The high-density lipoprotein cholesterol (HDL-C)-concentration-dependent association between anti-inflammatory capacity and sepsis: A single-center cross-sectional study.

INTRODUCTION: Known to have pleiotropic functions, high-density lipoprotein (HDL) helps to regulate systemic inflammation during sepsis. As preserving HDL-C level is a promising therapeutic strategy for sepsis, the interaction between HDL and sepsis worth further investigation. This study aimed to determine the impact of sepsis on HDL's anti-inflammatory capacity and explore its correlations with disease severity and laboratory parameters. METHODS AND MATERIALS: We enrolled 80 septic subjects admitted to the intensive care unit and 50 controls admitted for scheduled coronary angiography in this cross-sectional study. We used apolipoprotein-B depleted (apoB-depleted) plasma to measure the anti-inflammatory capacity of HDL-C. ApoB-depleted plasma's anti-inflammatory capacity is defined as its ability to suppress tumor necrosis factor-α-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical-vein endothelial cells. A subgroup analysis was conducted to investigate in septic subjects according to disease severity. RESULTS: ApoB-depleted plasma's anti-inflammatory capacity was reduced in septic subjects relative to controls (VCAM-1 mRNA fold change: 50.1% vs. 35.5%; p < 0.0001). The impairment was more pronounced in septic subjects with than in those without septic shock (55.8% vs. 45.3%, p = 0.0022). Both associations were rendered non-significant with the adjustment for the HDL-C level. In sepsis patients, VCAM-1 mRNA fold change correlated with the SOFA score (Spearman's r = 0.231, p = 0.039), lactate level (r = 0.297, p = 0.0074), HDL-C level (r = -0.370, p = 0.0007), and inflammatory markers (C-reactive protein level: r = 0.441, p <0.0001; white blood cell: r = 0.353, p = 0.0013). CONCLUSION: ApoB-depleted plasma's anti-inflammatory capacity is reduced in sepsis patients and this association depends of HDL-C concentration. In sepsis patients, this capacity correlates with disease severity and inflammatory markers. These findings explain the prognostic role of the HDL-C level in sepsis and indirectly support the rationale for targeting HDL-C as sepsis treatment.

Vertical Sleeve Gastrectomy Offers Protection against Disturbed Flow-Induced Atherosclerosis in High-Fat Diet-Fed Mice.

Bariatric surgery reduces body weight, enhances metabolic and diabetic control, and improves outcomes on obesity-related comorbidities. However, the mechanisms mediating this protection against cardiovascular diseases remain unclear. We investigated the effect of sleeve gastrectomy (SG) on vascular protection in response to shear stress-induced atherosclerosis using an overweighted and carotid artery ligation mouse model. Eight-week-old male wild-type mice (C57BL/6J) were fed a high-fat diet (HFD) for two weeks to induce weight gain and dysmetabolism. SG was performed in HFD-fed mice. Two weeks after the SG procedure, partial carotid-artery ligation was performed to promote disturbed flow-induced atherosclerosis. Compared with the control mice, HFD-fed wild-type mice exhibited increased body weight, total cholesterol level, hemoglobin A1c, and enhanced insulin resistance; SG significantly reversed these adverse effects. As expected, HFD-fed mice exhibited greater neointimal hyperplasia and atherosclerotic plaques than the control group, and the SG procedure attenuated HFD-promoted ligation-induced neointimal hyperplasia and arterial elastin fragmentation. Besides, HFD promoted ligation-induced macrophage infiltration, matrix metalloproteinase-9 expression, upregulation of inflammatory cytokines, and increased vascular endothelial growth factor secretion. SG significantly reduced the above-mentioned effects. Moreover, HFD restriction partially reversed the intimal hyperplasia caused by carotid artery ligation; however, this protective effect was significantly lower than that observed in SG-operated mice. Our study demonstrated that HFD deteriorates shear stress-induced atherosclerosis and SG mitigates vascular remodeling, and this protective effect was not comparable in HFD restriction group. These findings provide a rationale for using bariatric surgery to counter atherosclerosis in morbid obesity.

