-
Nature Sep 2023Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes. Previous metagenomic studies have described the characteristics of...
Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host's overall energy extraction, thereby playing a role in the pathogenesis of obesity and prediabetes. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host-microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.
Topics: Animals; Humans; Mice; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Insulin Resistance; Monosaccharides; Insulin; Metabolic Syndrome; Feces; Metabolomics
PubMed: 37648852
DOI: 10.1038/s41586-023-06466-x -
Philosophical Transactions of the Royal... Sep 2023The fructose survival hypothesis proposes that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response... (Review)
Review
The fructose survival hypothesis proposes that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response (survival switch) that aims to protect animals of crisis. The response is characterized by hunger, thirst, foraging, weight gain, fat accumulation, insulin resistance, systemic inflammation and increased blood pressure. The process is initiated by the ingestion of fructose or by stimulating endogenous fructose production via the polyol pathway. Unlike other nutrients, fructose reduces the active energy (adenosine triphosphate) in the cell, while blocking its regeneration from fat stores. This is mediated by intracellular uric acid, mitochondrial oxidative stress, the inhibition of AMP kinase and stimulation of vasopressin. Mitochondrial oxidative phosphorylation is suppressed, and glycolysis stimulated. While this response is aimed to be modest and short-lived, the response in humans is exaggerated due to gain of 'thrifty genes' coupled with a western diet rich in foods that contain or generate fructose. We propose excessive fructose metabolism not only explains obesity but the epidemics of diabetes, hypertension, non-alcoholic fatty liver disease, obesity-associated cancers, vascular and Alzheimer's dementia, and even ageing. Moreover, the hypothesis unites current hypotheses on obesity. Reducing activation and/or blocking this pathway and stimulating mitochondrial regeneration may benefit health-span. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.
Topics: Animals; Humans; Fructose; Obesity; Non-alcoholic Fatty Liver Disease; Hominidae; Insulin Resistance; Liver
PubMed: 37482773
DOI: 10.1098/rstb.2022.0230 -
Nutrients Jan 2024The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel... (Review)
Review
The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel syndrome (IBS). However, how the low FODMAP diet works is still not completely understood. These mechanisms encompass not only traditionally known factors such as luminal distension induced by gas and water but also recent evidence on the role of FOMAPs in the modulation of visceral hypersensitivity, increases in intestinal permeability, the induction of microbiota changes, and the production of short-chain fatty acids (SCFAs), as well as metabolomics and alterations in motility. Although most of the supporting evidence is of low quality, recent trials have confirmed its effectiveness, even though the majority of the evidence pertains only to the restriction phase and its effectiveness in relieving abdominal bloating and pain. This review examines potential pathophysiological mechanisms and provides an overview of the existing evidence on the effectiveness of the low FODMAP diet across various IBS subtypes. Key considerations for its use include the challenges and disadvantages associated with its practical implementation, including the need for professional guidance, variations in individual responses, concerns related to microbiota, nutritional deficiencies, the development of constipation, the necessity of excluding an eating disorder before commencing the diet, and the scarcity of long-term data. Despite its recognized efficacy in symptom management, acknowledging these limitations becomes imperative for a nuanced comprehension of the role of a low FODMAP diet in managing IBS. By investigating its potential mechanisms and evidence across IBS subtypes and addressing emerging modulations alongside limitations, this review aims to serve as a valuable resource for healthcare practitioners, researchers, and patients navigating the intricate landscape of IBS.
Topics: Humans; Irritable Bowel Syndrome; FODMAP Diet; Fermentation; Disaccharides; Oligosaccharides; Diet; Monosaccharides; Diet, Carbohydrate-Restricted
PubMed: 38337655
DOI: 10.3390/nu16030370 -
Cardiovascular Diabetology Oct 2023The association between the triglyceride-glucose (TyG) index and mortality in cardiovascular disease (CVD) patients with diabetes or pre-diabetes remains unclear. This...
BACKGROUND
The association between the triglyceride-glucose (TyG) index and mortality in cardiovascular disease (CVD) patients with diabetes or pre-diabetes remains unclear. This study aimed to investigate the relationship between baseline TyG index and all-cause and cardiovascular (CV) mortality in CVD patients with diabetes or pre-diabetes among American adults. .
METHODS
This study enrolled 1072 CVD patients with diabetes or pre-diabetes from the National Health and Nutrition Examination Survey (2001-2018). Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Multivariate Cox proportional hazards models were constructed to analyze explore the associations between baseline TyG index and mortality. Non-linear correlations were explored using restricted cubic splines, and a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed.
