Angiopoietin-Like 8 in Gestational Diabetes Mellitus: Reduced Levels in Third Trimester Maternal Serum and Placenta, Increased Levels in Cord Blood Serum.

Gestational diabetes mellitus (GDM) poses a significant health risk to pregnant women, and thus exploring the potential underlying mechanism is highly desirable. The aim of the study was to compare maternal serum, cord blood serum, and placental angiopoietin-like 8 (ANGPTL8) levels in the third trimester of pregnancy in women with and without gestational diabetes and explore the potential underlying mechanism. A total of 42 pregnant women (23 with GDM and 19 with normal glucose tolerance (NGT)) along with 29 age-matched non-pregnant healthy females were enrolled. All pregnant subjects were in the late third trimester. Maternal serum and cord blood serum ANGPTL8 levels were measured with an enzyme-linked immunosorbent assay and the protein levels of ANGPTL8 in placentas were assessed with western blotting. The associations between maternal serum and cord blood serum ANGPTL8 levels and metabolic parameters were investigated with the Spearman correlation analysis. Significantly lower levels of maternal serum and placental ANGPTL8 levels were observed in GDM patients compared to NGT pregnant women, while remarkably higher ANGPTL8 levels were present in the cord blood serum samples. The maternal serum ANGPTL8 level was positively correlated with BMI, total cholesterol, triglycerides, and AUC for OGTT and birthweight. Additionally, the cord blood serum ANGPTL8 level was positively correlated with insulin and the homeostatic model assessment for insulin resistance. Both maternal serum and cord blood serum ANGPTL8 levels seemed to correlate with GDM and has the potential to be used as a biomarker for GDM and birthweight prediction.

Hyperbaric oxygen treatment improves pancreatic ß­cell function and hepatic gluconeogenesis in STZ­induced type­2 diabetes mellitus model mice.

Type­2 diabetes mellitus (T2DM) causes several complications that affect the quality of life and life span of patients. Hyperbaric oxygen therapy (HBOT) has been used to successfully treat several diseases, including carbon monoxide poisoning, ischemia, infections and diabetic foot ulcer, and increases insulin sensitivity in T2DM. The present study aimed to determine the effect of HBOT on ß­cell function and hepatic gluconeogenesis in streptozotocin (STZ)­induced type­2 diabetic mice. To establish a T2DM model, 7­week­old male C57BL/6J mice were fed a high­fat diet (HFD) and injected once daily with low­dose STZ for 3 days after 1­week HFD feeding. At the 14th week, HFD+HBOT and T2DM+HBOT groups received 1­h HBOT (2 ATA; 100% pure O2) daily from 5:00 to 6:00 p.m. for 7 days. The HFD and T2DM groups were maintained under normobaric oxygen conditions and used as controls. During HBOT, the 12­h nocturnal food intake and body weight were measured daily. Moreover, blood glucose was measured by using a tail vein prick and a glucometer. After the final HBO treatment, all mice were sacrificed to conduct molecular biology experiments. Fasting insulin levels of blood samples of sacrificed mice were measured by an ultrasensitive ELISA kit. Pancreas and liver tissues were stained with hematoxylin and eosin, while immunohistochemistry was performed to determine the effects of HBOT on insulin resistance. TUNEL was used to determine the effects of HBOT on ß­cell apoptosis, and immunoblotting was conducted to determine the ß­cell apoptosis pathway. HBOT notably reduced fasting blood glucose and improved insulin sensitivity in T2DM mice. After HBOT, ß­cell area and ß­cell mass in T2DM mice were significantly increased. HBOT significantly decreased the ß­cell apoptotic rate in T2DM mice via the pancreatic Bcl­2/caspase­3/poly(ADP­ribose) polymerase (PARP) apoptosis pathway. Moreover, HBOT improved the morphology of the liver tissue and increased hepatic glycogen storage in T2DM mice. These findings suggested that HBOT ameliorated the insulin sensitivity of T2DM mice by decreasing the ß­cell apoptotic rate via the pancreatic Bcl­2/caspase­3/PARP apoptosis pathway.

