Increased Fasting Blood Glucose Research Articles

Antioxidant Vitamins (Vit C and E) Protect the Kidney from Glyphosate- Exposed Renal Damage in Experimental Rats - A Molecular Study

Glyphosate is a widely used herbicide and the active ingredient in Monsanto's Roundup, among other herbicide formulations. Vitamin C (ascorbic acid) and vitamin E (tocopherol) are both antioxidants that play important roles in reducing oxidative DNA damage and protecting cells from the harmful effects of free radicals. The study aimed to analyse the effect of antioxidant vitamins (vitamins C and E) on the expression of IGF-1 and KIM-1 molecules in the kidneys of glyphosate-exposed rats. Adult male Albino Wistar rats were grouped into 3. Group I: Control; Group II: Glyphosate treated (100mg); Group III: Glyphosate+ vitamin E & C treated. Serum, insulin, and mRNA expression of insulin-like growth factor (IGF-1) and kidney injury molecules (KIM-1) mRNA expression by RT-PCR. Serum insulin was measured by the ELISA method. Glyphosate-exposed rats developed hyperglycaemia and hyper compared to control but antioxidant vitamins (Vitamin C and E) supplementation, reduced the glyphosate mediate increased fasting blood glucose and insulin near to that of the control level. Similarly, mRNA expression of both IGF-1 and KIM-1 were also significantly altered due to glyphosate induction whose effects were found to be reduced when vitamins C and E were treated. It is concluded that glyphosate exposure causes renal damage and develops diabetic nephropathy by modulating the expression of IGF-1 and KIM-1 molecules in the kidney. Vitamin C and E potentially were able to reduce the detrimental changes caused by glyphosate. Hence, vitamin C and E supplements could be considered therapeutic drugs for diabetic nephropathy.

Effects of Prevotella copri on insulin, gut microbiota and bile acids

ABSTRACT Obesity is becoming a major global health problem in children that can cause diseases such as type 2 diabetes and metabolic disorders, which are closely related to the gut microbiota. However, the underlying mechanism remains unclear. In this study, a significant positive correlation was observed between Prevotella copri (P. copri) and obesity in children (p = 0.003). Next, the effect of P. copri on obesity was explored by using fecal microbiota transplantation (FMT) experiment. Transplantation of P. copri. increased serum levels of fasting blood glucose (p < 0.01), insulin (p < 0.01) and interleukin-1β (IL-1β) (p < 0.05) in high-fat diet (HFD)-induced obese mice, but not in normal mice. Characterization of the gut microbiota indicated that P. copri reduced the relative abundance of the Akkermansia genus in mice (p < 0.01). Further analysis on bile acids (BAs) revealed that P. copri increased the primary BAs and ursodeoxycholic acid (UDCA) in HFD-induced mice (p < 0.05). This study demonstrated for the first time that P. copri has a significant positive correlation with obesity in children, and can increase fasting blood glucose and insulin levels in HFD-fed obese mice, which are related to the abundance of Akkermansia genus and bile acids.

Relevance of PNPLA3, TM6SF2, HSD17B13, and GCKR Variants to MASLD Severity in an Egyptian Population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a frequent clinical condition globally. Single nucleotide polymorphisms (SNPs) associated with NAFLD have been proposed in the literature and based on bioinformatic screening. The association between NAFLD and genetic variants in Egyptians is still unclear. Hence, we sought to investigate the association of some genetic variants with NAFLD in Egyptians. Egyptians have been categorized into either the MASLD group (n = 205) or the healthy control group (n = 187). The severity of hepatic steatosis and liver fibrosis was assessed by a Fibroscan device. TaqMan-based genotyping assays were employed to explore the association of selected SNPs with MASLD. PNPLA3 rs738409 C>G variant is associated with the presence of MASLD with liver fibrosis, the severity of both hepatic steatosis and liver fibrosis, increased systolic and diastolic blood pressure and increased alanine aminotransferase (all p < 0.05), while the TM6SF2 rs58542926 C>T, HSD17B13 rs9992651 G>A, and GCKR rs1260326 T>C variants were not (all p > 0.05). The TM6SF2 rs58542926 T allele is associated with increased fasting blood glucose and a decreased waist circumference. The GCKR rs1260326 C allele is associated with decreased aspartate transaminase and diastolic blood pressure (all p < 0.05). Only after adjusting for the risk factors (age, sex, BMI, WC, HDL, TG, diabetes mellitus, and hypertension) F2 liver fibrosis score is negatively correlated with the HSD17B13 rs9992651 GA genotype. This study offers evidence for the association of the PNPLA3 rs738409 C>G variant with MASLD among Egyptians and for the association of the PNPLA3 rs738409 G allele, the TM6SF2 rs58542926 T allele, and the GCKR rs1260326 C allele with some parameters of cardiometabolic criteria.