Melatonin Improves Ischemia-Induced Circulation Recovery Impairment in Mice with Streptozotocin-Induced Diabetes by Improving the Endothelial Progenitor Cells Functioning.

Patients with diabetes mellitus tend to develop ischemia-related complications and have compromised endothelial progenitor cell (EPC) function. Melatonin protects against ischemic injury, possibly via EPC modulation. We investigated whether melatonin pretreatment could restore EPC function impairment and improve circulation recovery in a diabetic critical limb ischemia mouse model. Under 25 mM high-glucose medium in vitro, EPC proliferation, nitric oxide production, tube formation, and endothelial nitric oxide synthase (eNOS) phosphorylation were significantly suppressed. Hyperglycemia promoted EPC senescence and apoptosis as well as increased reactive oxygen species (ROS) production. Melatonin treatment reversed the harmful effects of hyperglycemia on EPC through adenosine monophosphate-activated protein kinase-related mechanisms to increase eNOS phosphorylation and heme oxygenase-1 expression. In an in-vivo study, after a 4-week surgical induction of hindlimb ischemia, mice with streptozotocin (STZ)-induced diabetes showed significant reductions in new vessel formation, tissue reperfusion, and EPC mobilization in ischemic hindlimbs compared to non-diabetic mice. Mice with STZ-induced diabetes that received melatonin treatment (10 mg/kg/day, intraperitoneal) had significantly improved blood perfusion ratios of ischemic to non-ischemic limb, EPC mobilization, and densities of capillaries. In addition, a murine bone marrow transplantation model to support these findings demonstrated that melatonin stimulated bone marrow-originated EPCs to differentiate into vascular endothelial cells in femoral ligation-induced ischemic muscles. In summary, this study suggests that melatonin treatment augments EPC function along with neovascularization in response to ischemia in diabetic mice. We illustrated the protective effects of melatonin on EPC H2O2 production, senescence, and migration through melatonin receptors and modulating eNOS, AMPK, and HO-1 activities at the cellular level. Thus, melatonin might be used to treat the impairment of EPC mobilization and circulation recuperation in response to ischemic injury caused by chronic hyperglycemia. Additional studies are needed to elucidate the applicability of the results in humans.

Change of cardiovascular risk associated serologic biomarkers after gastric bypass: A comparison of diabetic and non-diabetic Asian patients.

BACKGROUND: While clinical findings demonstrate a superior benefit of cardiovascular (CV) risk reduction in obese patients with type 2 diabetes mellitus (T2D) receiving bariatric surgery over non-T2D patients, the mechanism is unclear. This study aimed to investigate the changes in the CV risk score and five CV-associated biomarkers after gastric bypass surgery. METHOD: We enrolled 80 obese subjects who underwent gastric bypass (40 T2D and 40 non-T2D). CV risks were assessed using the United Kingdom Prospective Diabetes Study (UKPDS) engine before and after surgery. Levels of five biomarkers -fasting serum fibroblast growth factor (FGF)-19, FGF-21, corin, oxidized low-density lipoprotein (ox-LDL), and soluble receptor for advanced glycation end-products (sRAGE)-were measured before surgery and one year after surgery. RESULTS: The T2D group was significantly older and had a higher CV risk score than the non-T2D group, but body mass index (BMI) was similar between the groups. Preoperative biomarker levels were similar in both the T2D and the non-T2D groups. One year after surgery, the percentage of total weight loss (%TWL) was similar between the two groups (32.2 ± 19.5% versus 34.1% ± 8.8%, p = 0.611). Complete T2D remission (hemoglobin A1c (HbA1c) < 6.0%) was achieved in 29 patients (72.5%). The 10-year CV risk scores by the UKPDS risk engine reduced significantly in both the T2D and the non-T2D groups, but more in the T2D group. Three of five biomarkers changed significantly after surgery: the FGF-19 increased from 195.6 ± 249.1 pg/mL to 283.2 ± 211.8 pg/mL, corin increased from 3.3 ± 2.3 ng/mL to 4.6 ± 3.7 ng/mL, and ox-LDL decreased from 148.5 ± 71.7-107.9 U/L; the P values were 0.002, 0.002 and < 0.001, respectively. The T2D group showed a significantly different change in FGF-19 increase and FGF-21 decrease compared to the non-T2D group. The changes in corin and ox-LDL levels were not different between the T2D and non-T2D groups. CONCLUSION: Gastric bypass surgery resulted in a higher UKPDS CV risk score reduction in obese T2D Asians than in those without. FGF-19 and FGF-21 may be associated with the underlying mechanism of this difference.