The Association of Trp64Arg Polymorphism in the Beta-Adrenergic Receptor With Insulin Resistance: Meta-Analysis.

Background: Insulin resistance is a metabolic disorder that occurs in type 2 diabetes mellitus and obesity. Genetic factors such as ß3-adrenoceptor polymorphism (Trp64Arg) may be involved in IR and insulin secretion. However, their association is controversial. Therefore, the current meta-analysis was conducted to clarify the relationship between the Trp64Arg and IR. Methods: The literature search was performed in PubMed, Embase, and Web of Science using the keywords "Receptors, Adrenergic, beta-3, Receptors, Adrenergic, Insulin Resistance, Protein-Coupled Receptor Kinase 3" from 2005 to February 7, 2021. We used a random-effects model to calculate the pooled effect size. We conducted subgroup analysis and regression analysis to identify sources of heterogeneity; and Egger's test and funnel plot were used to test publication bias. Finally, we conducted a sensitivity analysis. Results: We included eight papers with 1,586 subjects. There was a positive correlation between Trp64Arg mutation and insulin level (standardized mean difference = 0.20, 95% confidence intervals: 0.00 to 0.39, I2 = 57.6%, p = 0.016). However, there was no association between Trp64Arg and the homeostasis model (HOMA-IR) assessment. Egger's tests showed no publication bias; the sensitivity analysis showed that our results were stable. Regression analysis revealed no source of heterogeneity. Conclusion: Trp64Arg may be associated with IR. European ancestry, obesity, plasma insulin level, and test status may be potential factors affecting the relationship between Trp64Arg and IR.

The effects of bariatric surgery on dyslipidemia and insulin resistance in overweight patients with or without type 2 diabetes: a systematic review and network meta-analysis.

Obesity has become an epidemic in several regions globally; it may lead to cardiovascular diseases, diabetes, and dyslipidemia. Despite many therapies, all bariatric procedures fail in some patients. There is a lack of literature comparing treatment effects on specific metabolic indexes. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant articles. GeMTC and R software were used to perform a network meta-analysis, draw forest plots, investigate the possibility of statistical heterogeneity, generate I2 statistics, rank probabilities, and evaluate relative effects of surgical procedures. All analyses were based on a Bayesian consistency model. We included 35 randomized controlled trials, comprising 2198 individuals and 13 interventions. For patients with high insulin resistance, single-anastomosis (mini-) gastric bypass (SAGB) and sleeve gastrectomy (SG) may be effective options, with mean differences (95% confidence intervals [CIs]) of -4.45 (-9.04 to -.34) and -4.23 (-6.74 to -2.22), respectively, compared with control groups. For patients with severe dyslipidemia, in addition to SAGB and SG, duodenal switch (DS) may be an effective surgery, with mean differences (95% CIs) of -.97 (-1.39 to -.55), -1.98 (-3.76 to -.19), .53 (.04 to 1.04), and -.94 (-1.66 to -.16) compared with control groups in terms of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations, respectively. In adult overweight patients with or without diabetes, SAGB and SG are most effective at ameliorating insulin resistance. SAGB, Roux-en-Y gastric bypass + omentectomy, and DS are useful for reducing triglycerides, total cholesterol, and LDL-C. SG + omentectomy elevates HDL-C concentrations best. Adjustable gastric band and biliopancreatic diversion may not control insulin resistance or dyslipidemia well.

