Combined metformin and insulin treatment reverses metabolically impaired omental adipogenesis and accumulation of 4-hydroxynonenal in obese diabetic patients

ObjectiveObesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype.MethodsOM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment.ResultsPreadipocytes isolated from insulin resistant (IR) and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS) individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin.ConclusionThis study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic action of insulin and metformin. Further studies are needed to evaluate involvement of 4-HNE in metabolically impaired abdominal adipogenesis and to confirm benefits of combined metformin-insulin therapy in T2DM patients

Downregulation of CYP17A1 by 20-hydroxyecdysone: plasma progesterone and its vasodilatory properties

Aim: To investigate the effect of 20-hydroxyecdysone on steroidogenic pathway genes and plasma progesterone, and its potential impact on vascular functions. Methods: Chimeric mice with humanized liver were treated with 20-hydroxyecdysone for 3 days, and hepatic steroidogenic pathway genes and plasma progesterone were measured by transcriptomics and GC–MS/MS, respectively. Direct effects on muscle and mesenteric arterioles were assessed by myography. Results: CYP17A1 was downregulated in 20-hydroxyecdysone-treated mice compared with untreated group (p = 0.04), with an insignificant increase in plasma progesterone. Progesterone caused vasorelaxation which was blocked by 60 mM KCl, but unaffected by nitric oxide synthase inhibition. Conclusion: In the short term, 20-hydroxyecdysone mediates CYP17A1 downregulation without a significant increase in plasma progesterone, which has a vasodilatory effect involving inhibition of voltage-dependent calcium channels, and the potential to enhance 20-hydroxyecdysone vasorelaxation

Association Between Glucose Level And Prevalence of Headache Among Saudi Population: A Cross-Sectional Study

Objective: To investigate the association between glucose levels and the prevalence of headaches among the adult Saudi population. Methods: This research will employ a cross-sectional study design, which involves collecting data from a sample of the Saudi population at a single point in time. This design allows for the investigation of the association between glucose levels and headache prevalence in a cost-effective and time-efficient manner. Results: The study included 574 participants. The most frequent weight among them was 51-65 kg (n= 196, 34.1%), followed by 66-75 kg (n= 130, 22.6%). The most frequent height among study participants was 151-160 cm (n= 229, 39.9%), followed by 161-170 cm (n= 195, 34%). The most frequent age among study participants was less than 25 years (n= 203, 35.4%), followed by 25-30 years (n= 143, 24.9%). The most frequent nationality among study participants was Saudi (n= 547, 95.3%), followed by non-Saudi (n= 27, 4.7%). The most frequent gender among study participants was female (n= 351, 61.1%), followed by male (n= 223, 38.9%). The perceived blood sugar level intake varied among study participants, with most having normal blood sugar levels. Participants were asked if they smoked. Most were not smoking (n=482, 84%), and non-smoking were (n=92, 26%). Participants were asked about the nature of the headache. The most frequent were they don’t have (n= 345, 60.1%), followed by sharp (n= 116, 20.2%), and the least was continuous (n=113, 19.7%). Participants were asked about a kind of headache. The most frequent were they don’t have (n= 367, 63.9%), followed by stress headaches (n= 116, 20.2%), and the lowest cluster (n=15, 2.6%). Conclusion: The results of the study showed that most of the participants were Saudis. Most of them are women. In addition, the majority of people have normal fasting blood sugar levels. Their physical activity is moderate and the majority are non-smokers. In addition, most of the study participants had good and effective social communication

Depot-specific differences in vascular noradrenergic sensitivity in morbidly obese Qataris

