Incretins Enhance PGF2α-Induced Synthesis of IL-6 and Osteoprotegerin in Osteoblasts

Incretins including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are secreted from the small intestine after oral food ingestion, are currently well-known to stimulate insulin secretion from pancreatic β-cells and used for the treatment of type 2 diabetes mellitus. We have previously reported that prostaglandin F2α (PGF2α) stimulates the synthesis of interleukin-6 (IL-6) and osteoprotegerin in osteoblast-like MC3T3-E1 cells, and that IL-6 and osteoprotegerin release are mediated through the p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways. In the present study, we investigated the effects of incretins including GLP-1 and GIP, on the PGF2α-induced synthesis of IL-6 and osteoprotegerin and examined the detailed mechanism in osteoblast-like MC3T3-E1 cells. We found that GIP and GLP-1 significantly stimulated the PGF2α-induced synthesis of IL-6 in osteoblast-like MC3T3-E1 cells. In addition, GIP and GLP-1 significantly enhanced the PGF2α-induced mRNA expression levels of IL-6. On the other hand, GIP and GLP-1 markedly stimulated the PGF2α-induced synthesis of osteoprotegerin. However, the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, or JNK induced by PGF2α was not affected by GIP or GLP-1. Therefore, these results strongly suggest that incretins enhance the PGF2α-induced synthesis of IL-6 and osteoprotegerin in osteoblast-like MC3T3-E1 cells. However, these syntheses are not mediated through p44/p42 MAP kinase, p38 MAP kinase, or JNK pathways.

The Association of Thyroid Hormones with Coronary Atherosclerotic Severity in Euthyroid Patients

The aim of the work was to explore the correlation between thyroid hormones and coronary atherosclerotic severity. This cross-sectional study included 340 euthyroid patients who underwent diagnostic coronary artery angiography (CAG). Gensini Score (GS) was applied to assess the severity of coronary atherosclerosis. Thyroid hormones and routine biochemical parameters were measured. The associations between thyroid hormones and coronary atherosclerosis severity were analyzed. Thyroid hormones levels or parameters were taken as both continuous variables and tertiles into analysis, and the lowest tertile was usually used as the reference (OR=1) for medium and highest tertiles. Free triiodothyronine (FT3) level was associated with GS≥22 (Median GS) in Model I adjusted for age and sex [Continuous: OR=0.46, 95% CI (0.23, 0.92), p=0.029; Tertile 3: OR=0.54, 95% CI (0.30, 0.97), p=0.038], and Model II adjusted for all known risk factors of coronary artery disease (CAD) [Continuous: OR=0.44, 95% CI (0.20, 0.95), p=0.036; Tertile 3: OR=0.49, 95% CI (0.25, 0.96), p=0.039]. Subjects with highest tertile of FT3 to free thyroxine (FT4) ratio (FT3/FT4 ratio) appeared to have the remarkably decreased risk of CAD in both Non-adjusted Model [OR=0.49, 95% CI (0.24, 0.98), p=0.044] and Model I [OR=0.45, 95% CI (0.22, 0.93), p=0.031]. Higher FT3 level within normal range was independently and negatively associated with severity of coronary atherosclerosis. Besides, FT3/FT4 ratio was remarkably correlated with the prevalence of CAD in euthyroid population.

Glucocorticoids Increase Fracture Risk and Fracture Prevalence Independently from Bone Mineral Density and Clinical Risk Factors: Results from the Gliwice Osteoporosis (GO) Study