Evaluating the potential of daily intake of polystyrene microplastics via drinking water in inducing PCOS and its ovarian fibrosis progression using female zebrafish

Polystyrene microplastics, extensively considered endocrine disrupting chemicals, disturb the reproductive system of living organisms. Polycystic ovary syndrome (PCOS), the reproductive endocrinopathy, is longstanding concern due to its eternal impacts as reproductive disorder and infertility. Despite several reports in reproductive and endocrine toxicity, there is inadequate literature regarding the daily intake of polystyrene-microplastics via drinking water in causing PCOS and leading to ovarian fibrosis in long-term. The present study investigated whether daily consumption of polystyrene-microplastics at doses equivalent to human exposure can cause PCOS and progress to ovarian fibrosis, using female zebrafish as model. Resembling letrozole-PCOS zebrafish model, daily intake of polystyrene-microplastics displayed hallmark PCOS pathophysiology; like excess body weight and %Gonadosomatic index, decreased Follicle Stimulating Hormone and β-estradiol, increased Luteinising Hormone, brain and ovarian Testosterone (39.3% and 75% respectively). Correspondingly, ovarian histology revealed more developing (stage I and II) oocytes and less mature oocytes alongwith cystic lesions; like follicular membrane disorganization, zona pellucida invagination, theca hypertrophy, basophilic granular accumulation and oocyte buddings. Lipid deposition in intestinal and ovarian tissues was evidenced and increased fasting blood glucose manifesting insulin resistance. The expression of PCOS biomarkers (tox3, dennd1a, fem1a) was significantly disturbed. Polystyrene microplastics played vital role in inducing PCOS further enhancing oxidative stress, which positively influences inflammation and aggravate ovarian mitophagy, shedding light on its ability to harshen PCOS into ovarian fibrosis, which is characterized by collagen deposition and upregulation of pro-fibrogenic biomarker genes. These findings illustrate the potential of daily microplastics intake via drinking water in triggering PCOS and its progression to ovarian fibrosis.

Social jet lag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training.

Social jet lag (SJL) is a misalignment between sleep and wake times on workdays and free days. SJL leads to chronic circadian rhythm disruption and may affect nearly 70% of the general population, leading to increased risk for cardiometabolic diseases. This study investigated the effects of SJL on metabolic health, exercise performance, and exercise-induced skeletal muscle adaptations in mice. Ten-week-old C57BL/6J mice (n = 40) were allocated to four groups: control sedentary (CON-SED), control exercise (CON-EX), social jet lag sedentary (SJL-SED), and social jet lag exercise (SJL-EX). CON mice were housed under a 12:12-h light-dark cycle. SJL was simulated by implementing a 4-h phase delay for 3 days to simulate "weekends," followed by a 4-h phase advance back to "weekdays," for 6 wk. EX mice had free access to a running wheel. Graded exercise tests (GXTs) and glucose tolerance tests (GTTs) were performed at baseline and after intervention to monitor the effects of exercise and social jet lag on cardiorespiratory and metabolic health, respectively. SJL led to alterations in activity and running patterns and clock gene expression in skeletal muscle and decreased average running distance (P < 0.05). SJL-SED mice gained significantly more weight compared with CON-SED and SJL-EX mice (P < 0.01). SJL impaired fasting blood glucose and glucose tolerance compared with CON mice (P < 0.05), which was partially restored by exercise in SJL-EX mice. SJL also blunted improvements in exercise performance and mitochondrial content in the quadriceps. These data suggest that SJL blunted some cardiometabolic adaptations to exercise and that proper circadian hygiene is necessary for maintaining health and performance.NEW & NOTEWORTHY In mice, disrupting circadian rhythms with social jet lag for 6 wk caused significant weight gain, higher fasting blood glucose, and impaired glucose tolerance compared with control. Voluntary exercise in mice experiencing social jet lag prevented weight gain, though the mice still experienced increased fasting blood glucose and impaired exercise performance compared with trained mice not experiencing social jet lag. Social jet lag seems to be a potent circadian rhythm disruptor that impacts exercise-induced training adaptations.