Sleeve Gastrectomy in Mice using Surgical Clips.

The number of people who are overweight and obese is continually increasing both in the adult and adolescent populations. This coincides with the increased universal phenomenon of type 2 diabetes (T2D) and other metabolic problems. Bariatric surgery, such as SG, is currently one of the most effective and commonly used long-term treatment for obesity and T2D, but the association between them is not completely explored yet. The mechanisms underlying the outcomes seen after bariatric surgery in humans can be investigated based on preclinical animal studies. The SG reduces body weight, glucose levels and many metabolic parameters, and is easy to perform with a low incidence of complications. The goal of this work is to provide a simple method and an uncomplicated preclinical model of bariatric surgery in animals for researchers.

Metabolic surgery ameliorates cardiovascular risk in obese diabetic patients: Influence of different surgical procedures.

BACKGROUND: In recent years, bariatric surgery was found to have therapeutic potential for the treatment of type 2 diabetes (T2D) in severely obese patients (body mass index [BMI] ≥35 kg/m2) and to reduce cardiovascular disease (CVD) risk and mortality. However, the benefit of CVD risk reduction after metabolic surgery in nonseverely obese T2D patients (BMI <35 kg/m2) remained to be proven. OBJECTIVE: To evaluate the CVD risk after metabolic surgery in T2D patients using The UK Prospective Diabetes Study score. SETTING: Tertiary referral general hospital, Taiwan, Republic of China. METHODS: Outcomes of 392 patients (235 women and 147 men) who had undergone sleeve gastrectomy (87) or gastric bypass (305) for treatment of T2D with 1-year follow-up were assessed. Data were prospectively collected for study, and cerebral and coronary heart disease risk was calculated by using The UK Prospective Diabetes Study risk engine. Outcomes of patients who had undergone different surgical procedures were assessed. RESULTS: One year after surgery, weight and glycemic control with complete and partial remission of T2D were significant in most of the patients. The 10-year coronary heart disease risk and fatal coronary heart disease risk were also reduced from 8.8% to 4.6% and from 4.6% to 2.1%, respectively (both P < .001). Similar CVD risk reduction was seen in both patients with BMI ≥35 and BMI <35. Multivariable analysis confirmed that surgical procedure of sleeve gastrectomy was a negative independent predictor of CVD risk reduction after metabolic surgery. CONCLUSION: The present study confirms the efficacy of metabolic surgery for the T2D treatment and reduction of CVD risk up to 50% 1 year after surgery. Gastric bypass surgery has more power on CVD risk reduction than sleeve gastrectomy.

High Incidence of Secondary Hyperparathyroidism in Bariatric Patients: Comparing Different Procedures.

