Impaired Glucose Tolerance Research Articles

Postpartum dysglycaemia after early gestational diabetes: Follow-up of women in the TOBOGM randomised controlled trial

AimTo evaluate the incidence and predictors of postpartum dysglycaemia among high-risk women who develop early gestational diabetes (eGDM) prior to 20 weeks’ gestation. MethodsThis is a sub-study of the Treatment of Booking Gestational Diabetes (TOBOGM) Study, a randomised controlled trial of early or deferred treatment for women with risk factors for diabetes diagnosed with eGDM, using current WHO criteria. Overt diabetes in pregnancy was excluded. A repeat oral glucose tolerance test (oGTT) was recommended at 6–12 weeks postpartum. ResultsOf 793 participants, 352 (44.4%) underwent a postpartum oGTT. Baseline characteristics of participants with and without an oGTT were similar. Ninety-two (26.1%) had postpartum dysglycaemia: 11 (3.1%) diabetes, 31 (8.8%) impaired fasting glucose (IFG), 39 (11.1%) impaired glucose tolerance (IGT), and 11 (3.1%) combined IFG/IGT. Participants with postpartum dysglycaemia were more likely to have had past GDM, lower body mass index, more gestational weight gain, and higher 1 and 2-hour glucose concentrations on the early pregnancy oGTT. On logistic regression, higher 1 and 2-hour glucose concentration, previous GDM and greater gestational weight gain were independently associated with postpartum dysglycaemia. ConclusionThere is a high incidence of postpartum dysglycaemia among high-risk women with eGDM.

Deletion of Stimulator of Interferons Genes Aggravated Cardiac Dysfunction in Physiological Aged Mice

BackgroundStimulator of interferons genes (STING) is crucial for innate immune response. It has been demonstrated that cGAS-STING pathway was the driver of aging-related inflammation. However, whether STING is involved in cardiac dysfunction during the physiological aging process remains unclear. MethodsGene expression profiles were obtained from the Gene Expression Omnibus database, followed by weighted gene co-expression network analysis, gene ontology analysis and protein network interaction analysis to identify key pathway and genes associated with aging. The effects of STING on cardiac function, glucose homeostasis, inflammation, and autophagy in physiological aging were investigated with STING knockout mice. ResultsBioinformatics analysis revealed STING emerged as a hub gene of interest. Subsequent experiments demonstrated the activation of STING pathway in the heart of aged mice. Knockout of STING alleviated the inflammation in aged mice. However, Knockout of STING impaired glucose tolerance, inhibited autophagy, enhanced oxidative stress and aggravated cardiac dysfunction in aged mice. ConclusionAlthough reducing inflammation, long-term STING inhibition by genetic ablation exacerbated cardiac dysfunction in aged mice. Given the multifaceted nature of aging and the diverse cellular functions of STING beyond immune regulation, the negative effects of targeting STING as a strategy to mitigate aging phenotype should be fully considered.

Метаболічний синдром: механізми розвитку та експериментальні моделі

Metabolic syndrome is a condition characterized by the presence of insulin resis­tance and the presence of two of the following risk factors: obesity, hyperlipidemia (hypertriglyceridemia, decreased high-density lipoprotein cholesterol), hypertension, or microalbuminuria. The multifactorial nature of metabolic syndrome makes it difficult to create an adequate experimental model that would best represent the entire spectrum of the pathophysiology of this condition. This review aims to summarize current literature data on the pathophysiological mechanisms of metabolic syndrome in the context of the development of insulin resistance, obesity, dyslipidemia, impaired glucose tolerance, and inflammation. The article also summarizes modern approaches to the induction of metabolic syndrome in rodents, among which dietary manipulation, genetic modifications, and the use of pharmaceuticals are the most common. As genetic models of metabolic syndrome, rodents with leptin or leptin receptor deficiency are most often used, in particular leptin-deficient mice (ob/ob), leptin receptor-deficient mice (db/db), Zucker obese rats (ZF), diabetic rats lines Zucker with obesity (ZDF) and others. Pharmaceutical drugs that can be used to induce metabolic syndrome include endogenous glucocorticoids and antipsychotic drugs. Several dietary manipulations are used to induce metabolic syndrome in laboratory animals. In particular, one type of diet or a combination of diets can be used, such as diets high in fructose, sucrose and fat, or a diet characterized by a high content of both fructose and fat or sucrose and fat. Manipulations with the composition of products consumed by experimental animals make it possible to simulate the development of metabolic syndrome, since the diet affects the metabolism of the entire body, and has a regulatory effect on hormones, glucose and lipid metabolism pathways.

