese patients with type 2 diabetes mellitus (T2DM). METHODS: This study enrolled 6339 patients on DPP-4i (DPP-4i group) and 25 356 patients without DPP-4i (non-DPP-4i group). They were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication, and index year. Cox proportional hazards analysis was used to compare hospitalization and mortality during an average follow-up period of 7 years. RESULTS: The mean age of patients in the two groups was 66 years. Men were slightly higher in number (51.79%) than women. At the end of the follow-up period, 113 (0.36%) patients had osteoporosis, of which 15 (0.24%) were in the case group and 98 (0.39%) in the control group. The risk of all-cause osteoporosis was significantly lower in the DPP-4i group than in the non-DPP-4i group (adjusted hazard ratio [HR] 0.616; 95% confidence interval [CI] 0.358-0.961; p = 0.011). Kaplan-Meier analysis showed that the preventive effect on osteoporosis was positively correlated with the cumulative dose of DPP-4i (log-rank, p = 0.039) with the class effect. CONCLUSION: Compared with not using DPP-4i, the use of DPP-4i in Taiwanese T2DM patients was associated with a lower risk of osteoporosis due to the class effect, and the preventive effect was dose-dependent. However, larger prospective studies are needed to validate this finding and to explore the possible mechanism of the preventive effect of DPP-4i.

PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue.

Increasing evidence supporting a causal link between obesity and endoplasmic reticulum (ER) stress in adipose tissue is being reported. Protein disulfide isomerase 4 (PDIA4) is a novel ER chaperone involved in the pancreatic ß-cells pathogenesis in diabetes. However, the role of PDIA4 in obesity progression remains poorly understood. To assess the relationship between PDIA4, adiponectin, and metformin, we used the palmitate-induced inflammation in hypertrophic adipocytes and the high-fat diet-induced obesity mouse model. Our results revealed that palmitate-induced hypertrophic adipocytes exhibit obesity-associated conditions such as increased lipid accumulation, inflammation, and reduced glucose uptake. Pharmacological and genetic inhibition of PDIA4 significantly reverses these obesity-associated conditions in adipocytes. PDIA4 mechanistically promotes obesity progression via adiponectin downregulation. Furthermore, metformin modulates PDIA4 and adiponectin expression and improves obesity-associated conditions in both in vitro adipocytes and in vivo mouse models. Serum PDIA4 concentrations are also associated with body mass index, adiponectin, triglycerides, and inflammatory cytokines in humans. This is the first study demonstrating that PDIA4 modulates adipocytes by downregulating adiponectin. Moreover, metformin may serve as a potential therapeutic for preventing obesity via PDIA4-targeting.

Association between Non-Steroidal Anti-Inflammatory Drugs Use and the Risk of Type 2 Diabetes Mellitus: A Nationwide Retrospective Cohort Study.

BACKGROUND: Although the link between non-steroidal anti-inflammatory drugs (NSAIDs) and tramadol and symptomatic hypoglycemia has been documented, there is a limited understanding of the associations of NSAIDs and tramadol with the risk of type 2 diabetes mellitus (T2DM). This study was established to evaluate the association between the clinical use of NSAIDs and the risk of T2DM. PATIENTS AND METHODS: A historical cohort study was conducted using the National Health Insurance Research Database in Taiwan dated from 2000 to 2013. Patients who received NSAIDs for at least 3 prescription orders and without co-treatment of tramadol in the exposure period (from 2000 to 2005) were considered as the exposed cohort (n = 3047). In comparison, patients who received tramadol for at least 3 prescription orders and without concomitant use of NSAIDs in the exposure period were considered as the comparison cohort (n = 9141). The primary outcome was the occurrence of T2DM. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) derived from the Cox proportional hazard models were applied to determine the association between NSAIDs use and the risk of T2DM. RESULTS: In the average follow-up period of 9.56 years, there were 159 newly diagnosed T2DM, with an incidence rate of 56.96 per 10,000 person years in the exposed cohort. Comparatively, there were 1737 incident T2DM cases, with an incidence rate of 161.23 per 10,000 person years in the comparison cohort. Compared to the comparison cohort, the NSAIDs cohort showed a significantly reduced risk of T2DM with an adjusted HR of 0.31 (95% CI, 0.26-0.36). CONCLUSIONS: Our cohort study provides longitudinal evidence that the use of NSAIDs was associated with a reduced risk of T2DM.

Circulating protein disulfide isomerase family member 4 is associated with type 2 diabetes mellitus, insulin sensitivity, and obesity.

