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The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions.

Summary: Background: In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. Methods: Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. Findings: Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. Interpretation: Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. Funding: Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.

Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity (OB) and clinical criteria for bariatric surgery were enrolled in this study. We identified and quantified 44 different circulating T cell subsets and assessed their activation status and the expression of immune-checkpoint molecules, immediately before (T1) and 7–18 months after (T2) the bariatric surgery. Twelve age- and sex-matched healthy individuals (nOB) were also recruited. The OB participants showed higher leukocyte counts and a higher percentage of neutrophils. The percentage of circulating Th1 cells were negatively correlated to HbA1c and insulin levels. OB Th1 cells displayed a higher activation status and lower PD-1 expression. The percentage of Th17 and Th1/17 cells were increased in OB, whereas the CD4+ Tregs’ percentage was decreased. Interestingly, a higher proportion of OB CD4+ Tregs were polarized toward Th1- and Th1/17-like cells and expressed higher levels of CCR5. Bariatric surgery induced the recovery of CD4+ Treg cell levels and the expansion and activation of Tfh and B cells. Our results show alterations in the distribution and phenotype of circulating T cells from OB people, including activation markers and immune-checkpoint proteins, demonstrating that different metabolic profiles are associated to distinct immune profiles, and both are modulated by bariatric surgery.

Abstract Objective Adipose tissue is a specialized endocrine organ that is involved in modulating whole‐body energy homeostasis and expresses a specific subset of genes, which may play a role in adipose tissue metabolism. The aim of this study was to search for novel adipose tissue‐specific genes using a tissue panel of RNAseq expression profiles. Methods RNAseq expression profiles from 53 human tissues were downloaded from the GTex database. SLC19A3 expression was analyzed by microarray or real‐time PCR in two sets of paired subcutaneous and omental adipose tissue samples, in two studies with adipose tissue from persons with high or low body mass index (BMI), in adipose tissue from patients who underwent weight loss with a very‐low caloric diet and during preadipocyte‐adipocyte differentiation. Results The RNAseq‐based tissue distribution expression screen identified SLC19A3 (encoding the thiamine transporter 2) as adipose tissue‐specific. SLC19A3 expression was higher in subcutaneous compared with omental adipose tissue in both sample sets (p = 0.043 and p

Partial and total blockages due to wax deposition in wells and pipelines gather consensus as a billion-dollar problem in the oil and gas industry. However, an exact quantification is still required for production shifts towards heavy and paraffinic oils, extreme climate regions, and ultra-deep offshore oilfields. Motivated by such a problem, this research endeavour developed a case-specific methodology for assessing the economic impact at stake based on state-of-the-art methodologies. It is deemed to perform meta-analyses upon the current scientific and technical literature. It has been found that the economic impact of wax deposition has an expected value of 47.62 billion USD/year and may oscillate between 14.74 and 330.59 billion USD/year. Moreover, the upper bound is deeply influenced by the costs of potential environmental impacts, with a trend for assuming new record values with each new significant spill.

Sugarcane processing produces a significant amount of byproducts in the form of straw and bagasse, which are rich in cellulose, hemicellulose, and lignin. This work aims to provide a valorization approach to sugarcane straw by optimizing a two-step alkaline extraction of arabinoxylans by a response surface methodology to evaluate a potential industrial-scale production. Sugarcane straws were delignified using an alkaline–sulfite pretreatment, followed by alkaline extraction and precipitation of arabinoxylan, a two-step process optimized using a response surface methodology. A KOH concentration of (2.93–17.1%) and temperature (18.8–61.2 °C) were chosen as independent variables, and the arabinoxylan yield (%) as a response variable. The model application shows that KOH concentration, temperature, and the interaction between both independent variables are significant in extracting arabinoxylans from straw. The best-performing condition was further characterized by FTIR, DSC, and chemical and molecular weight evaluation. The straws arabinoxylans presented high purities levels, ca. 69.93%, and an average molecular weight of 231 kDa. The overall estimated production cost of arabinoxylan from straw was 0.239 €/g arabinoxylan. This work demonstrates a two-step alkaline extraction of the arabinoxylans method, as well as their chemical characterization and economic viability analysis, that can be used as a model for industrial scale-up production.