Association Between Serum Insulin and C-Peptide Levels and Breast Cancer: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have reported that hyperinsulinemia plays a part in the etiology of breast cancer. However, no consensus has been reached. Therefore, we conducted a meta-analysis to explore the role of insulin and C-peptide in breast cancer. METHODS: A systematic search in PubMed, Embase, and The Cochrane Library was conducted up to September, 2020. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to measure effect sizes. Publication bias was assessed using the Egger test. Stability of these results was evaluated using sensitivity analyses. RESULTS: Fourteen articles including 27,084 cases and five articles including 2,513 cases were extracted for serum insulin levels and C-peptide levels. We found that C-peptide levels were positively associated with breast cancer with overall SMD = 0.37 (95% CI = 0.09-0.65, I2 = 89.1%). Subgroup analysis by control source illustrated a positive relationship between breast cancer and C-peptide levels in population-based control. Subgroup analysis by C-peptide level indicated a positive correlation between breast cancer and C-peptide levels no matter C-peptide levels in case group is ≤3 ng/ml or >3 ng/ml. Subgroup analysis by age showed that C-peptide level positively correlated to breast cancer in women between the ages of 50 and 60. However, we did not identify any relationship between breast cancer and insulin levels (SMD = 0.22, 95% CI = -0.06-0.50, I2 = 97.3%). CONCLUSION: This meta-analysis demonstrated that C-peptide levels were positively related to breast cancer in women, and no relationship between insulin levels and breast cancer was found.

Ghrelin in the lateral parabrachial nucleus influences the excitability of glucosensing neurons, increases food intake and body weight.

Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR-/- mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR-/- mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.

Ghrelin system is involved in improvements in glucose metabolism mediated by hyperbaric oxygen treatment in a streptozotocin­induced type 1 diabetes mouse model.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder for which the only effective therapy is insulin replacement. Hyperbaric oxygen (HBO) therapy has demonstrated potential in improving hyperglycemia and as a treatment option for T1DM. Ghrelin and HBO have been previously reported to exert proliferative, anti­apoptotic and anti­inflammatory effects in pancreatic cells. The present study investigated the mechanism underlying HBO­ and ghrelin system­mediated regulation of glucose metabolism. Male C57BL/6 mice were intraperitoneally injected with streptozotocin (STZ; 150 mg/kg) to induce T1DM before the diabetic mice were randomly assigned into the T1DM and T1DM + HBO groups. Mice in the T1DM + HBO group received HBO (1 h; 100% oxygen; 2 atmospheres absolute) daily for 2 weeks. Significantly lower blood glucose levels and food intake were observed in mice in the T1DM + HBO group. Following HBO treatment, islet ß­cell area were increased whereas those of α­cell were decreased in the pancreas. In addition, greater hepatic glycogen storage in liver was observed, which coincided with higher pancreatic glucose transporter 2 (GLUT2) expression levels and reduced hepatic GLUT2 membrane trafficking. There were also substantially higher total plasma ghrelin concentrations and gastric ghrelin­O­acyl transferase (GOAT) expression levels in mice in the T1DM + HBO group. HBO treatment also abolished reductions in pancreatic GOAT expression levels in T1DM mice. Additionally, hepatic growth hormone secretagogue receptor­1a levels were found to be lower in mice in the T1DM + HBO group compared with those in the T1DM group. These results suggest that HBO administration improved glucose metabolism in a STZ­induced T1DM mouse model. The underlying mechanism involves improved insulin­release, glucose­sensing and regulation of hepatic glycogen storage, an observation that was also likely dependent on the ghrelin signalling system.

The Effects of Hyperbaric Oxygen Therapy on Pelvic Radiation Induced Gastrointestinal Complications (Rectal Bleeding, Diarrhea, and Pain): A Meta-Analysis.