Influence of impaired glucose tolerance and type 2 diabetes on the multimorbidity cluster of cardiovascular disease and cancer: a post hoc analysis of the Da Qing Diabetes Prevention Outcome Study.

This study explored the influence of type 2 diabetes and impaired glucose tolerance (IGT) on the risk of the multimorbidity cluster of cardiovascular disease (CVD) and cancer. A total of 1629 participants in the Da Qing Diabetes Prevention Outcome Study were recruited in the present analysis, including normal glucose tolerance (NGT, N = 492), IGT (N = 540), and newly diagnosed type 2 diabetes (N = 597) groups. Cox proportional hazards analyses were performed to assess the relationship between NGT, IGT, and newly diagnosed type 2 diabetes and the risk of the multimorbidity cluster of CVD and cancer. The incidence rates for multimorbidity cluster CVD and cancer were 1.25, 3.17, and 3.23 per 1000 person-years in people with NGT, IGT, and the newly diagnosed type 2 diabetes groups, respectively, over 34-year follow-up. Cox analysis revealed that diabetes status (as time-dependent variable) was significantly associated with the subsequent increased risk of multimorbidity cluster of CVD and cancer compared with non-diabetes (hazard ratios [HR] = 2.55, 95% confidence interval [CI] 1.51-4.31) after adjustment of potential confounders. Similar analysis showed that this risk was significantly higher in the IGT and newly diagnosed type 2 diabetes groups compared with NGT, with HR of 3.28 (95% CI 1.83-5.87) and HR of 3.90 (95% CI 2.14-7.09), respectively. Whereas compared diabetes with IGT group, this risk was not significantly different. Similar to newly diagnosed type 2 diabetes, IGT is significantly associated with an increased risk of the multimorbidity cluster of CVD and cancer compared with NGT. This finding highlights the urgent need for an active detection of IGT and effective prevention and management of diabetes.

Continuous Glucose Monitoring for the Diagnosis of Post-Transplantation Diabetes Mellitus and Impaired Glucose Tolerance From Years One to Five After Kidney Transplantation—A Prospective Pilot Study

Post-transplantation diabetes mellitus (PTDM) and prediabetes are associated with increased cardiovascular morbidity and mortality in kidney transplant recipients (KTR), when diagnosed by an oral glucose tolerance test (oGTT). Hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) display low concordance with the oGTT in the early phase posttransplant. For this prospective cross-sectional pilot study, 41 KTR from years one to five after transplantation without known preexisting PTDM (defined by HbA1c ≥ 6.5% (NGSP) or 48 mmol/mol (IFCC) at last visit or glucose-lowering therapy) were recruited at the Charité Transplant Outpatient Clinic. For each study participant HbA1c, FPG and an oGTT were followed by CGM. 38 of the 41 patients recruited had sufficient CGM-recordings (≥10 days). PTDM and impaired glucose tolerance (IGT), as defined by the gold standard oral glucose tolerance test (oGTT)-derived 2-h plasma glucose (2hPG), were diagnosed in one (3%) and twelve (32%) patients, respectively. HbA1c exhibited good test characteristics regarding IGT (ROC-AUC: 0.87); sensitivity/specificity of HbA1c-threshold 5.7% (NGSP) or 39 mmol/mol (IFCC) were 1.0/0.64, respectively. Best performing CGM-readouts mean sensor glucose and percent of time >140 mg/dL (%TAR (140 mg/dL)) displayed acceptable diagnostic performance (ROC-AUC: 0.78 for both). Thus, HbA1c can aid in timely diagnosis of IGT in the stable phase after kidney transplantation.

