Reduction in Insulin Mediated ERK Phosphorylation by Palmitate in Liver Cells Is Independent of Fatty Acid Induced ER Stress

Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38–45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress

ATP-Binding Cassette Protein ABCC10 Deficiency Prevents Diet-Induced Obesity but Not Atherosclerosis in Mice

Excess plasma lipid levels are a risk factor for various cardiometabolic disorders. Studies have shown that improving dyslipidemia lowers the progression of these disorders. In this study, we investigated the role of ATP-binding cassette transporter C10 (ABCC10) in regulating lipid metabolism. Our data indicate that deletion of the Abcc10 gene in male mice results in lower plasma and intestinal triglycerides by around 38% and 36%, respectively. Furthermore, deletion of ABCC10 ameliorates diet-induced obesity in mice and leads to a better response during insulin and glucose tolerance tests. Unexpectedly, ABCC10 deficiency does not affect triglyceride levels or atherosclerosis in ApoE-deficient mice. In addition, our studies demonstrate low oleate uptake by enterocytes (~25–30%) and less absorption (~37%) of triglycerides in the small intestine of ABCC10 knockout mice. Deletion of the Abcc10 gene also alters several lipid metabolism genes in the intestine, suggesting that ABCC10 regulates dietary fat absorption, which may contribute to diet-induced obesity in mice

Leu72Met and Other Intronic Polymorphisms in the and Genes Are Not Associated with Type 2 Diabetes Mellitus, Insulin Resistance, or Serum Ghrelin Levels in a Saudi Population

BackgroundGhrelin (GHRL), a gastric peptide encoded by the GHRL gene, is known to be involved in energy homeostasis via its G protein receptor, encoded by the growth hormone secretagogue receptor (GHSR) gene. Some studies have shown associations between plasma GHRL levels and GHRL single-nucleotide polymorphisms (SNPs), namely the Leu72Met polymorphism (rs696217 TG), with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), while others have not. The controversies in these associations raise the issue of ‘which SNPs in which populations.’ The aim of this study was to investigate whether SNPs in GHRL and/or GHSR genes were associated with T2DM, IR, or plasma GHRL levels among Arab Saudis.MethodsBlood was collected from 208 Saudi subjects with (n=107) and without (n=101) T2DM. DNA samples from these subjects were analyzed by real-time polymerase chain reaction to genotype five intronic SNPs in the GHRL (rs696217 TG, rs27647 CT, rs2075356 CT, and rs4684677 AT) and GHSR (rs509030 GC) genes. In addition, plasma GHRL levels were measured by a radioimmunoassay.ResultsNone of the SNPs were associated with T2DM, IR, or plasma GHRL levels. The frequencies of the alleles, genotypes, and haplotypes of the five SNPs were comparable between the T2DM patients and the non-diabetic subjects. A large number of the GHRL haplotypes indicates the molecular heterogeneity of the preproghrelin gene in this region.ConclusionNeither the Leu72Met polymorphism nor the other intronic GHRL and GHSR SNPs were associated with T2DM, IR, or GHRL levels. Further investigations should be carried out to explain the molecular basis of the association of the GHRL peptide with T2DM and IR

Association of Plasma Ghrelin Levels with Insulin Resistance in Type 2 Diabetes Mellitus among Saudi Subjects

BackgroundAlthough the exact mechanism of insulin resistance (IR) has not yet been established, IR is the hallmark characteristic of type 2 diabetes mellitus (T2DM). The aim of this study was to examine the relationship between plasma ghrelin levels and IR in Saudi subjects with T2DM.MethodsPatients with T2DM (n=107, cases) and non-diabetic apparently healthy subjects (n=101, controls) from Saudi Arabia were included in this study. The biochemical profiles and plasma insulin levels of all subjects were analyzed, and IR was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR) index. Active ghrelin levels in plasma were measured using the radioimmunoassay technique.ResultsOnly 46.7% (50 of 107) of the T2DM subjects had IR, including 26% (28 of 107) with severe IR (HOMA-IR ≥5), while 5.9% (six of 101) of the controls had moderate IR (3 ≤HOMA-IR <5). HOMA-IR values were not associated with age, disease duration, or gender. Importantly, T2DM itself and the co-occurrence of IR with T2DM were significantly associated with low plasma ghrelin levels. However, ghrelin levels were inversely correlated with the HOMA-IR index, body weight, and fasting plasma insulin levels, mainly in the control subjects, which was indicative of the breakdown of metabolic homeostasis in T2DM.ConclusionThe prevalence of IR was relatively low, and IR may be inversely associated with plasma ghrelin levels among Saudi patients with T2DM