RESULTS
During 7541 person-years of follow-up, a total of 461 all-cause deaths and 154 CVD-related deaths were recorded. The restricted cubic splines revealed a U-shaped association between the baseline TyG index with all-cause and CVD mortality in CVD patients with diabetes or pre-diabetes. Specifically, baseline TyG index lower than the threshold values (TyG index < 9.05 in all-cause mortality and < 8.84 in CVD mortality) was negatively associated with mortality (HR 0.47, 95% CI = 0.27-0.81 for all-cause mortality and HR 0.25, 95% CI = 0.07-0.89 for CVD mortality). In contrast, baseline TyG index higher than the threshold values (TyG index > 9.05 in all-cause mortality and > 8.84 in CVD mortality) was positively associated with mortality (HR 1.42, 95% CI = 1.02-1.99 for all-cause mortality and HR 1.77, 95% CI = 1.08-2.91 for CVD mortality).
CONCLUSIONS
A U-shaped association was observed between the baseline TyG index with CVD and all-cause mortality in CVD patients with diabetes or pre-diabetes in a American population. The thresholds of 8.84 and 9.05 for CVD and all-cause mortality, respectively.
Topics: Adult; Humans; Prediabetic State; Cardiovascular Diseases; Nutrition Surveys; Diabetes Mellitus; Glucose; Triglycerides; Blood Glucose; Risk Factors; Biomarkers
PubMed: 37848879
DOI: 10.1186/s12933-023-02030-z -
Cell Metabolism Jun 2023Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and...
Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.
Topics: Humans; Mice; Animals; Fructose; Fructose-Bisphosphatase; Proto-Oncogene Proteins c-akt; Insulin; Hepatomegaly; Hypoglycemia; Glucose
PubMed: 37084733
DOI: 10.1016/j.cmet.2023.03.021 -
Cardiovascular Diabetology Nov 2023This study aimed to explore the association between the triglyceride-glucose (TyG) index and the risk of in-hospital mortality in critically ill patients with sepsis. (Observational Study)
Observational Study
BACKGROUND
This study aimed to explore the association between the triglyceride-glucose (TyG) index and the risk of in-hospital mortality in critically ill patients with sepsis.
METHODS
This was a retrospective observational cohort study and data were obtained from the Medical Information Mart for Intensive Care-IV (MIMIC IV2.2) database. The participants were grouped into three groups according to the TyG index tertiles. The primary outcome was in-hospital all-cause mortality. Multivariable logistics proportional regression analysis and restricted cubic spline regression was used to evaluate the association between the TyG index and in-hospital mortality in patients with sepsis. In sensitivity analysis, the feature importance of the TyG index was initially determined using machine learning algorithms and subgroup analysis based on different subgroups was also performed.
RESULTS
1,257 patients (56.88% men) were included in the study. The in-hospital, 28-day and intensive care unit (ICU) mortality were 21.40%, 26.17%, and 15.43% respectively. Multivariate logistics regression analysis showed that the TyG index was independently associated with an elevated risk of in-hospital mortality (OR 1.440 [95% CI 1.106-1.875]; P = 0.00673), 28-day mortality (OR 1.391; [95% CI 1.52-1.678]; P = 0.01414) and ICU mortality (OR 1.597; [95% CI 1.188-2.147]; P = 0.00266). The restricted cubic spline regression model revealed that the risks of in-hospital, 28-day, and ICU mortality increased linearly with increasing TyG index. Sensitivity analysis indicate that the effect size and direction in different subgroups are consistent, the results is stability. Additionally, the machine learning results suggest that TyG index is an important feature for the outcomes of sepsis.
CONCLUSION
Our study indicates that a high TyG index is associated with an increased in-hospital mortality in critically ill sepsis patients. Larger prospective studies are required to confirm these findings.
Topics: Female; Humans; Male; Blood Glucose; Cohort Studies; Critical Illness; Glucose; Hospital Mortality; Risk Factors; Sepsis; Triglycerides; Retrospective Studies
PubMed: 37940931
DOI: 10.1186/s12933-023-02041-w -
Cardiovascular Diabetology Jun 2023Stroke has been found to be highly correlated with the triglyceride-glucose (TyG) index. The relation between the TyG index changes and stroke, however, has seldom been...