The aim of the study was to establish the influence of glucocorticoids (GC) on fracture risk, probability, and prevalence. A set of 1548 postmenopausal women were divided into study group – treated with GC (n=114, age 66.48±7.6 years) and controls (n=1434, age 66.46±6.83 years). Data on clinical risk factors for osteoporosis and fractures were collected. Hip bone densitometry was performed using a device Prodigy (GE, USA). Fracture probability was established by FRAX, and fracture risk by Garvan algorithm and POL-RISK. Fracture risk and fracture probability were significantly greater for GC-treated women in comparison to controls. In the study group, there were 24, 3, 24, and 6 fractures noted at spine, hip, forearm, and arm, respectively. The respective numbers of fractures reported in controls at those skeletal sites were: 186, 23, 240, and 25. The use of GCs increased significantly prevalence of all major, spine and arm fractures. Also the number of all fractures was affected by GC use. Following factors significantly increased fracture probability: age (OR 1.04 per each year; 95% CI: 1.03–1.06), GC use (OR 1.54; 95% CI: 1.03–2.31), falls (OR 2.09; 95% CI: 1.60–2.73), and FN T-score (OR 0.62 per each unit; 95% CI: 0.54–0.71). In conclusion, in patients treated with GCs the fracture risk, probability, and prevalence were increased. This effect was evident regardless of whether GC therapy is included in the algorithm as a risk factor (FRAX, POL-RISK) or not taken into consideration (Garvan nomogram).

The Triglycerides and Glucose Index is Negatively Associated with Insulin Secretion in Young Adults with Normal Weight

Several studies have supported the usefulness of the triglycerides and glucose (TyG) index as a surrogate measure of insulin resistance; however, it has not been evaluated in insulin secretion. The aim of this study was to assess the association between the TyG index and insulin secretion in young adults with normal weight. Apparently healthy non-pregnant women and men, aged 18 to 23 years, were enrolled in a cross-sectional study. Overweight, obesity, pregnancy, smoking, alcohol consumption, diabetes, liver disease, renal disease, cardiovascular disease, and neoplasia were the exclusion criteria. Normal weight was defined by a body mass index (BMI)≥18.5<25.0 kg/m2 and the TyG index was calculated as the Ln [fasting triglycerides (mg/dl) x fasting glucose (mg/dl)]/2. A total of 1676 young adults with normal-weight, 1141 (68%) women, and 535 (32%) men were enrolled. Of them, 269 (16%) individuals exhibited insulin resistance; 213 (12.7%) women and 56 (3.3%) men. The linear regression analysis adjusted by gender, BMI, and waist circumference showed a significant association between the TyG index and HOMA-B (B=−35.90; 95% CI:−68.25 to−3.54, p=0.03) in the overall population. An additional analysis adjusted by BMI and waist circumference revealed that the TyG index is significantly associated with HOMA-B in subjects with and without insulin resistance (B=−104.73; 95% CI:−204.28 to−5.18, p=0.03 and B=−74.72; 95% CI:−108.04 to−41.40, p<0.001). The results of this study showed that the TyG index is negatively associated with insulin secretion in young adults with normal weight.

Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=−0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.

Association Between Prediabetes and Retinopathy: A Meta-Analysis

Diabetes confers an increased risk of microvascular complications, including retinopathy. However, whether prediabetes is also related to retinopathy has not been comprehensively examined. We performed a meta-analysis to evaluate the relationship between prediabetes and retinopathy. This meta-analysis included relevant observational studies from Medline, Embase, and Web of Science databases. A random-effect model after incorporation of the intra-study heterogeneity was selected to pool the results. Subgroup analyses were applied to evaluate the influences of study characteristics on relationship. Nine cross-sectional studies including 14 751 community dwelling adult participants were included; 3847 (26.1%) of them were prediabetic. Results showed that prediabetes was associated with a higher prevalence of retinopathy compared to normoglycemia [odds ratio (OR): 1.55, 95% confidence interval (CI): 1.10–2.20, p=0.01, I2=34%]. Sensitivity analysis by excluding one study at a time showed consistent result (OR: 1.35 to 1.73, p all<0.05). Subgroup analysis showed study characteristics such as definition of prediabetes, country of study, sample size, mean age of participants, or univariate or multivariate analyses may not significantly affect the association (p for subgroup difference all>0.05). Current evidence suggests that patients with prediabetes may be associated with higher prevalence of retinopathy as compared to those with normoglycemia. Although prospective cohort studies are needed to validate these findings, results of our meta-analysis highlighted the importance of early prevention of retinopathy in patients with prediabetes.