MRI-Based Phenotyping for Osteosarcopenic Adiposity in Subjects from a Population-Based Cohort

Objective: Imaging biomarkers of bone, muscle, and fat by magnetic resonance imaging (MRI) may depict osteopenia, sarcopenia, and adiposity as the three different conditions of osteosarcopenic adiposity (OSA). Methods: Subjects from a prospective, population-based case–control study underwent a health assessment and 3 Tesla whole-body MRI scan. Imaging biomarkers of bone (bone marrow fat-fraction (BMFF)), skeletal muscle (skeletal muscle FF (SMFF)), and fat (total adipose tissue (TAT)) were determined. Participants were allocated to one phenotype according to the OSA complex. Results: Among 363 participants forming the study cohort, 81 (22.3%, 48.1% males, 62.4 ± 6.9 years) were allocated into the OSA subgroup. Participants with an OSA phenotype were significantly older compared to all remaining subjects and showed the highest grades of SMFF (all p < 0.005). Together with subjects from the osteopenic sarcopenia group, OSA subjects exhibited the highest amounts of BMFF and together with the three other adiposity-containing subgroups also exhibited the highest BMIs. The highest prevalence of an impaired glucose tolerance as well as significantly higher blood pressure, blood dyslipidemia, and hepatic steatosis was found in the OSA subgroup (all p < 0.005). Conclusions: MR biomarkers of bone, skeletal muscle and fat are feasible for body composition phenotyping and may allow for targeted risk stratification in suspected OSA syndrome.

Effectiveness of metformin in combination with intranasal insulin for the treatment of metabolic and hormonal disturbances in adult male rats with metabolic syndrome induced by impaired breastfeeding

BACKGROUND: Limiting or temporally stopping breastfeeding can lead to the development of metabolic syndrome in adulthood, which requires the development of approaches for its prevention and correction. One such approach is treatment with metformin or intranasal insulin. Since the targets of these agents differ and may complement each other, it has been suggested that their combined use could be effective. AIM: To study the effect of a four-week co-administration of metformin (orally, 120 mg/kg/day) and intranasal insulin (1.2 IU/kg/day) in male rats with metabolic syndrome, induced by breastfeeding disruption on postnatal days 19–21, on their metabolic and hormonal parameters. MATERIALS AND METHODS: The study treatment was compared with monotherapy using the same drugs. RESULTS: It was found that adult male rats with disrupted breastfeeding developed obesity, dyslipidemia, hyperleptinemia, impaired glucose tolerance, and a reduction in the number of β-cells and the area of pancreatic islets, which are characteristic of metabolic syndrome. Long-term treatment with metformin and its combination with intranasal insulin partially or fully normalized body weight, abdominal fat, and metabolic and hormonal parameters, with the restorative effect of combination treatment on such parameters as body weight, fat mass, glucose tolerance, and blood glycated hemoglobin levels being more pronounced than with metformin alone. CONCLUSIONS: The results of the study support the use of a combination of metformin and intranasal insulin to normalize metabolic and hormonal parameters in metabolic syndrome induced by breastfeeding disruption in early days of life.

Abstract 4147634: Important Role of Prediabetes in Stroke Patients including ESUS

Stroke including ESUS is one of the common causes of disability and death worldwide. Furthermore, diabetes mellitus and prediabetes are among the main risk factors for cerebrovascular events. If the criteria for apparent diabetes mellitus is not met, a glucose metabolism disorder may still exist. Prediabetes can be present as impaired fasting glucose (IFG), impaired glucose tolerance or an increased, but not yet diabetic, HbA1c. To determine the frequency of diabetes mellitus (DM) and prediabetes mellitus (PDM) in patients with cardiovascular events, we analyzed the aspects of prediabetes in a stroke population of one of the largest stroke centers in Germany and collected the data in a prospective manner over 6 months. Among 714 included patients, 163 (30.8%) suffered a cryptogenic Stroke, including 98 (19%) ESUS. 185 (26%) TIA, 209 (39%) cardioembolic, 110 (21%) atherosclerotic, 40 (8%) lacunar and 7 (1%) other specific strokes were registered. >50% had a diabetic or prediabetic metabolic state, among which, the highest proportion was seen in lacunar strokes, followed by atherosclerotic infarctions. >80% of lacunar, >70% of atherosclerotic infarctions, 60% of ESUS, 50% of cardioembolic infarctions indicate DM or PDM. Both PDM and DM show a positive correlation with age. PDM is most common in 75-84y old patients. In the male population, PDM is most prevalent in the oldest patients (<85y) at >50%, and least prevalent in the youngest patients (<65y) at 15%. In this age group, women show a significantly higher frequency of DM and PDM. The highest number of female patients with glucose metabolism disorders is seen in the age group of 66-74y at >40%. In the oldest patient group, relatively speaking, more than twice as many men are affected by glucose metabolism disorders as women (52% vs. 24%). In summary the largest relative proportion of prediabetics and diabetics is seen at 80% among the lacunar infarction group and the second largest proportion at 70% among those with atherosclerotic infarctions. Among ESUS and cryptogenic stroke patients show a proportion of over 60% with impaired glucose tolerance. PD presents a positive correlation with increasing age, just like other risk factors. 40% of the 75-84-year-olds have DM or PDM. Therefore, diabetogenic micro- and macroangiopathies could be a major contributing factor to the causes of stroke.