Background &amp; Objectives: Expanding adipose tissue in obesity requires effective vasoreactivity to combat hypoxia and its consequences, such as insulin resistance and type 2 diabetes. While recent evidence suggests that the adipose tissue is highly angiogenic, the tissue arteriolar vasoreactivity has been less investigated. Furthermore, the omental adipose tissue (OAT) synthesizes greater levels of vasocontrictive molecules, such as cytokines and catecholamines, compared to the sub-cutaneous (SAT) depot and these are likely to impact the maintenance of vascular tone leading to greater susceptibility to hypoxia. The aim of the study was to investigate differences in the contractile responses of adipose tissue arterioles between the SAT and OAT depots in an insulin-resistance prone, morbidly obese Qatari population. Methods: SAT and OAT from obese non-diabetic Qatari patients (age 29, BMI 43, HOMA 2.69), undergoing weight reducing surgery were used to investigate tissue noradrenaline (NA)-mediated vasoconstriction by wire myography. Vessels were cut into segments (~2 mm) and mounted on a dual wire myograph (510A) for measurement of isometric tension. Cumulative concentration-response curves were then constructed for noradrenaline (10-9 -10-5 M). Curves were also constructed for potassium Chloride (KCl, 1-70 mM). Results: Arterioles from SAT showed greater sensitivity to NA compared to OAT (log EC50 -6.9±0.1 vs -6.1±0.2 p&lt;0.05). The SAT curve was clearly shifted to the left of OAT although the maximum tensions for both were not statistically different. For KCl, maximum tension was greater in the SAT than in the OAT vessels but there were no differences in their sensitivities. Conclusions: OAT arterioles from morbidly obese Qataris were less sensitive to noradrenaline mediated vasoconstriction compared to SAT vessels; however, the contractile responses of the two depots to KCl were comparable. Therefore differences in adrenoceptor density/function may underlie the depot specific responses. The consequences of these differences between the arterioles are currently under investigation. </jats:p

Endothelial dysfunction in morbidily obese young Qataris

Background &amp; objectives: The prevalence of metabolic syndrome (MetS), including obesity, dyslipidemia, hyperglycemia and hypertension, associated with an increased predisposition to cardiovascular disease (CVD), is especially high in the Middle East, primarily amongst young Qataris. Both insulin resistance and endothelial dysfunction have been proposed to contribute to the pathogenesis of CVD in obese patients. Recent reports have shown that abdominal adipose tissue depot-specific differences impact on endothelial vasomotor function, with the visceral/omental environment considered more pathogenic. It is, however, unclear how severe the effect would be on a relatively young obese population. This study investigated endothelium-dependent relaxation of small arteries embedded in two adipose tissue depots, the sub-cutaneous and the omental. Methods: Arteries were isolated from omental (OM) and subcutaneous (SC) adipose tissues collected from consented Qatari patients undergoing bariatric surgery for weight reduction. The arteries (ID ~251 µM for SC and ~ 262 µM for OM) were cut into segments (~2 mm) and mounted on a dual wire Myograph (510A) for measurement of isometric tension. Cumulative concentration-response curves were constructed for acetylcholine (1- 10000 nM, the classical endothelium-dependent relaxant) in the absence or presence of Nω-Nitro-L-arginine methyl ester (L-NAME,100 µM, nitric oxide synthase inhibitor) on initial tone generated with noradrenaline (5 µM). Relaxation to sodium nitroprusside (SNP) and prostaglandin E2 were also recorded. Results: The mean age of the patients was 32 years, their blood glucose 5.6 mmol/L, Insulin 19.3 µU/ml , the index of insulin sensitivity/resistance (HOMA) 5.5 and body mass index 43.4 Kg/m2. Relaxation to Ach was significantly attenuated in OM vessels (Emax 51±9 %) compared with SC vessels (Emax 79±6 %, p&lt;0.05) from same patients. The Ach response was further reduced in the presence of L-NAME. In contrast, the relaxation to SNP and PGE2 were greater in OM vessels compared with the SC vessels. Conclusions: These results demonstrate adipose tissue depot-specific differences in the impact of obesity on endothelial function in morbidly obese, insulin resistant, young Qataris, with a marked reduction in endothelium NO-dependent relaxation in the OM compared with SC vessels. The reversibility of this lesion by weight loss are yet to be ascertained. </jats:p