Serum Irisin and Diabetic Nephropathy in Patients with Diabetes Mellitus

Dear Editor,I read the article by Wang et al., who conducted a meta-analysis to investigate the association between serum irisin levels and diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM) 1. The mean serum irisin level in T2DM patients with microalbuminuria was significantly lower than that in T2DM patients with normoalbuminuria. In addition, the mean serum irisin level in T2DM patients with macroalbuminuria was significantly lower than that in T2DM patients with microalbuminuria. Furthermore, the mean serum irisin level in T2DM patients with estimated glomerular infiltration rate (eGFR)<60 ml/min 1.73 m2 was significantly lower than that in T2DM patients with eGFR≥60 ml/min 1.73 m2. The authors concluded that decreased serum irisin level was associated with albuminuria and reduced eGFR in T2DM patients. DN was significantly related to decreased serum irisin level in T2DM patients with dose-response manner. Progression of DN may be considered as advanced DM status, and serum irisin level would reflect glucose intolerance via insulin resistance. I have a comment about their study with special reference to the fundamental relationship between the types of DM and serum irisin levels.

Sunitinib-Induced Hypothyroidism and Survival in Pancreatic Neuroendocrine Tumors

Sunitinib has been approved for the treatment of pancreatic neuroendocrine tumors, renal-cell carcinoma, and gastrointestinal stromal tumors. The elevation of thyroid-stimulating hormone serum levels is a common side effect. Studies suggest a correlation between sunitinib-induced hypothyroidism and treatment outcome in patients with renal-cell carcinoma and gastrointestinal stromal tumors. This study assessed whether sunitinib-induced hypothyroidism is a predictive marker of the objective response rate, progression-free survival, and overall survival in pancreatic neuroendocrine tumor patients. Twenty-nine patients treated with sunitinib for advanced pancreatic neuroendocrine tumors were included. The incidence of sunitinib-induced hypothyroidism was 33%. The median progression-free survival of patients who developed hypothyroidism was 16 months (95% confidence interval: 6.2–25.8 months) as compared with six months among euthyroid patients (95% confidence interval: 0.1–12.2 months) (p=0.02). The median overall survival was 77 months (95% confidence interval: 31.4–122.6 months) in hypothyroid patients but 12 months (95% confidence interval: 5.9–18.1 months) in subjects with euthyroidism (p=0.001). The median overall survival from the time of initial diagnosis ranged from 247 months in patients with hypothyroidism to 65 months in euthyroid subjects (p=0.015). Elevated thyroid-stimulating hormone levels are a prognostic biomarker of improved outcomes of sunitinib therapy in pancreatic neuroendocrine tumor patients.

Long Non-Coding RNA Small Nucleolar RNA Host Gene 5 (SNHG5) Regulates Renal Tubular Damage in Diabetic Nephropathy via Targeting MiR-26a-5p

The study explored the diagnostic value of SNHG5 in diabetic nephropathy (DN) and investigated the role and mechanism on DN via establishing the in vitro HK2 cell model. This study recruited 62 types 2 diabetes mellitus (T2DM) patients, 58 DN patients and 60 healthy controls (HC). The expressions of serum SNHG5 and miR-26a-5p were measured by RT-qPCR analysis. The diagnostic value of SNHG5 in DN was assessed by ROC curve. The in vitro cell model was built to estimate the effects of SNHG5 on cell viability, cell apoptosis, inflammation response and oxidative stress. Serum SNHG5 was increased in DN patients (relative expression: 2.04±0.34) and had the diagnostic value in DN. After HK2 cells were treated with high glucose, the cell viability decreased and apoptosis increased, and the production of inflammatory cytokines and ROS enhanced significantly. It was noticed that inhibition of SNHG5 could reverse the above phenomenon caused by high glucose. Besides, serum miR-26a-5p was diminished in DN patients, and luciferase reporter gene revealed that miR-26a-5p is direct target of SNHG5. These results indicated that inhibition of SNHG5 may mitigate HG-induced renal tubular damage via targeting miR-26a-5p, which providing a new insight into the mechanism of renal tubule damage in DN patients.