Identifying and validating the key regulatory transcription factor YY1 in the aging process of pancreatic beta cells based on bioinformatics.

The aging of pancreatic beta cells is closely associated with various diseases, such as impaired glucose tolerance, yet the underlying regulatory mechanisms remain unclear. In this study, we screened young and aged mouse pancreatic beta cells' high-throughput sequencing data from the GEO public database. Utilizing bioinformatics techniques, we identified the key regulatory factor YY1 in the aging process of pancreatic islets. We observed a significant decrease in the expression of YY1 in a D-gal-induced mouse model of pancreatic aging and an H2O2-induced MIN6 cell model of aging. Moreover, both vivo and vitro models, we found that the YY1 agonist eudesmin (EDN) improved glucose intolerance in mice, alleviated aging of pancreatic beta cells, and downregulated the expression of cell cycle protein P21. Mechanistically, we discovered that EDN inhibited the P38/JNK MAPK pathway in aging cells. In summary, our study confirms the regulatory role of the transcription factor YY1 in the aging process of pancreatic beta cells. This finding may provide a new approach for the clinical treatment of pancreatic aging-related diseases such as impaired glucose tolerance or diabetes.

Association between systemic immunity-inflammation index and glucose regulation in non-diabetic population: A population-based study from the NHANES (2005-2016).

To investigated the link between the systemic immunity-inflammation index (SII), a new inflammatory biomarker, and the risk of abnormal glucose regulation in non-diabetic population. Using data from the 2005-2016 National Health and Nutrition Examination Survey (NHANES), we conducted a cross-sectional study on non-diabetic adults with data on SII and glucose regulation markers. We analyzed the relationship between SII and indicators of glucose regulation, including fasting plasma glucose, fasting insulin, hemoglobin A1c, oral glucose tolerance test (OGTT), and states of abnormal glucose regulation like impaired glucose tolerance (IGT), insulin resistance, and prediabetes. Adjusting for confounders, higher SII levels were significantly associated with a higher OGTT and a greater likelihood of IGT (OR = 2.673, 95% CI: 1.845, 3.873). In subgroup analysis, participants without hyperlipidemia in the highest SII quartile had a 240% higher odds of IGT compared to those in the lowest quartile (OR = 3.407, 95%CI: 1.995, 5.820), an association not observed in those with hyperlipidemia (p for interaction < 0.05). SII emerges as a useful biomarker for identifying IGT in non-diabetic individuals, specifically in those without hyperlipidemia.

Assessing corneal dendritic cells in glucose dysregulation small-fibre neuropathy.

Small-fibre neuropathy (SFN) is associated with glucose dysregulation, including impaired glucose tolerance (IGT) and type 2 diabetes (T2D). Corneal confocal microscopy (CCM) offers a non-invasive tool to assess corneal nerve damage and dendritic cell density (DCD). In this study, we investigated corneal DCD in patients with SFN and glucose dysregulation, defined as IGT or T2D. We enrolled 38 patients with SFN + glucose dysregulation, 51 with SFN + non-glucose dysregulation and 20 healthy controls. All participants underwent neurological examination, neurophysiology and CCM. Individuals with SFN and glucose dysregulation had higher DCD compared with healthy controls (p = .01), and mature DCD was higher in IGT SFN patients than in T2D patients. Higher DCD in IGT compared with controls and patients with established T2D may suggest that DCD is a biomarker of early neuropathy.

The interplay of body mass index, gestational weight gain, and birthweight over 3800 g in vaginal breech birth: A retrospective study.