TLR7 activation by imiquimod worsens glycemic control in female FVB/N mice consuming a high-fat diet.

Toll-like receptor-7 (TLR7) activation promotes autoimmunity, and metabolic syndrome (MetS) is a common comorbidity in patients with autoimmune disease. We previously demonstrated hyperinsulinemia in TLR7 agonist imiquimod (IMQ)-treated, high-fat diet (HFD)-fed female C57BL/6 mice. Since mouse strains differ in susceptibility to MetS and target organ damage, this study investigated whether 12 weeks of exposure to HFD and IMQ promoted MetS, autoimmunity, and target organ damage in female FVB/N mice. Supporting early-stage autoimmunity, spleen-to-tibia ratio, and anti-nuclear antibodies (ANA) were significantly increased by IMQ. No significant effect of IMQ on urinary albumin excretion or left ventricular hypertrophy was observed. HFD increased liver-to-tibia ratio, which was further exacerbated by IMQ. HFD increased fasting blood glucose levels at the end of 12 weeks, but there was no significant effect of IMQ treatment on fasting blood glucose levels at 6 or 12 weeks of treatment. However, oral glucose tolerance testing at 12 weeks revealed impaired glucose tolerance in HFD-fed mice compared to control diet mice together with IMQ treatment exacerbating the impairment. Accordingly, these data suggest TLR7 activation also exacerbates HFD-induced dysregulation of glucose handling FVB/N mice, supporting the possibility that endogenous TLR7 activation may contribute to dysglycemia in patients with autoimmune disease.

Glucocorticoid excess and insulin resistance in rat models of vascular contributions to cognitive impairment and dementia

AbstractBackgroundHypertension and insulin resistance are major risk factors for the development of dementia. While insulin resistance is considered an important risk factor for the development of hypertension and dementia, little consideration has been given to the idea that vascular disease could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We previously showed that bilateral carotid artery stenosis results in HPA‐axis dysfunction and insulin resistance (Lansdell et al., 2022). We hypothesized that hypertension would also cause glucocorticoid excess and insulin resistance.MethodTo test this hypothesis, we measured fecal corticosterone and the expression of steroid biosynthetic genes in the adrenal glands of six‐month‐old spontaneously hypertensive rat/stroke‐prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To assess glycemic control, rats were subjected to glucose and insulin tolerance tests.ResultSHRSP were hypertensive and cognitively impaired. Corticosterone was elevated in hypertensive compared to normotensive rats (Male SD vs. SHRSP: 167±29 pg/g vs.1091±166 pg/g, P&lt;0.0001; Female SD vs. SHRSP: 134±19 pg/g vs. 376±47 pg/g, P = 0.0017). Adrenal CYP11B1 mRNA expression was increased in SHRSP (Males 14.44±1.44, P = 0.0009; Females 710±59, P = 0.0016). STARD1 mRNA expression provided a marker of HPA negative feedback. Male SHRSPs had decreased STARD1 mRNA expression (0.56±0.09, P = 0.0217). However, female SHRSPs had increased STARD1 mRNA expression (12.5± 2.25, P = 0.0028). Female, but not male, hypertensive rats had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (female SD vs. SHRSP: 73±6 vs. 92±4 mg/dL glucose, P = 0.0045; 33±2.0 vs. 12±5 pmol/L insulin, P = 0.0111; AUC 185±37 vs. 279±27 mg/dL/h, P = 0.0368). When fasting rats were challenged with insulin, both male and female hypertensive rats had decreased clearance of glucose compared to normotensive rats (Male SD vs. SHRSP AUC 87 ± 2 vs. 58 ± 4 mg/dL/h, P&lt; 0.0001, Female SD vs. SHRSP AUC 82 ± 2 vs. 68 ± 3 mg/dL/h, P = 0.0007).ConclusionThese results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female hypertensive rats developing hyperglycemia at an earlier age than males.

