scholarly journals Which Role Plays 2-Hydroxybutyric Acid on Insulin Resistance?

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 835
Author(s):  
André P. Sousa ◽  
Diogo M. Cunha ◽  
Carolina Franco ◽  
Catarina Teixeira ◽  
Frantz Gojon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Metabolism ◽  
Metabolic Pathways ◽  
Chronic Condition ◽  
Metabolic Disorders ◽  
Cell Loss ◽  
Hydroxybutyric Acid ◽  
Novel Biomarkers

Type 2 Diabetes Mellitus (T2D) is defined as a chronic condition caused by beta cell loss and/or dysfunction and insulin resistance (IR). (1) Background: The discovering of novel biomarkers capable of identifying T2D and other metabolic disorders associated with IR in a timely and accurate way is critical. In this review, 2-hydroxybutyric acid (2HB) is presented as that upheaval biomarker with an unexplored potential ahead. Due to the activation of other metabolic pathways during IR, 2HB is synthesized as a coproduct of protein metabolism, being the progression of IR intrinsically related to the increasing of 2HB levels. Hence, the focus of this review will be on the 2HB metabolite and its involvement in glucose homeostasis. (2) Methods: A literature review was conducted, which comprised an examination of publications from different databases that had been published over the previous ten years. (3) Results: A total of 19 articles fulfilled the intended set of criteria. The use of 2HB as an early indicator of IR was separated into subjects based on the number of analytes examined simultaneously. In terms of the association between 2HB and IR, it has been established that increasing 2HB levels can predict the development of IR. (4) Conclusions: Thus, 2HB has demonstrated considerable promise as a clinical monitoring molecule, not only as an IR biomarker, but also for disease follow-up throughout IR treatment.

scholarly journals Elevated circulating follistatin associates with an increased risk of type 2 diabetes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chuanyan Wu ◽  
Yan Borné ◽  
Rui Gao ◽  
Maykel López Rodriguez ◽  
William C. Roell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Genome Wide Association Study ◽  
Regulatory Protein ◽  
Alcoholic Fatty Liver ◽  
Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

scholarly journals Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

2021 ◽  
Vol 22 (21) ◽  
pp. 11629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Arturo Santos ◽  
Juan Armendariz-Borunda
Keyword(s):  
Insulin Resistance ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Causes Of Death ◽  
Cardiovascular Prevention ◽  
Atherogenic Dyslipidemia ◽  
Metabolic Dysfunction ◽  
Systemic Insulin Resistance ◽  
Underlying Mechanisms

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

scholarly journals Sustained Improvements in Glucose Metabolism Late After Roux-En-Y Gastric Bypass Surgery in Patients with and Without Preoperative Diabetes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nils B. Jørgensen ◽  
Kirstine N. Bojsen-Møller ◽  
Carsten Dirksen ◽  
Christoffer Martinussen ◽  
Maria S. Svane ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Gastric Bypass ◽  
Glucose Metabolism ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Relative Change

Abstract To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (RYGB) in patients with and without preoperative type 2 diabetes we invited 55 RYGB-operated persons from two existing cohorts to participate in a late follow-up study. 44 (24 with normal glucose tolerance (NGT)/20 with type 2 diabetes (T2D) before surgery) accepted the invitation (median follow-up 2.7 [Range 2.2–5.0 years]). Subjects were examined during an oral glucose stimulus and results compared to preoperative and 1-year (1 y) post RYGB results. Glucose tolerance, insulin resistance, beta-cell function and incretin hormone secretion were evaluated. 1 y weight loss was maintained late after surgery. Glycemic control, insulin resistance, beta-cell function and GLP-1 remained improved late after surgery in both groups. In NGT subjects, nadir glucose decreased 1 y after RYGB, but did not change further. In T2D patients, relative change in weight from 1 y to late after RYGB correlated with relative change in fasting glucose and HbA1c, whereas relative changes in glucose-stimulated insulin release correlated inversely with relative changes in postprandial glucose excursions. In NGT subjects, relative changes in postprandial nadir glucose correlated with changes in beta-cell glucose sensitivity. Thus, effects of RYGB on weight and glucose metabolism are maintained late after surgery in patients with and without preoperative T2D. Weight loss and improved beta-cell function both contribute to maintenance of long-term glycemic control in patients with type 2 diabetes, and increased glucose stimulated insulin secretion may contribute to postprandial hypoglycemia in NGT subjects.

scholarly journals Glycolysis/gluconeogenesis- and tricarboxylic acid cycle–related metabolites, Mediterranean diet, and type 2 diabetes