Optimal counseling of women for vaginal breech birth requires consideration of both established and emerging risk factors for adverse perinatal outcomes. Currently, rising prevalences of maternal obesity and impaired glucose tolerance challenge obstetric care. We aimed to investigate the effects of these parameters on the outcome of vaginal breech birth to improve counseling practices. A total of 361 women (without previous vaginal births) attending vaginal birth of a singleton fetus in breech presesntation between 01/2015 and 11/2021 were included in this retrospective single-center study. Data were derived from the hospital data base. We analyzed the effect of the maternal body mass index (BMI) at birth (compared to pre-pregnancy BMI), excessive weight gain, gestational diabetes, and neonatal birthweight on obstetrical and neonatal short-term outcomes (intrapartum cesarean delivery, performance of obstetric maneuvers (Løvset-, Bracht-, Veit-Smellie maneuver and Bickenbach's arm delivery), admission to the neonatal unit, Apgar score after 5 minutes<7, and arterial cord pH-value <7.10). Multivariable logistic regression was used for analysis and adjustment of variables. Overall, 246 women (68.1%) had a successful vaginal birth. Intrapartum cesarean delivery (n = 115/361; 31.9%) was independently associated with maternal BMI at birth (p = 0.0283, aOR = 1.87 (1.19-3.97)) if birthweight was ≥3800 g. The rate of intrapartum cesarean delivery was also higher in women with gestational diabetes (p = 0.0030, aOR = 10.83 (2.41-60.84)). A significantly higher risk of neonatal acidosis (arterial pH-value <7.10) was observed in women with BMI at birth ≥30 kg/m2 (p = 0.0345, aOR = 1.84 (1.04-3.22)) without affecting other outcomes. Pre-pregnancy BMI, gestational weight gain and BMI-gain did not significantly affect the obstetrical and neonatal birth outcomes. When neonatal birthweight is ≥3800 g, maternal BMI at birth (p = 0.0283; aOR = 1.87 (1.19-3.97)) is independently associated with the rate of intrapartum cesarean delivery. However, pre-pregnancy BMI and BMI-gain during pregnancy were not associated with the need for intrapartum cesarean delivery or other adverse outcomes. Consequently, BMI at the time of birth could be more informative than pre-pregnancy BMI and may improve counseling of women attempting vaginal breech birth.

Improving diabetic wound healing: The therapeutic potential of allulose supplement in diabetic skin tissue repair and inflammation modulation

The increasing prevalence of type 2 diabetes mellitus (T2DM) worldwide presents significant challenges in the management of impaired tissue repair in diabetic skin wounds, which has emerged as a critical health concern. Addressing this issue while minimizing adverse effects remains crucial. Allulose has been shown to exhibit hypolipidemic and anti-inflammatory properties, alleviating obesity and atherosclerosis by improving insulin resistance and impaired glucose tolerance. However, its underlying effects and mechanisms in repairing diabetic skin damage remain poorly understood. In this study, we demonstrated that oral administration of allulose remarkably ameliorated T2DM-compromised skin tissue wound associated with the stimulation of skin granulation, surrounding tissue formation, and activated fibroblasts, under high-fat diet (HFD) feeding condition. In addition, administration partially promoted collagen deposition, reduced M1 macrophage polarization, facilitated neovascularization, and mitigated tissue inflammation in the T2DM rats upon HFD feeding. Moreover, allulose could significantly alleviate high glucose stress condition-induced inflammatory response, correlative with modulation of p38/NLRP3/Caspase-1 signaling. In addition, allulose could also ameliorate high glucose stress-compromised cell viability and proliferative capacity, related to stimulation of mTOR pathway in part. Taken together, our study revealed that T2DM compromised some certain factors which are crucial for skin tissue healing and wound repair upon HFD condition. The work highlighted the potential beneficial effects of orally administered allulose for healing diabetic skin wounds and supported a novel strategy for managing diabetes patients adjunctively with allulose dietary supplement.

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells.