BACKGROUND
Stroke has been found to be highly correlated with the triglyceride-glucose (TyG) index. The relation between the TyG index changes and stroke, however, has seldom been reported, and current researches mentioning the TyG index concentrate on individual values. We aimed to investigate whether the level and the change of TyG index was associated with the incidence of stroke.
METHODS
Sociodemographic, medical background, anthropometric and laboratory information were retrospectively collected. Classification was conducted using k-means clustering analysis. Logistic regressions were to determine the relationship between different classes with changes in the TyG index and incidence of stroke, taking the class with the smallest change as a reference. Meanwhile, restricted cubic spline regression was applied to examine the links of cumulative TyG index and stroke.
RESULTS
369 (7.8%) of 4710 participants had a stroke during 3 years. Compared to class 1 with the best control of the TyG Index, the OR for class 2 with good control was 1.427 (95% CI, 1.051-1.938), the OR for class 3 with moderate control was 1.714 (95% CI, 1.245-2.359), the OR for class 4 with worse control was 1.814 (95% CI, 1.257-2.617), and the OR for class 5 with consistently high levels was 2.161 (95% CI, 1.446-3.228). However, after adjusting for multiple factors, only class 3 still had an association with stroke (OR 1.430, 95%CI, 1.022-2.000). The relation between the cumulative TyG index and stroke was linear in restricted cubic spline regression. In subgroup analysis, similar results were shown in participants without diabetes or dyslipidemia. There is neither additive nor multiplicative interaction between TyG index class and covariates.
CONCLUSION
A constant higher level with worst control in TyG index indicated a higher risk of stroke.
Topics: Humans; Middle Aged; Incidence; Retrospective Studies; Glucose; Stroke; Triglycerides; Blood Glucose; Risk Factors; Biomarkers
PubMed: 37296457
DOI: 10.1186/s12933-023-01870-z -
Nature Genetics Sep 2023Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA... (Meta-Analysis)
Meta-Analysis
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Topics: Humans; Glucose; Genome-Wide Association Study; Blood Glucose; Diabetes Mellitus, Type 2; Colon
PubMed: 37679419
DOI: 10.1038/s41588-023-01462-3 -
JPMA. the Journal of the Pakistan... Apr 2024Glucokathexis is a clinical state characterized by low plasma glucose levels, in the presence of adequate glucose precursor stores. We conceive and construct this rubric...
Glucokathexis is a clinical state characterized by low plasma glucose levels, in the presence of adequate glucose precursor stores. We conceive and construct this rubric to initiate interest and inspire insight into this field of metabolic medicine. We list various conditions that can cause true as well as pseudo-glucokathexis.
Topics: Humans; Blood Glucose
PubMed: 38751289
DOI: 10.47391/JPMA.24-28 -
BMC Public Health Oct 2023Obesity and metabolic syndrome are observed more frequently in infertile women, and insulin resistance (IR) is closely related to them. However, there are no studies...
BACKGROUND
Obesity and metabolic syndrome are observed more frequently in infertile women, and insulin resistance (IR) is closely related to them. However, there are no studies that have examined the association between different IR surrogates and female infertility, hence we investigated the potential association between them in the general population.
METHODS
This was a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES, 2013-2018). The association of different IR surrogates (HOMA-IR index, TyG index and TyG-BMI index) with female infertility was estimated by multivariable regression analysis.
RESULTS
After adjusting for confounders, the HOMA-IR index and TyG index did not show an association with female infertility, while the TyG-BMI index was found to have a positive association with female infertility (OR = 1.01, 95% CI: 1.00, 1.01; P < 0.0001), and the OR of the TyG-BMI group T3 (≥ 255.55) was significantly different compared to the group T1 (< 185.31) (OR = 3.02, 95% CI: 1.62, 5.60). Similar results were seen in most of the subgroup participants by stratified analysis (P-interaction > 0.05). However, different IR surrogates did not show variability in their ability to predict infertility [TyG-BMI: 0.68 (95% CI: 0.62, 0.74) vs. TyG: 0.62 (95% CI: 0.57, 0.68) vs. HOMA-IR: 0.65 (95% CI: 0.60, 0.71)].
CONCLUSIONS
Our result suggests that high levels of TyG-BMI index were positively associated with female infertility in US reproductive-aged females.
Topics: Humans; Female; Adult; Insulin Resistance; Infertility, Female; Nutrition Surveys; Blood Glucose; Cross-Sectional Studies; Biomarkers; Triglycerides; Glucose
PubMed: 37828472
DOI: 10.1186/s12889-023-16813-2