Adipokines as mediators of components of metabolic syndrome in a Qatari population

Background and Objectives: There is a high prevalence of obesity and its co-morbidities within the Arab population, especially in Qatar. Furthermore, the younger age of onset of obesity and its preponderance amongst females have seen an increase in type 2 diabetes and cardiovascular disease in this cohort. Adipose tissue dysfunction preceding frank obesity may underlie the increased risk of metabolic syndrome (MeS). Therefore aims of this study were to characterize the relationship between components of MeS and adipokines in a Qatari population. Methods: Non-diabetic subjects were recruited from the general Qatari population and patients awaiting weight reduction surgery (Al-Emadi Hospital). Lipid profiling and liver function were determined by conventional techniques (HMC). Insulin resistance was measured by HOMA. Adipokines were measured by ELISA. Results: In the whole study population (n=56, 13 males/43 females, 30.5+/-7.5 years old, BMI of 37.5+/-11kg/m-2) significant positive correlations between plasma leptin and BMI were confirmed. However, after controlling for BMI, partial correlations showed that leptin was associated negatively with all measures of blood pressure (all p≤0.01), triglycerides, total- and LDL-cholesterol (all p≤0.01), with liver enzymes (SGPT, AST and Billirubin, p=0.009, p≤0.01 and p=0.02 respectively), and positively with HDL cholesterol (p=0.05). Furthermore, leptin, was also negatively correlated with fasting blood glucose and HOMA (p=0.03 and p=0.01 respectively). In order to investigate this further, the population was dichotomized into age-matched normal weight (n=14) and obese (n=42) sub-groups. The obese group had significantly higher SBP (p=0.006), triglycerides (p=0.03), leptin (p≤0.001) and lower HDL (p≤0.001). Obesity was also associated with deteriorating liver functions manifested as elevation in SGPT (p =0.02), ALP (p= 0.01) and AST (p =0.02). Conclusions: Leptin was elevated in obesity. After correcting for BMI, an inverse relationship between leptin and risk factors for MeS was apparent, suggesting a protective role for leptin in this population, perhaps through its vasodilatory capability. However, when dichotomized into lean and obese groups, chronic elevation in leptin appeared to be associated with increased risk of MeS and deterioration of liver function, as previously described. These novel data are currently being confirmed in a larger ethnicity matched cohort.</jats:p

Hosted Cuckoo Optimization Algorithm with Stacked Autoencoder-Enabled Sarcasm Detection in Online Social Networks

Sarcasm detection has received considerable interest in online social media networks due to the dramatic expansion in Internet usage. Sarcasm is a linguistic expression of dislikes or negative emotions by using overstated language constructs. Recently, detecting sarcastic posts on social networking platforms has gained popularity, especially since sarcastic comments in the form of tweets typically involve positive words that describe undesirable or negative characteristics. Simultaneously, the emergence of machine learning (ML) algorithms has made it easier to design efficacious sarcasm detection techniques. This study introduces a new Hosted Cuckoo Optimization Algorithm with Stacked Autoencoder-Enabled Sarcasm Detection and Classification (HCOA-SACDC) model. The presented HCOA-SACDC model predominantly focuses on the detection and classification of sarcasm in the OSN environment. To achieve this, the HCOA-SACDC model pre-processes input data to make them compatible for further processing. Furthermore, the term frequency-inverse document frequency (TF-IDF) model is employed for the useful extraction of features. Moreover, the stacked autoencoder (SAE) model is utilized for the recognition and categorization of sarcasm. Since the parameters related to the SAE model considerably affect the overall classification performance, the HCO algorithm is exploited to fine-tune the parameters involved in the SAE, showing the novelty of the work. A comprehensive experimental analysis of a benchmark dataset is performed to highlight the superior outcomes of the HCOA-SACDC model. The simulation results indicate that the HCOA-SACDC model accomplished enhanced performance over other techniques