Psychopharmacological Investigation to Explore the Neuroprotective Mechanism of Quercetin and Naringenin in an Experimental Model of Insulin Resistance and Related Cognitive Dysfunction

AbstractBackground Alzheimer’s disease is a brain ailment that causes cell degradation and is the leading cause of dementia, which is defined by a deterioration in thinking and independence in routine everyday activities. Insulin possesses neuroprotective and memory‐enhancing effects indicating a permissive function for insulin in cognition. Defective insulin signaling promotes Aβ aggregation and accelerates Aβ formation in the brain. Based on this evidence, Alzheimer’s is also defined as diabetes of the brain or Type 3 Diabetes.MethodDiabetes was induced in mice by Alloxan (100mg/kg) and sucrose 35% solution. Glucose level was monitored, and test drugs were given accordingly. Behavioral models employed in the current study were elevated plus maze, morris water maze, actophotometer, and novel object recognition test. Biochemicals performed were all mitochondrial complexes, glutathione level, protein carbonyl level, lipid peroxidase, and acetylcholinesterase activity. Histopathological evaluation of the hippocampal region was carried out under a bright field microscope.ResultAlloxan administration produced significant hyperglycemia characterized by a significant increase in serum glucose level as compared to the naïve. During the acquisition test (learning), alloxan‐treated mice significantly delayed the escape latency period to reach the submerged platform as compared to the naïve group. However, quercetin and naringenin administration significantly improved memory performance. In novel object recognition, alloxan treated spent more time near the familiar object, and the treatment group spent more time near the novel object. Alloxan treatment also disrupted the mitochondrial levels and lowered the antioxidant enzyme levels, whereas the treatment group significantly reversed the changes.ConclusionIn the present study, alloxan administration caused significant impairment in cognitive behavior as evidenced by the Morris water maze (MWM) test, increased fasting blood glucose oxidative stress [through alteration of endogenous antioxidant markers i.e. superoxide dismutase (SOD), and catalase antioxidant enzyme activity and reduced glutathione (GSH) levels and oxidative stress markers i.e. reactive oxygen species (ROS) and protein carbonyls levels] and increased acetylcholinesterase activity in different areas of the brain (frontal cortex and hippocampus). Administration of quercetin and naringenin in different doses significantly reversed alloxan administration‐induced behavioral, biochemical, and cellular alteration in both the frontal cortex as well as in hippocampus.

Foxj3 Regulates Thermogenesis of Brown and Beige Fat Via Induction of PGC-1α.

Enhancing the development and thermogenesis in brown and beige fat represents a potential treatment for obesity. In the present study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impairs the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice display increased fasting blood glucose levels and hepatic steatosis on a chow diet. Foxj3 deficiency inhibits the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduces the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhances the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and inguinal WAT increases energy expenditure and improves systemic metabolism on either a chow diet or a high-fat diet. Finally, Foxj3 deletion in fat inhibits the β3 agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulates the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. The present study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.

The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation.

Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8. The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity. ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation.

Gestational exposure to ambient fine particulate matter disrupts maternal hepatic lipid metabolism

Pregnancy is a unique physiological stage for females as well as a vulnerable period for pollutant exposure. The effect of gestational ambient fine particulate matter (PM2.5) exposure on maternal lipid metabolism during pregnancy is rarely observed, and the mechanism is unknown. In the current study, pregnant C57BL/6 mice were randomly assigned to either ambient PM2.5 or filtered air exposure chambers since gestational day (GD) 0. Meanwhile, non-pregnant female mice were housed as controls in each exposure chamber. PM2.5 exposure exerted no significant effect on body weight gain or the body composition during pregnancy. Pregnant mice exposed to PM2.5 demonstrated improved glucose tolerance, whereas non-pregnant mice showed an increased fasting blood glucose level after PM2.5 exposure with no alterations in glucose tolerance. PM2.5 exposure exerted no significant effect on total lipid content in serum during pregnancy, while an increased serum total lipid level was found in non-pregnant mice exposed to PM2.5. PM2.5 exposure had no effect on total liver lipid levels, it increased several triacylglycerol (TAG) species and total cholesterol esters (CEs) in pregnant mice but lowered a considerable amount in non-pregnant mice’ livers. Furthermore, gestational exposure to PM2.5 enhanced the expression of key enzymes in fatty acid uptake, de novo lipid synthesis, and β oxidation, and inhibited molecules for lipid export in mice liver. Conversely, PM2.5 exposure upregulated proteins involved in hepatic lipolysis and lipid export in non-pregnant mice. These results suggest that the interference of PM2.5 exposure during pregnancy on the lipid metabolism, particularly the hepatic lipid metabolism, differs from that during non-pregnancy. This study provides toxicological evidence that PM2.5 exposure during pregnancy disrupts the lipid metabolism of the liver and provides a basis for protecting vulnerable populations.