Association of Advanced Lipoprotein Subpopulation Profiles with Insulin Resistance and Inflammation in Patients with Type 2 Diabetes Mellitus

Plasma lipoproteins exist as several subpopulations with distinct particle number and size that are not fully reflected in the conventional lipid panel. In this study, we sought to quantify lipoprotein subpopulations in patients with type 2 diabetes mellitus (T2DM) to determine whether specific lipoprotein subpopulations are associated with insulin resistance and inflammation markers. The study included 57 patients with T2DM (age, 61.14 ± 9.99 years; HbA1c, 8.66 ± 1.60%; mean body mass index, 35.15 ± 6.65 kg/m2). Plasma lipoprotein particles number and size were determined by nuclear magnetic resonance spectroscopy. Associations of different lipoprotein subpopulations with lipoprotein insulin resistance (LPIR) score and glycoprotein acetylation (GlycA) were assessed using multi-regression analysis. In stepwise regression analysis, VLDL and HDL large particle number and size showed the strongest associations with LPIR (R2 = 0.960; p = 0.0001), whereas the concentrations of the small VLDL and HDL particles were associated with GlycA (R2 = 0.190; p = 0.008 and p = 0.049, respectively). In adjusted multi-regression analysis, small and large VLDL particles and all sizes of lipoproteins independently predicted LPIR, whereas only the number of small LDL particles predicted GlycA. Conventional markers HbA1c and Hs-CRP did not exhibit any significant association with lipoprotein subpopulations. Our data suggest that monitoring insulin resistance-induced changes in lipoprotein subpopulations in T2DM might help to identify novel biomarkers that can be useful for effective clinical intervention

The Impact of Work-Related Stress on Medication Errors in Eastern Region Saudi Arabia

Objective To examine the relationship between overall level and source-specific work-related stressors on medication errors rate. Design A cross-sectional study examined the relationship between overall levels of stress, 25 source-specific work-related stressors and medication error rate based on documented incident reports in Saudi Arabia (SA) hospital, using secondary databases. Setting King Abdulaziz Hospital in Al-Ahsa, Eastern Region, SA. Participants Two hundred and sixty-nine healthcare professionals (HCPs). Main Outcome Measures The odds ratio (OR) and corresponding 95% confidence interval (CI) for HCPs documented incident report medication errors and self-reported sources of Job Stress Survey. Results Multiple logistic regression analysis identified source-specific work-related stress as significantly associated with HCPs who made at least one medication error per month (P \u3c 0.05), including disruption to home life, pressure to meet deadlines, difficulties with colleagues, excessive workload, income over 10 000 riyals and compulsory night/weekend call duties either some or all of the time. Although not statistically significant, HCPs who reported overall stress were two times more likely to make at least one medication error per month than non-stressed HCPs (OR: 1.95, P = 0.081). Conclusion This is the first study to use documented incident reports for medication errors rather than self-report to evaluate the level of stress-related medication errors in SA HCPs. Job demands, such as social stressors (home life disruption, difficulties with colleagues), time pressures, structural determinants (compulsory night/weekend call duties) and higher income, were significantly associated with medication errors whereas overall stress revealed a 2-fold higher trend

Deletion of retinoic acid-related orphan receptor gamma reduces body weight and hepatic lipids in mice by modulating the expression of lipid metabolism genes

Aim: Retinoic acid-related orphan receptor γ (RORγ) functions as a ligand-dependent transcription factor and its loss has been shown to affect the circadian expression of lipid metabolism genes. However, its effect on body weight gain and hepatic lipids is not well understood. In this study, we investigated the impact of Rorγ gene deletion on changes in body weight and hepatic lipids.Methods: Body weight and lipids were analyzed in the plasma and liver. Expression of lipid metabolism genes in the liver was evaluated in wild type and Rorγ knockout mice.Results: We show that deletion of RORγ results in reduced body weight and fewer lipids in the liver. Analysis of gene expression showed that deletion of Rorγ resulted in an overall lower expression of genes and transcription factors involved in lipid biosynthesis. We observed a decrease in the gene expression of cholesterol biosynthesis, efflux, and esterification but an increase in bile acid synthesis. There was a decrease in fatty acid and triglycerides biosynthesis genes and an increase in the fatty acid uptake genes. The decrease in the expression of lipid biosynthesis genes was accompanied by the decrease in the sterol response element binding protein (Srebp) genes. We observed an increase in the expression of peroxisome proliferator-activated receptor alpha (Ppara) and a decrease in the expression of acetyl-CoA carboxylase 2 (Acc2) genes.Conclusion: Our data suggest that RORγ regulates body weight and lipid metabolism genes and its modulation may be beneficial for the management of obesity and related lipid metabolic disorders