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

Prediabetes and cardiovascular diseases: a serious but overlooked issue

The elevated risk of cardiovascular diseases and prediabetes is a practical area of concern although there is dearth of data coming from across the globe despite epidemiological studies connecting the duo. Recent meta-analysis in BMJ reported relative risk of 1.15 for a composite of cardiovascular disease and 1.16 for ischaemic heart disease in the prediabetic population as opposed to that in the population with normal sugar levels. A recent research placed a 25% elevated risk of myocardial infarction in the prediabetic population along with greater chances of undergoing various forms of revascularization. Prediabetes although defined by numbers and classified as IFG (Impaired fasting glucose) and IGT (Impaired glucose tolerance), debates still exit on the cutoffs to be used and also on use of HbA1C to define prediabetes. Recent Chinese study looked at age specific cut offs for the interplay between prediabetes and elevated cardiovascular disease risk and found family history as an important pointer in the younger age group and life style factors to be of importance in older age group. More research and studies encompassing the global population at large needs to be done to eliminate the population bias involved in a nationwide studies, with insights into the Sirtuin proteins SRT1- 7 and its modulators, whose impact on cardiovascular disease is well established.

Effects of Obesity and Hyperglycemia on Postprandial Insulin-Mediated and Non-Insulin-Mediated Glucose Disposal.

To evaluate total, insulin-mediated, and non-insulin-mediated glucose disposal (TGD, IMGD, and NIMGD) after ingesting glucose in people with obesity and different glycemic status. We developed and validated a new glucose tracer model in conjunction with an oral glucose tolerance test to determine IMGD, NIMGD, and TGD (sum of IMGD and NIMGD) after glucose ingestion in four groups of people: 1) lean with normal glucose tolerance (NGT), 2) obese with insulin resistance and NGT due to hyperinsulinemia (Ob-NGT group), 3) obese with insulin resistance and impaired glucose tolerance (IGT) due to inadequate hyperinsulinemia (Ob-IGT group), and 4) obese with insulin resistance and type 2 diabetes due to marked insulin insufficiency (Ob-T2D group). In addition, we evaluated the effect of intensive lifestyle therapy (ILT) that caused ∼15% weight loss on IMGD and NIMGD in people with obesity and type 2 diabetes (T2D). IMGD progressively decreased and NIMGD progressively increased from lean to Ob-NGT to Ob-IGT to Ob-T2D. IMGD accounted for about 70%, 65%, 50%, and 20% of TGD, and NIMGD accounted for ∼40%, 35%, 50%, and 80% of TGD in lean, Ob-NGT, Ob-IGT and Ob-T2D, respectively. Although NIMGD was approximately twofold and approximately threefold higher in Ob-IGT and Ob-T2D compared with Ob-NGT, NIMGD only partially compensated for markedly impaired IMGD in the Ob-IGT and Ob-T2D. ILT in people with obesity and T2D increased IMGD and decreased NIMGD. NIMGD is a major mechanism of postprandial TGD in people with insulin resistance and inadequate insulin secretion.

Integrated gut microbiome and UHPLC-MS metabolomics to reveal the prevention mechanism of pidanjiangtang granules on IGT Rats

IntroductionPidanjiangtang (PDJT) is a traditional Chinese medicine formula empirically used to treat impaired glucose tolerance (IGT) based on the "Pidan" theory from the classic ancient book Nei Jing. However, the mechanism of PDJT intervention for IGT remains to be studied. ObjectiveThis study aims to explore the mechanism of PDJT granules intervention in IGT by integrating gut microbiome and UHPLC-MS untargeted metabolomics. Materials and methodsThe IGT model was established in 6-week-old male Sprague-Dawley (SD) rats by feeding them a high-fat diet and using an STZ injection. The low, medium, and high doses of PDJT were used for six weeks. metformin (Glucophage) was used as the positive control drug. The efficacy of PDJT was evaluated using fasting blood glucose (FBG), blood glucose maximum (BGmax), blood lipid, and inflammatory factor levels. Finally, 16S rDNA gut microbiome sequencing with metabolomics analysis was used to explore the pharmacological mechanism of PDJT intervention in IGT. ResultsPDJT could reverse the phenotype of IGT rats, reduce blood glucose levels, improve lipid metabolism disorder, and reduce inflammatory response. Gut microbiome analysis found that PDJT can improve gut microbiota composition and abundance of three phyla (Firmicutes, Bacteroidota, Desulfobacterota) and four genera (unclassified_f__Lachnospiraceae, Ruminococcus, Allobaculum, Desulfovibrio), which play an important role in the process of PDJT intervention on glucose metabolism and lipid metabolism in IGT rats. UHPLC-MS untargeted metabolomics showed that PDJT could regulate the levels of 258 metabolites in lipid metabolism pathways, inflammatory response pathways, fat and protein digestion, and absorption. The combined analysis of the two omics showed that improving the body's metabolism by gut microbes may be the possible mechanism of PDJT in treating IGT. Thus, this study provides a new method to integrate gut microbiome and UHPLC-MS untargeted metabolomics to evaluate the pharmacodynamics and mechanism of PDJT intervention in IGT, providing valuable ideas and insights for future research on the treatment of IGT with traditional Chinese medicine.