Metabolic inflexibility is a hallmark of insulin resistance and can be extensively explored with high-throughput metabolomics techniques. However, the dynamic regulation of the metabolome during an oral glucose tolerance test (OGTT) in subjects with type 2 diabetes (T2D) is largely unknown. We aimed to identify alterations in metabolite responses to OGTT in subjects with T2D using untargeted metabolomics of both plasma and subcutaneous adipose tissue (SAT) samples. Twenty subjects with T2D and twenty healthy controls matched for sex, age, and body mass index (BMI) were profiled with untargeted metabolomics both in plasma (755 metabolites) and in the SAT (588) during an OGTT. We assessed metabolite concentration changes 90 min after the glucose load, and those responses were compared between patients with T2D and controls. Post-hoc analyses were performed to explore the associations between glucose-induced metabolite responses and markers of obesity and glucose metabolism, sex, and age. During the OGTT, T2D subjects had an impaired reduction in plasma levels of several metabolite families, including acylcarnitines, amino acids, acyl ethanolamines, and fatty acid derivates (p < 0.05), compared to controls. Additionally, patients with T2D had a greater increase in plasma glucose and fructose levels during the OGTT compared to controls (p < 0.05). The plasma concentration change of most metabolites after the glucose load was mainly associated with indices of hyperglycemia rather than insulin resistance, insulin secretion, or BMI. In multiple linear regression analyses, hyperglycemia indices (glucose area under the curve (AUC) during OGTT and glycosylated hemoglobin (HbA1c)) were the strongest predictors of plasma metabolite changes during the OGTT. No differences were found in the adipose tissue metabolome in response to the glucose challenge between T2D and controls. Using a metabolomics approach, we show that T2D patients display attenuated responses in several circulating metabolite families during an OGTT. Besides the well-known increase in monosaccharides, the glucose-induced lowering of amino acids, acylcarnitines, and fatty acid derivatives was attenuated in T2D subjects compared to controls. These data support the hypothesis of inflexibility in several metabolic pathways, which may contribute to dysregulated substrate partitioning and turnover in T2D. These findings are not directly associated with changes in adipose tissue metabolism; therefore, other tissues, such as muscle and liver, are probably of greater importance.

Within the oil and gas industry, there is unanimity that wax deposits-driven pipeline blockages are a critical environmental concern and an economic liability of up to billions of dollars. However, a quantitative assessment of such an impact and, especially, of the different individual impacts that add up is absent from the current scientific literature. Such a gap is a deterrent for better-focused research. Given the production transition to heavy and paraffinic oils, harsh climatic zones, and extremely deep offshore oilfields, an extensive investigation is increasingly needed. The current endeavour was inspired by such a challenge and a review of the most recent technical and scientific publications was devised. A PRISMA-inspired and adapted methodology for systematic reviews was adopted. Over two hundred research articles, conference papers, books, theses, reviews, public databases and industry and government agencies reports were considered. As a result, a significant research gap is filled, both with the compilation, critical revision, and systematisation of the dispersed published scientific and technical data on the matter and with the definition of a quantitative economic impact appraisal for the wax deposition issue.

In the oil and gas industry, wax formation and deposition are common problems, particularly during production and transportation. To better understand the expected behaviour of a given waxy crude oil and consequently select the best solution to prevent wax deposition, it is vital to conduct laboratory tests or numerical simulations to model its performance. For a Brazilian oil field, the phase behaviour of 17 crude oils was modelled using Multiflash software. To tune the model, laboratory tests were used, including true boiling point curves and viscosity tests. This study followed two stages: the first allowed characterization of the wax appearance temperature (WAT) and determination of the expected precipitation curves for these crude samples, and the second stage was evaluation of the impact on wax precipitation after the addition of methane (CH4), carbon dioxide (CO2) or fatty acid (CH3(CH2)nCOOH). Results showed that WAT varied between 47.5 °C and 51.6 °C for these crude oil samples at atmospheric pressure, considering the differential scanning calorimetry (DSC) method. Furthermore, the percentage of wax mass formed varied between 13.3% and 18.3%. By adding the aforementioned chemicals as an inhibitor, it is possible to observe a reduction in the paraffin precipitation tendency. Inhibition was compared in terms of effectiveness between the chemicals studied, and it was concluded that adding myristic acid (C14:0), oleic acid (C18:1), palmitic acid (C16:0), or lauric acid (C12:0) was the most effective in reducing the WAT value. In fact, when adding 25% mole fraction, CH4 and CO2 can reduce the WAT value by up to 4%, but the results are strongly dependent on the fluid pressure. Myristic acid was the most effective in reducing the WAT value by up to 5%, and the results were less pressure dependent.