2020 ◽  
Vol 111 (4) ◽  
pp. 835-844 ◽  
Author(s):  
Marta Guasch-Ferré ◽  
José L Santos ◽  
Miguel A Martínez-González ◽  
Clary B Clish ◽  
Cristina Razquin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Relative Risk ◽  
Mediterranean Diet ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Model Assessment ◽  
Weighted Score

ABSTRACT Background Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear. Objectives We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions. Methods We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC–tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach. Results Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17–44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons. Conclusions We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites. This trial was registered at controlled-trials.com as ISRCTN35739639.

scholarly journals Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Haya Al-Sulaiti ◽  
Ilhame Diboun ◽  
Maha V. Agha ◽  
Fatima F. S. Mohamed ◽  
Stephen Atkin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Serum Samples ◽  
Metabolic Markers ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Novel Biomarkers ◽  
Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

scholarly journals Complement Factor 3 Is Associated With Insulin Resistance and With Incident Type 2 Diabetes Over a 7-Year Follow-up Period: The CODAM Study

Diabetes Care ◽  
2014 ◽  
Vol 37 (7) ◽  
pp. 1900-1909 ◽  
Author(s):  
Nick Wlazlo ◽  
Marleen M.J. van Greevenbroek ◽  
Isabel Ferreira ◽  
Edith J.M. Feskens ◽  
Carla J.H. van der Kallen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Complement Factor ◽  
Incident Type ◽  
Incident Type 2 Diabetes

EXPRESSION OF IL6 mRNA IS INDEPENDENT WITH EXPRESSION OF TLRS mRNA IN LIPOPOLYSACCHARIDE-TREATED MYOTUBES

2020 ◽  
Vol 65 (6) ◽  
pp. 130-135
Author(s):  
Hoan Le Ngoc ◽  
Toi Chu Dinh ◽  
Hung Nguyen Phuc ◽  
Van Ho Thi Hong
Keyword(s):  
Insulin Resistance ◽  
Inflammatory Cytokine ◽  
Metabolic Disorders ◽  
Mrna Level ◽  
Current Data ◽  
C2c12 Cells ◽  
Modern World ◽  
C2c12 Skeletal Muscle Cells ◽  
Tlr2 Mrna

Obesity-related metabolic disorders such as insulin resistance and type 2 diabetes are raising as critical health problems of the modern world. Obesity induces an increased plasma level of lipopolysaccharide (LPS) that contributing to system chronic inflammation. This response has been shown as a marked factor linking obesity and its related metabolic disorders. In the present study, we use LPS to treat C2C12 skeletal muscle cells and observe the expression of several inflammatory makers. Our results show that the expression of inflammatory cytokine IL6 mRNA is strongly induced in the LPS-treated C2C12 cells compared to the control cells. Surprisingly, the expression of the upper controller of inflammation TLR2 mRNA in the LPS-treated C2C12 cells is similar to that in the control cells. Consistent with this expression mRNA level of TLR4, another upper regulator of inflammation does not differ between the two group cells. Taken together, our current data suggest that the LPS induced expression of IL6 mRNA in C2C12 cells is not dependent on the regulation of neither TLR2 nor TLR4

scholarly journals Pathobiochemical Changes in Diabetic Skeletal Muscle as Revealed by Mass-Spectrometry-Based Proteomics

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Kay Ohlendieck
Keyword(s):  
Mass Spectrometry ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Diagnostic Procedures ◽  
Global Changes ◽  
Cellular Mechanisms ◽  
Muscle Tissues ◽  
Organ Systems ◽  
Novel Biomarkers

Insulin resistance in skeletal muscle tissues and diabetes-related muscle weakness are serious pathophysiological problems of increasing medical importance. In order to determine global changes in the protein complement of contractile tissues due to diabetes mellitus, mass-spectrometry-based proteomics has been applied to the investigation of diabetic muscle. This review summarizes the findings from recent proteomic surveys of muscle preparations from patients and established animal models of type 2 diabetes. The potential impact of novel biomarkers of diabetes, such as metabolic enzymes and molecular chaperones, is critically examined. Disease-specific signature molecules may be useful for increasing our understanding of the molecular and cellular mechanisms of insulin resistance and possibly identify new therapeutic options that counteract diabetic abnormalities in peripheral organ systems. Importantly, the biomedical establishment of biomarkers promises to accelerate the development of improved diagnostic procedures for characterizing individual stages of diabetic disease progression, including the early detection of prediabetic complications.

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