Establishing a Female Animal Model of Prediabetes Using a High-Carbohydrate, High-Fat Diet

Prediabetes is a condition that often precedes the onset of type 2 diabetes and is characterized by moderate levels of insulin resistance. This condition is well established in male animal models for diabetes; however, few female models exist. There is accumulating evidence that sex variations affect the pathogenesis, treatment, and consequences of numerous diseases, such as type 2 diabetes. Therefore, we sought to develop a diet-induced prediabetic female animal model to better understand prediabetes development and its effects in females. Female Sprague Dawley rats were randomly allocated to one of two groups: the standard diet (SD) group fed a standard diet with normal drinking water, and the high-carbohydrate, high-fat (HCHF) group fed a high-carbohydrate and high-fat diet with drinking water supplemented with fructose. During induction, we measured food intake, body weight, body mass index (BMI), and oral glucose tolerance response (OGT). After the induction period, biochemical analyses were conducted to assess the levels of plasma leptin, ghrelin, insulin, and glycated hemoglobin (HbA1c). Glycogen concentrations were quantified in the liver and skeletal muscles. The HCHF diet-fed group presented higher body weight gain, food intake, and BMI levels, which were accompanied by elevated plasma insulin, ghrelin, and liver and skeletal muscle glycogen levels compared to the SD-fed group. In the HCHF diet-fed group, the HOMA-IR was above 1.9, suggesting the presence of moderate levels of insulin resistance. The OGT response was significantly higher in the HCHF-fed group versus the SD-fed group, suggesting impaired glucose tolerance, thus displaying the signs and symptoms of prediabetes. The HCHF diet with fructose led to the induction of prediabetes in female Sprague Dawley rats. This model could be used to investigate and outline the pathophysiological complications associated with prediabetes in females as a result of the prolonged ingestion of a high carbohydrate, high-fat diet with fructose. The development of this model could also serve as an effort to further bridge the gap regarding the inclusion of females in biomedical research, thus providing advancements in deriving better, specified treatment strategies for women.

Early Pathological Mechanisms in a Mouse Model of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF cases, yet evidence-based therapies remain lacking due to limited understanding of its underlying pathological mechanisms. Our study aimed to uncover early pathological mechanisms in HFpEF by exposing mice to dietary conditions resembling a Western diet-rich in fats, salt, and low in fiber-alongside excess mineralocorticoids to replicate significant aspects of human HFpEF. Echocardiography was performed at both 3-week and 6-week intervals post-challenge, revealing cardiac alterations as early as 3-weeks. While ejection fraction remained preserved, mice exhibited signs of diastolic dysfunction, reduced stroke volume, and left atrial enlargement. Additionally, changes in pulmonary flow velocities were noted by the 3-week mark, suggesting elevated pulmonary pressure. Extracardiac comorbidities included organ congestion, increased adiposity, impaired glucose tolerance, and hypercholesterolemia. Molecular analyses unveiled evidence of low-grade inflammation, oxidative stress, and impaired NO-cGMP-PKG signaling, contributing to the observed decrease in titin phosphorylation, thereby impacting myocardial stiffness. Additionally, impaired NO signaling might have influenced the alterations observed in coronary flow reserve. Moreover, dysregulation of calcium signaling in cardiomyocytes and reduced SR load were observed. Interestingly, elevated phosphorylation of cMyBP-C was linked to preserved ejection fraction despite reduced SR load. We also observed intestinal atrophy, possibly due to low dietary fiber intake and diminished gut perfusion, potentially contributing to systemic low-grade inflammation. These findings reveal how excess mineralocorticoids-salt-induced hypertension, and dietary factors, like high-fat and low-fiber intake, contribute to cardiac dysfunction and metabolic disturbances, offering insights into early HFpEF pathology in this model.