Hosted Cuckoo Optimization Algorithm with Stacked Autoencoder-Enabled Sarcasm Detection in Online Social Networks

Sarcasm detection has received considerable interest in online social media networks due to the dramatic expansion in Internet usage. Sarcasm is a linguistic expression of dislikes or negative emotions by using overstated language constructs. Recently, detecting sarcastic posts on social networking platforms has gained popularity, especially since sarcastic comments in the form of tweets typically involve positive words that describe undesirable or negative characteristics. Simultaneously, the emergence of machine learning (ML) algorithms has made it easier to design efficacious sarcasm detection techniques. This study introduces a new Hosted Cuckoo Optimization Algorithm with Stacked Autoencoder-Enabled Sarcasm Detection and Classification (HCOA-SACDC) model. The presented HCOA-SACDC model predominantly focuses on the detection and classification of sarcasm in the OSN environment. To achieve this, the HCOA-SACDC model pre-processes input data to make them compatible for further processing. Furthermore, the term frequency-inverse document frequency (TF-IDF) model is employed for the useful extraction of features. Moreover, the stacked autoencoder (SAE) model is utilized for the recognition and categorization of sarcasm. Since the parameters related to the SAE model considerably affect the overall classification performance, the HCO algorithm is exploited to fine-tune the parameters involved in the SAE, showing the novelty of the work. A comprehensive experimental analysis of a benchmark dataset is performed to highlight the superior outcomes of the HCOA-SACDC model. The simulation results indicate that the HCOA-SACDC model accomplished enhanced performance over other techniques.</jats:p

Hyperinsulinaemia and hyperleptinaemia are BMI independent features of morbid obesity in a Qatari, compared to a Caucasian, population: Effect of surgical weight loss.

Background: Recent trends suggest that the sharpest increases in the prevalence of obesity are in countries of the Middle East, especially in Qatar. Early and rapid onset of the disease in this population, along with a primarily abdominal omental deposition of adipose tissue, is closely associated with insulin resistance, whilst longer duration of obesity in Caucasians is associated with maintenance of insulin sensitivity, independently of BMI. The impact of more aggressive treatments for obesity, such as surgery, on the metabolic health of the Qataris is not known. Objectives: To test the hypothesis that inherent differences between the Qataris and Caucasians in adipose tissue secretory function and sensitivity to insulin determines their response to interventions that reduce their adipose tissue mass. Methods: Non-diabetic morbidly obese subjects were recruited from Qatari and Caucasian patients awaiting weight reduction surgery (Al-Emadi Hospital, Doha, Qatar and Whittington Hospital, London, UK). Anthropometric measures were recorded. Blood samples were obtained before, and in a sub-set after weight loss for determination of lipids, glucose, insulin and adipokines. Insulin resistance was measured by HOMA. Results: The Qataris were significantly younger (p=0.005), despite having comparable BMI (Qatari 47.7±7.0; Caucasian 48.4±7.6 kg/m-2, p=0.70). They also had lower diastolic blood pressure and a better lipid profile. However, the Qataris had significantly higher insulin and HOMA index of insulin resistance, and higher leptin and interleukin-6. Also, in Qataris, leptin was negatively correlated with a number of risk factors for metabolic syndrome, independent of BMI. However, these correlations seem to be BMI-dependent in Caucasians. Further, weight loss in Caucasians did not significantly change insulin sensitivity but did reduce dyslipidemia. While in Qataris, characterized by high insulin resistance, weight loss causes sharp reduction in insulin resistance but not in dyslipidemia. Conclusion: Obesity in Qatari subjects was accompanied by a higher degree of hyperinsulinaemia and hyperleptinaemia compared to Caucasians. The nature of obesity and high insulin resistance in Qataris makes it amenable to aggressive weight loss treatment, whereas in Caucasians other less aggressive treatments for obesity may be applicable. </jats:p