BACKGROUND: Bariatric surgery is an effective therapy for morbid obesity but may reduce calcium absorption and significantly decrease the bone mineral density. This study examined the prevalence of secondary hyperparathyroidism (SHPT) in obese subjects during follow-up after different bariatric surgeries. We investigated predictors of SHPT. METHODS: We enrolled 1470 obese subjects undergoing bariatric/metabolic surgery with at least 1-year follow-up, including 322 patients undergoing Roux-en-Y gastric bypass (RYGB), 695 undergoing single anastomosis (mini-) gastric bypass (SAGB), 93 undergoing laparoscopic adjustable gastric banding (LAGB), and 360 undergoing sleeve gastrectomy (SG). Five years of data were available for 215 patients. Patients were instructed to supplement their diet according to the guideline. Calcium, parathyroid hormone (PTH), and vitamin D levels were measured before surgery and at 1 and 5 years after surgery. SHPT was defined as PTH > 69 pg/mL. RESULTS: The overall prevalence of SHPT was high, 21.0% before surgery and was not different between patients with different bariatric procedures. Pre-operative PTH correlated with age, BMI, and vitamin D levels. Multi-variate analysis confirmed that vitamin D level was the only independent predictor of SHPT before surgery. The prevalence of SHPT increased to 35.4% at 1 year after surgery and 63.3% at 5 years after surgery. SAGB had the highest prevalence of SHPT (50.6%) followed by RYGB (33.2%), LAGB (25.8%), and SG (17.8%) at 1 year after surgery. At 5 years after surgery, SAGB still had the highest prevalence of SHPT (73.6%), followed by RYGB (56.6%), LAGB (38.5%), and SG (41.7%). Serum PTH at 1 year after surgery correlated with decreased BMI and weight loss. Multi-variate analysis confirmed that age, sex, calcium level, and bypass procedure were independent predictor of SHPT after surgery. CONCLUSIONS: The prevalence of SHPT is high in morbidly obese patients before bariatric surgery which is related to vitamin D deficiency. The prevalence of SHPT increased continually along with the time after bariatric surgery, especially in patients receiving SAGB, followed by RYGB. The supplementation of vitamin D and calcium have to be higher in bypass procedure, especially in malabsorptive procedure.

Comparative decline of the protein profiles of nebulin in response to denervation in skeletal muscle.

The sliding filament model of the sarcomere was developed more than half a century ago. This model, consisting only of thin and thick filaments, has been efficacious in elucidating many, but not all, features of skeletal muscle. Work during the 1980s revealed the existence of two additional filaments: the giant filamentous proteins titin and nebulin. Nebulin, a giant myofibrillar protein, acts as a protein ruler to maintain the lattice arrays of thin filaments and plays a role in signal transduction and contractile regulation. However, the change of nebulin and its effect on thin filaments in denervation-induced atrophic muscle remains unclear. The purpose of this study is to examine the content and pattern of nebulin, myosin heavy chain (MHC), actin, and titin in innervated and denervated tibialis anterior (TA) muscles of rats using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), densitometry and electron microscopic (EM) analyses. The results revealed that denervation induced muscle atrophy is accompanied by decreased nebulin content in a time-dependent manner. For instant, the levels of nebulin in denervated muscles were markedly (P < 0.05) decreased, about 24.6% and 40.2% in comparison with innervated muscle after denervation of 28 and 56 days, respectively. The nebulin/MHC, nebulin/actin, and nebulin/titin ratios were decreased, suggesting a concomitant reduction of nebulin in denervated muscle. Moreover, a western blotting assay proved that nebulin declined faster than titin on 28 and 56 days of denervated muscle. In addition, EM study revealed that the disturbed arrangements of myofilaments and a disorganized contractile apparatus were also observed in denervated muscle. Overall, the present study provides evidence that nebulin is more sensitive to the effect of denervation than MHC, actin, and titin. Nebulin decline indeed resulted in disintegrate of thin filaments and shortening of sarcomeres.

Gastro-intestinal Quality of Life After Metabolic Surgery for the Treatment of Type 2 Diabetes Mellitus.