AIMS: Endoplasmic reticulum (ER) stress is associated with obesity and type 2 diabetes mellitus (T2DM) and increasing evidence demonstrates that some ER stress markers can represent the severity of metabolic dysfunction in either cellular or animal models. However, no appropriate molecule has been identified to demonstrate these relationships in clinical practice. METHODS: To determine whether the serum level of the ER chaperone, protein disulfide isomerase family A, member 4 (PDIA4), is associated with type 2 diabetes mellitus, obesity, and insulin sensitivity, we conducted a cross-sectional study for which a total of 553 adults, including 159 with normal glucose tolerance (NGT), 169 with prediabetes (Pre-DM), and 225 with newly diagnosed T2DM, were recruited. RESULTS: Serum PDIA4 levels were significantly higher in patients with T2DM than in those with NGT (P < 0.001), even after adjustment for potential confounders. These levels correlated positively with fasting plasma glucose, BMI, waist circumference as well as high-sensitivity C-reactive protein levels, and negatively and strongly correlated with insulin sensitivity. In a multivariate logistic regression analysis, higher serum PDIA4 concentration was observed to be significantly associated with an increased risk of T2DM. CONCLUSIONS: Our findings provide new mechanistic insights linking ER stress, T2DM, insulin sensitivity, and obesity, which may, in part, account for the ER chaperone properties associated with PDIA4. The results suggest that PDIA4 may serve as a potential instigator of and a putative therapeutic target for T2DM.

Association between glucokinase regulator gene polymorphisms and serum uric acid levels in Taiwanese adolescents.

The glucokinase regulator gene (GCKR) is located on chromosome 2p23. It plays a crucial role in maintaining plasma glucose homeostasis and metabolic traits. Recently, genome-wide association studies have revealed a positive association between hyperuricemia and GCKR variants in adults. This study investigated this genetic association in Taiwanese adolescents. Data were collected from our previous cross-sectional study (Taipei Children Heart Study). The frequencies of various genotypes (CC, CT, and TT) or alleles (C and T) of the GCKR intronic single-nucleotide polymorphism (SNP) rs780094 and the coding SNP rs1260326 (Pro446Leu, a common 1403C-T transition) were compared between a total of 968 Taiwanese adolescents (473 boys, 495 girls) with hyperuricemia or normal uric acid levels on the basis of gender differences. Logistic and linear regression analyses explored the role of GCKR in abnormal uric acid (UA) levels. Boys had higher UA levels than girls (6.68 ± 1.29 and 5.23 ± 0.95 mg/dl, respectively, p < 0.001). The analysis of both SNPs in girls revealed that the T allele was more likely to appear in patients with hyperuricemia than the C allele. After adjusting for confounders, the odds ratio (OR) for hyperuricemia incidence in the TT genotype was 1.75 (95% confidence interval [CI] 1.02-3.00), which was higher than that in the C allele carriers in rs1260326 in the girl population. Similarly, the TT genotypes had a higher risk of hyperuricemia, with an OR of 2.29 (95% CI 1.11-4.73) for rs1260326 and 2.28 (95% CI 1.09-4.75) for rs780094, than the CC genotype in girl adolescents. The T (Leu446) allele of GCKR rs1260326 polymorphism is associated with higher UA levels in Taiwanese adolescent girls.

Traditional Chinese medicine attenuates hospitalization and mortality risks in diabetic patients with carcinoma in situ in Taiwan.

BACKGROUND: Diabetic patients are at high risk of developing cancer. Traditional Chinese medicine (TCM) has become increasingly popular as an adjuvant treatment for patients with chronic diseases, and some studies have identified its beneficial effect in diabetic patients with cancer. The purpoes of this study was to outline the potential of TCM to attenuate hospitalization and mortality rates in diabetic patients with carcinoma in situ (CIS). METHODS: A total of 6,987 diabetic subjects with CIS under TCM therapy were selected from the National Health Insurance Research Database of Taiwan, along with 38,800 of 1:1 sex-, age-, and index year-matched controls without TCM therapy. Cox proportional hazard analysis was conducted to compare hospitalization and mortality rates during an average of 15 years of follow-up. RESULTS: A total of 3,999/1,393 enrolled-subjects (28.62%/9.97%) had hospitalization/mortality, including 1,777/661 in the TCM group (25.43%/9.46%) and 2,222/732 in the control group (31.80%/10.48%). Cox proportional hazard regression analysis showed a lower rate of hospitalization and mortality for subjects in the TCM group (adjusted HR=0.536; 95% CI=0.367-0.780, P<0.001; adjusted HR=0.783; 95% CI=0.574-0.974, P = 0.022). Kaplan-Meier analysis showed that the cumulative risk of hospitalization and mortality in the case and control groups was significantly different (log rank, P<0.001 and P = 0.011, respectively). CONCLUSIONS: Diabetic patients with CIS under TCM therapy were associated with lower hospitalization and mortality rates compared to those without TCM therapy. Thus, TCM application may reduce the burden of national medical resources.