Objective: Olanzapine and Aripiprazole are widely used second-generation antipsychotic drugs. Olanzapine, more than Aripiprazole, leads to considerable metabolic side effects including obesity and diabetes. While the underlying mechanisms are not fully understood, these side effects are likely associated with mild inflammation in the metabolic organs. An in vitro model that accurately recapitulates the metabolic impact of olanzapine and aripiprazole should be useful to elucidate the underlying mechanisms. Methods: We established co-cultures of matured adipocytes derived from the human SGBS cell line and the THP-1 human monocytic cell-derived or primary macrophages to explore the effects of both drugs on the response to insulin. Results: Olanzapine, but not aripiprazole induced insulin resistance in SGBS adipocytes only when co-cultured with THP-1 or primary macrophages, polarized either into M0, M1 or M2. Noteworthy, M2 macrophages induced olanzapine-dependent insulin resistance in the absence of induction of pro-inflammatory cytokines. Insulin resistance by olanzapine was stronger than induced by high concentration of pro-inflammatory cytokines even in combinations, suggesting the contribution of factors other than the classical inflammatory cytokines to promote insulin resistance in adipocytes by olanzapine. Conclusion: Macrophage/adipocyte co-cultures recapitulate the features of olanzapine-induced insulin resistance and implicate the existence of yet unknown factors in mediating this effect.

Aim: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype–phenotype relationships. Methods: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments. Results: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups. Conclusions: Our report highlights that from a practical perspective, GBR can be used to study genotype–phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20–250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8–30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance.

ABSTRACTCdk5 and Abl enzyme substrate 1 (CABLES1) is a cell cycle regulator that has previously been identified as a candidate gene for obesity-related phenotypes, but little is known about its role in adipose tissue metabolism. In this study, we explore the role of CABLES1 in obesity and type 2 diabetes (T2D) in human subcutaneous adipose tissue (SAT). We performed gene expression analysis of SAT obtained from subjects with and without T2D, and from a second validation cohort consisting of subjects without T2D. We used CRISPR/Cas9 genome editing to perform CABLES1 loss-of-function studies in human primary preadipocytes and assessed them functionally after differentiation. CABLES1 gene expression in SAT was decreased in T2D by almost 25%, and inversely associated with insulin resistance markers and hyperglycaemia. mRNA levels were reduced with increasing BMI and negatively correlated with obesity markers. We found that adipocytes are likely the main CABLES1-expressing cell type in SAT, but CABLES1 depletion in adipocytes caused no phenotypical changes in regards to differentiation, glucose uptake, or expression of key genes of adipocyte function. These findings suggest that CABLES1 gene expression in SAT might be altered in obesity and T2D as a consequence of metabolic dysregulation rather than being a causal factor.

Purpose: In patients with type 2 diabetes mellitus (T2DM), Roux-en-Y gastric bypass (RYGB) leads to beneficial metabolic adaptations, including enhanced incretin secretion, beta-cell function, and systemic insulin sensitivity. We explored the impact of RYGB on pituitary, pancreatic, gut hormones, and cortisol responses to parenteral and enteral nutrient stimulation in patients with obesity and T2DM with repeated sampling up to 2 years after intervention. Methods: We performed exploratory post hoc analyses in a previously reported randomized trial. Levels of adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), ACTH, insulin, and glucagon were measured in 13 patients with T2DM and obesity at four different visits: before and 4, 24, and 104 weeks after RYGB; and in three sequential conditions on the same day: fasting, intravenous arginine challenge, and OGTT. Results: RYGB surprisingly induced a rise in ACTH, cortisol, and GH levels upon an oral glucose load, together with enhanced GLP-1 and PYY responses. Fasting and post-arginine GH levels were higher after RYGB, whereas insulin, glucagon, GLP-1, GIP, and cortisol were lower. These endocrine adaptations were seen as early as 4 weeks after surgery and were maintained for up to 2 years. Conclusion: These findings indicate adaptations of glucose sensing mechanisms and responses in multiple endocrine organs after RYGB, involving the gut, pancreatic islets, the pituitary gland, the adrenals, and the brain.