Background: Radiotherapy is a routine treatment for pelvic cancer patients. While it had been proven effective, gastrointestinal side effects remain a concern, impairing the quality of life. A few studies focused on the effects of hyperbaric oxygen (HBO) treatment to alleviate radiation-induced gastrointestinal complications. This meta-analysis aimed to critically review and summarize existing literature, assessing the effectiveness of HBO therapy for the treatment of radiation-induced gastrointestinal side effects. Methods: Medical literature search was performed with PubMed, Cochrane Library, and EMBASE up to March 14, 2019. Literatures about HBO treatment upon patients undergoing pelvic cancer (endometrial, cervix, rectum, or prostate cancers) radiotherapy were collected, and the effects of HBO treatment on radiotherapy-induced gastrointestinal complications were evaluated. A random-effects model was used to calculate the pooled effect size. Subgroup analyses were performed to search for sources of heterogeneity. Publication bias was detected with Funnel plots and Egger's test. Results: Three different radiotherapy-related gastrointestinal complications, including rectal bleeding, diarrhea, and pain, were analyzed after screening. It was revealed that the improvement rates were considerable in rectal bleeding (0.81, 95% CI: 0.74-0.89) and diarrhea (0.75, 95% CI: 0.61-0.90) and slightly in pain (0.58, 95% CI: 0.38-0.79). Subgroup analysis revealed factors that significantly influenced the heterogeneity of rectal bleeding, diarrhea, and pain (evaluation criteria, follow-up time, and scoring system, respectively). No significant publication bias was detected. Conclusion: HBO treatment might have the potential to alleviate radiotherapy-related gastrointestinal complications, including rectal bleeding, diarrhea, and pain, but more data are needed for further conclusions. Other symptoms were not further analyzed, as the number of studies was insufficient. More large-scale and prospective studies are needed for better evaluation of HBO's therapeutic values.

Hyperbaric Oxygen Ameliorates Insulin Sensitivity by Increasing GLUT4 Expression in Skeletal Muscle and Stimulating UCP1 in Brown Adipose Tissue in T2DM Mice.

Hyperbaric oxygen (HBO) therapy is a treatment modality useful for diseases. Hypoxia could stimulate the induction of insulin resistance. Therefore, we sought to determine whether hyperbaric oxygen would ameliorate insulin sensitivity by promoting glucose transporter type 4 (GLUT4) expression in muscle and by stimulating UCP1 in brown adipose tissue (BAT) in a streptozocin (STZ)-induced type 2 diabetes mellitus (T2DM) mouse model. Male C57BL/6J mice were treated three times with low-dose of streptozocin (60 mg/kg, i.p.) and were fed with high-fat diets (HFD) to establish the T2DM model. HBO was administered daily as 100% oxygen at 2.0 atmosphere absolute (ATA) for 1 h for a week. We found that HBO significantly reduced blood glucose levels and attenuated insulin resistance in T2DM mice. HBO modulated food intake by influencing the activity of neuropeptide Y (NPY)-positive neurons in the arcuate nucleus (Arc). HBO treatment increased GLUT4 amount and level of phosphorylated Akt (p-Akt) in muscles of T2DM mice whereas this treatment stimulated the phosphorylation of AMPK in muscles of both T2DM and HFD mice. The morphological staining of BAT and the increased expression of uncoupling of protein 1 (UCP1) demonstrated the promotion of metabolism after HBO treatment. These findings suggest that HBO ameliorates insulin sensitivity of T2DM mice by stimulating the Akt signaling pathway and by promoting GLUT4 expression in muscle, and by increasing UCP1 expression in BAT.

L-Carnitine Is Involved in Hyperbaric Oxygen-Mediated Therapeutic Effects in High Fat Diet-Induced Lipid Metabolism Dysfunction.

Lipid metabolism dysfunction and obesity are serious health issues to human beings. The current study investigated the effects of hyperbaric oxygen (HBO) against high fat diet (HFD)-induced lipid metabolism dysfunction and the roles of L-carnitine. C57/B6 mice were fed with HFD or normal chew diet, with or without HBO treatment. Histopathological methods were used to assess the adipose tissues, serum free fatty acid (FFA) levels were assessed with enzymatic methods, and the endogenous circulation and skeletal muscle L-carnitine levels were assessed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, western blotting was used to assess the expression levels of PPARα, CPT1b, pHSL/HSL, and UCP1. HFD treatment increased body/adipose tissue weight, serum FFA levels, circulation L-carnitines and decreased skeletal muscle L-carnitine levels, while HBO treatment alleviated such changes. Moreover, HFD treatment increased fatty acid deposition in adipose tissues and decreased the expression of HSL, while HBO treatment alleviated such changes. Additionally, HFD treatment decreased the expression levels of PPARα and increased those of CPT1b in skeletal muscle, while HBO treatment effectively reverted such changes as well. In brown adipose tissues, HFD increased the expression of UCP1 and the phosphorylation of HSL, which was abolished by HBO treatment as well. In summary, HBO treatment may alleviate HFD-induced fatty acid metabolism dysfunction in C57/B6 mice, which seems to be associated with circulation and skeletal muscle L-carnitine levels and PPARα expression.