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

Introduction: Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle. Methods: Herein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4. Results: In C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects. Discussion: Thus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.

High-Molecular-Weight Hyaluronic Acid Inhibits IL-1ß-Induced Synovial Inflammation and Macrophage Polarization through the GRP78-NF-κB Signaling Pathway.

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1ß to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1ß increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1ß-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1ß culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

Growth arrest-specific 6 modulates adiponectin expression and insulin resistance in adipose tissue.

AIMS/INTRODUCTION: Obesity is characterized by disturbed adipocytokine expression and insulin resistance in adipocytes. Growth arrest-specific 6 (GAS6) is a gene encoding the Gas6 protein, which is expressed in fibroblasts, and its related signaling might be associated with adipose tissue inflammation, glucose intolerance and insulin resistance. The aim of this study was to investigate the associations among Gas6, adipocytokines and insulin resistance in adipocytes. MATERIALS AND METHODS: Mature Simpson Golabi Behmel Syndrome adipocytes were treated with high levels of insulin to mimic insulin resistance, and were examined for the expressions of Gas6, cytokines and adipocytokines from preadipocytes in differentiation. In an animal study, high-fat diet-induced obese mice were used to verify the Gas6 expression in vitro. RESULTS: During the differentiation of adipocytes, the expression of Gas6 gradually decreased, and was obviously downregulated with adipocyte inflammation and insulin resistance. Gas6 levels were found to be in proportion to the expression of adiponectin, which has been regarded as closely relevant to improved insulin sensitivity after metformin treatment. Similar results were also confirmed in the animal study. CONCLUSIONS: Our results suggest that Gas6 might modulate the expression of adiponectin, and might therefore be associated with insulin resistance in adipose tissues.

Metformin Attenuates Osteoporosis in Diabetic Patients with Carcinoma in Situ: A Nationwide, Retrospective, Matched-Cohort Study in Taiwan.

Patients with diabetes are at increased risk of cancer development and osteoporosis. Metformin is an effective agent for diabetes management. Epidemiological studies have identified an association between metformin use and cancer prevention. This article outlines the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ (CIS). From the National Health Insurance Research Database of Taiwan, 7827 patients with diabetes with CIS who were receiving metformin therapy were selected, along with 23,481 patients as 1:3 sex-, age- and index year-matched controls, who were not receiving metformin therapy. A Cox proportional hazard analysis was used to compare the rate of osteoporosis during an average of 15-year follow-up. Of the subjects who were enrolled, 801 (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%). The metformin group presented a lower rate of osteoporosis at the end of follow-up (p = 0.009). The Cox proportional hazard regression analysis revealed a lower rate of osteoporosis for the metformin group (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691-0.972, p = 0.022). Diabetic patients with CIS under metformin therapy presented lower osteoporosis rate than those who were not receiving metformin therapy.

Comparison of 7-site skinfold measurement and dual-energy X-ray absorptiometry for estimating body fat percentage and regional adiposity in Taiwanese diabetic patients.

Obesity and regional adiposity are important risk factors for cardiometabolic disorders. The aim of this study is to compare 7-site skinfold (SF) measurement to dual-energy x-ray absorptiometry (DXA) as the reference method for estimating body fat percentage (BF%) and regional adiposity in diabetic outpatients. A total of 59 diabetic patients (36 females and 23 males) aged 28.5-78 years (median 67.7 years) with BMI 18.8-40.6 kg/m2 (median: 25.5 kg/m2) were enrolled. 7-site skinfold measurement and DXA were performed at the same visit day and biochemistry data were collected. Our results demonstrate the BF% calculated via Jackson & Pollock 7-site skinfold equation presents a strong correlation (r = 0.672, p < 0.001 in females; r = 0.885, p < 0.001 in males) with that measured by DXA, but the means of BF% between these two methods are significantly different in both sexes (paired t-test, p < 0.001). The Bland-Altman analysis showed the mean differences (DXA-SF) of BF% were positive for female (8.74%) and male (7.22%), suggesting Jackson & Pollock 7-site skinfold equation tends to underestimate the BF%. Besides, regional SF thicknesses of 7-site skinfold measurement were significantly correlated with the matched regional adiposity quantified by DXA. Furthermore, truncal and android SF thicknesses were notably positively correlated with several cardiometabolic risk factors in gender-specific manner. Our data indicate the 7-site skinfold measurement is not an interchangeable method for precisely measuring BF%, but might be practical for evaluating the cardiometabolic risks in Taiwanese diabetic outpatients.