An innovative study of the magnetocaloric effect (MCE) was performed by mapping the effect based on direct measurements of the temperature change during magnetic field cycles with microscopic resolution (85 μ m) on a Co-doped Ni–Mn–Ga bulk sample using infrared thermography on the whole sample. The MCE maps were constructed for different sample temperatures ( T _sample ), cycling both on heating (from 272.8 K up to T _sample , with T _sample ⩽ 327.0 K) and on cooling (from 340.0 K down to T _sample , with T _sample ⩾ 266.8 K), cycling a 1.2 T magnetic field at each T _sample value. The MCE maps were calculated to evaluate the amplitude of the effect at the microscale for all T _sample values. This allows to analyze the contribution of each micrometric portion of the sample to the spatially heterogeneous behavior that was found. Significant differences of the MCE on heating and cooling are present associated to inhomogeneity dynamics, mostly near the structural transformation. The amplitude of the MCE and its inhomogeneity are both much more pronounced on the heating process. On the cooling process the effect behaves quite homogeneously since the structural transformation already occurred during the cooling to reach T _sample . The behavior of the MCE at selected map coordinates was scrutinized, revealing significant differences amongst sample locations. Moreover, the extreme amplitudes of MCE registered for diverse micro-regions occur at different temperatures, suggesting that the structural transformation occurs at varying temperatures and with different magnitudes. The study innovates by constructing MCE maps to evaluate minority behaviors in the MCE in contrast with the average behavior of the effect. This study displays the capability to discriminate the behavior of the transformation at the microscale.

Beta cell dysfunction accompanies and drives the progression of type 2 diabetes mellitus (T2D), but there are few clinical biomarkers available to assess islet cell stress in humans. Secretagogin, a protein enriched in pancreatic islets, demonstrates protective effects on beta cell function in animals. However, its potential as a circulating biomarker released from human beta cells and islets has not been studied. In this study primary human islets, beta cells and plasma samples were used to explore secretion and expression of secretagogin in relation to the T2D pathology. Secretagogin was abundantly and specifically expressed and secreted from human islets. Furthermore, T2D patients had an elevated plasma level of secretagogin compared with matched healthy controls, which was confirmed in plasma of diabetic mice transplanted with human islets. Additionally, the plasma secretagogin level of the human cohort had an inverse correlation to clinical assessments of beta cell function. To explore the mechanism of secretagogin release in vitro, human beta cells (EndoC-βH1) were exposed to elevated glucose or cellular stress-inducing agents. Secretagogin was not released in parallel with glucose stimulated insulin release, but was markedly elevated in response to endoplasmic reticulum stressors and cytokines. These findings indicate that secretagogin is a potential novel biomarker, reflecting stress and islet cell dysfunction in T2D patients.

The aim of this study was to evaluate the prevalence of dental trauma in children aged 1 to 5 years old and its associated factors (gender, age group, malocclusion and labial-closing), interviewing parents and guardians for additional information on the trauma occurrence. A transversal study of 820 preschool children from the City of Caruaru, Pernambuco, Brazil was conducted. Data were collected by means of a clinical examination and a structured interview. The statistical analysis included a distribution of frequencies, a bi- and a multi-variate analysis at a significance level of 5%. Trauma prevalence was 20.1%, tooth 61 was the most often affected, and enamel fractures followed by the fractures of the enamel and the dentine were the most frequent alterations. Trauma prevalence was highest in 3- to 5-year-old males with malocclusion (open bite and protrusion) (p < 0.05). According to most parents and/or guardians, the most usual etiology was falling and the place most often cited was home. All the variables studied, except for lip coverage, were associated with dental trauma. The outcome of the present study showed high prevalence of dental trauma in a pediatric population under the age of 5 years. Falls and accidental collisions were the etiological factors most often cited. The front upper incisors were the teeth most often affected, and enamel fracture was the trauma most often observed.