Central nesfatin-1 activates lipid mobilization in adipose tissue and fatty acid oxidation in muscle via the sympathetic nervous system.

Little is known about the influence of central nesfatin-1 on lipid metabolism under diabetic conditions. The main objective of this study was to characterize the mechanisms by which central nesfatin-1 regulates lipid metabolism in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) and whether the sympathetic nervous system is involved. Male Kunming mice were fed high-fat diets (HFDs) and were treated twice with low-dose STZ (100 mg/kg, intraperitoneal [IP]) to generate the T2DM model. Pharmacological adrenergic blockage (phentolamine 10 mg/kg, propranolol 0.017 mmol) and surgical denervation of sympathetic nervous system of the hindlimb and inguinal fat were used to block nerve conduction to determine whether the effect of central nesfatin-1 required the hypothalamic-sympathetic nervous system axis. Plasma free fatty acid (FFA) and insulin levels were measured. AMP-activated protein kinase (AMPK) levels in skeletal muscle and hormone-sensitive lipase and adipose triglycerides lipase (HSL/ATGL) levels in white adipose tissue (WAT) were measured using western blot. mRNA expression of AMPK was measured. We found that there were significantly fewer NUCB2/nesfatin-1 immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) in T2DM mice. Central nesfatin-1 administration decreased levels of plasma FFA significantly and activated AMPK to enhance fatty-acid oxidation in skeletal muscle in T2DM mice. In addition, HSL and ATGL were significantly activated during triglyceride mobilization in WAT triggered by central nesfatin-1 administration. Adrenergic blockade and morphological denervation of the sciatic and femoral nerves reduced these changes. Taken together, these data suggest that central nesfatin-1 regulates peripheral lipid metabolism in type 2 diabetes via the sympathetic nervous system.

Relation of Circulating Resistin to Insulin Resistance in Type 2 Diabetes and Obesity: A Systematic Review and Meta-Analysis.

Background: Resistin, a cysteine-rich polypeptide encoded by the RETN gene, which plays an important role in many mechanisms in rodent studies, including lipid metabolism, inflammation and insulin resistance. Nevertheless, the relationship between resistin and insulin resistance in humans is under debate. The present study was designed to clarify the correlation between resistin and insulin resistance. Methods: A systematic literature search was performed using PubMed, Embase and Cochrane Library until March 3, 2019 with the keywords "resistin" and "insulin resistance." Funnel plots and Egger's test were used to detect publication bias. A random-effects model was used to calculate the pooled effect size. Subgroup analysis and meta regression was performed to identify the sources of heterogeneity. Results: Fifteen studies were included in our systematic review. Among them, 10 studies with Pearson coefficients were used for meta-analysis. We found resistin levels were weakly correlated with insulin resistance in those with T2DM and obesity (r = 0.21, 95% CI: 0.06-0.35, I 2 = 59.7%, P = 0.003). Nevertheless, subgroup analysis suggested that circulating resistin levels were significantly positively correlated with insulin resistance in individuals with hyperresistinemia (≥14.8 ng/ml) (r = 0.52, 95% CI: 0.35-0.68, I 2 = 0.0%, P = 0.513). And there was no relationship between circulating resistin and insulin resistance in those with normal circulating resistin levels (<14.8 ng/ml) (r = 0.08, 95% CI: -0.01-0.18, I 2 = 0.0%, P = 0.455). Publication bias was insignificant (Egger's test P = 0.592). Conclusion: In T2DM and obese individuals, resistin levels were positively correlated with insulin resistance in those with hyperresistinemia, but not in those with normal circulating resistin levels.