BACKGROUND: Emerging evidence has shown that bariatric/metabolic surgery ameliorates type 2 diabetes (T2DM) in mildly obese patients (BMI < 35 kg/m(2)) but long-term data is inadequate. We investigated the change of the quality of life after metabolic surgery in not well-controlled T2DM patients with BMI < 35 kg/m(2). METHODS: The quality of life was measured by the gastrointestinal quality of life index (GIQLI), a 36-item questionnaire divided into three domains of general health and one domain of specific gastro-intestinal symptoms, administered before operation, at 3, 6, and 12 months after surgery. A control group matched in age, gender, and BMI was recruited for comparison. RESULTS: A total of 86 patients were enrolled, and the preoperative BMI and HbA1C (mean ± SD) were 30.7 ± 2.8 kg/m(2) and 9.3 ± 2.1 %, respectively. At 1 year after surgery, the BMI and HbA1C were 24.3 ± 2.3 kg/m(2) and 6.2 ± 1.1 %, respectively. There was a significantly improvement in all of the measures of glucose metabolism. Complete remission (HbA1C < 6.0 %) was achieved in 56 subjects (65 %) at 12 months. The GIQLI score was significantly impaired in T2DM patients before surgery compared with the control group. The GIQLI score significantly increased from 109.2 ± 20.0 to 116.1 ± 14.2 points 1 year after surgery. The patients had improvement in the three domains of general health (social, physical, and emotional function) without a difference with the normal control but deteriorated in the domain of specific symptoms. Most of the patients experienced symptoms including abdominal pain, bloating, flatulence, belching, abdominal noise, regurgitation, dysphagia, slow eating speed, nausea, bowel urgency, and incontinence after metabolic syndrome. CONCLUSIONS: Health-related QOL improved dramatically after metabolic surgery for not well-controlled T2DM patients with BMI < 35 kg/m(2), but patients might develop specific gastro-intestinal symptoms after surgery.

Laparoscopic sleeve gastrectomy versus single anastomosis (mini-) gastric bypass for the treatment of type 2 diabetes mellitus: 5-year results of a randomized trial and study of incretin effect.

BACKGROUND: Bariatric surgery may be beneficial in mildly obese patients with poorly controlled diabetes. The optimal procedure to achieve diabetes remission is unknown. In 2011, we published the short-term results of a pilot study designed to evaluate the efficacy of diabetic control and the role of duodenal exclusion in mildly obese diabetic patients undergoing laparoscopic sleeve gastrectomy (SG) vs. a laparoscopic single anastomosis (mini-) gastric bypass (SAGB). This study analyzes the 5-year results and evaluates the incretin effect. METHODS: A double-blind randomized trial included 60 participants with a hemoglobin A1c (HbA1c) level higher than 7.5%, a body mass index (BMI) between 25 and 35 Kg/m(2), a C-peptide level ≥1.0 ng/mL, and a diagnosis of type 2 diabetes mellitus (T2DM) for at least 6 months. A SAGB with duodenal exclusion or a SG without duodenal exclusion was performed. RESULTS: The 5-year results of the primary outcome were as an intention-to-treat analysis for HbA1c ≤6.5% without glycemic therapy. Assessments of the incretin effect and ß cell function were performed at baseline and between 36 and 60 months. The patients were randomly assigned to SAGB (n = 30) and SG (n = 30). At 60 months, 18 participants (60%; 95% confidence interval (CI), 42 to 78%) in the SAGB group and nine participants (30%; 95% CI, 13 to 47%) in the SG group achieved the primary end points (odds ratio (OR), 0.3; 95% CI, 0.1 to 0.8%). The participants assigned to the SAGB procedure had a similar percentage of weight loss as the SG patients (22.8 ± 5.9 vs. 20.1 ± 5.3%; p > 0.05) but achieved a lower level of HbA1c (6.1 ± 0.7 vs. 7.1 ± 1.2 %; p < 0.05) than the SG patients. There was a significant increase in the incretin effect before and after surgery in both groups, but the SAGB group had a higher incretin effect than the SG group at 5 years. CONCLUSIONS: In mildly obese patients with T2DM, SG is effective at improving glycemic control at 5 years, but SAGB was more likely to achieve better glycemic control than SG and had a higher incretin effect compared to SG.