Simulated weightlessness induces hippocampal insulin resistance and cognitive impairment

Growing evidence highlights the potential consequences of long-term spaceflight, including gray matter volume reduction and cognitive dysfunction with subclinical manifestations of diabetes mellitus among astronauts, but the underlying mechanisms remain unknown. In this study, we found that long-term simulated weightlessness induced hippocampal insulin resistance and subsequent neuronal damage and cognitive impairment in rats. Rats subjected to 4-week tail suspension exhibited peripheral insulin resistance, evidenced by increased fasting blood glucose and abnormal glucose tolerance and insulin tolerance, alongside reduced spontaneous activity and impaired recognition memory. In addition, 4 weeks of simulated weightlessness induced neuronal apoptosis and degeneration in the hippocampus, as evidenced by increased TUNEL and Fluoro-Jade B staining-positive neurons. Mechanistically, insulin-stimulated hippocampal Akt phosphorylation was decreased, while PTEN, the negative regulator of insulin signaling, was increased in the hippocampus in tail-suspended rats. Interestingly, treatment with berberine, an insulin sensitizer, partly reversed the above-mentioned effects induced by simulated weightlessness. These data suggest that long-term simulated weightlessness induces cognitive impairment as well as neuronal apoptosis and neural degeneration, partially through hippocampal insulin resistance via PTEN up-regulation. Berberine treatment attenuates hippocampal insulin resistance and improves cognitive function.

Olfr78, a novel short‐chain fatty acid receptor, regulates glucose homeostasis and gut GLP‐1 secretion in mice

AbstractOlfr78, which is a novel receptor for short‐chain fatty acid (SCFA) acetate and propionate, plays essential roles in some cellular processes. The present study aimed to investigate the role of olfr78 in regulating energy metabolism and delineate the underlying mechanisms using olfr78−/− mice. Deletion of olfr78 did not influence the adiposity of mice fed either normal chow or a high‐fat diet (HFD). However, olfr78−/− mice exhibited glucometabolic dysfunction, as evidenced by increased fasting blood glucose levels, decreased serum insulin levels, and impaired oral glucose tolerance under HFD feeding. When compared to wild‐type (WT) mice, olfr78 deficiency enhanced HFD‐induced gluconeogenesis and increased the mRNA expression of key gluconeogenic genes in the liver and kidney. Quantitative real‐time PCR results revealed that olfr78 expression was higher in the colon compared with other tissues in WT mice. Analysis of the gut microbiota in the feces of olfr78−/− mice using 16S rRNA gene sequencing revealed altered relative abundances of some representative SCFAs producers along with decreased levels of SCFAs, including propionic, isobutyric, 2‐methylbutyric, valeric, isovaleric, and 4‐methylvaleric acids. Importantly, mice lacking olfr78 had low circulating levels of glucagon‐like peptide 1 (GLP‐1). In the STC‐1 enteroendocrine cell line, propionate and acetate induced the secretion of the gut hormone GLP‐1, and this effect was partially abolished by olfr78 siRNA‐mediated knockdown. Together, these results suggest a previously undescribed, specific regulatory role for gut olfr78 in glucose homeostasis and highlight olfr78 as a potential target for diabetes treatment.

Altered expression of long noncoding RNA MEG3 in the offspring of gestational diabetes mellitus induces impaired glucose tolerance in adulthood.

Gestational diabetes mellitus (GDM) affects a significant number of women worldwide and has been associated with lifelong health consequences for their offspring, including increased susceptibility to obesity, insulin resistance, and type II diabetes. Recent studies have suggested that aberrant expression of the long non-coding RNA Meg3 in the liver may contribute to impaired glucose metabolism in individuals. In this study, we aimed to investigate whether intrauterine exposure to hyperglycemia affects glucose intolerance in puberty by mediating the overexpression of LncMeg3 in the liver. To test our hypothesis, we established an animal model of intrauterine hyperglycemia to mimic GDM. The progeny was observed for phenotypic changes, and intraperitoneal glucose tolerance tests, insulin tolerance tests, and pyruvate tolerance tests were conducted to assess glucose and insulin tolerance. We also measured LncMeg3 expression in the liver using real-time quantitative PCR and examined differential methylation areas (DMRs) in the Meg3 gene using pyrophosphoric sequencing. To investigate the role of LncMeg3 in glucose tolerance, we conducted Meg3 intervention by vein tail and analyzed the changes in the phenotype and transcriptome of the progeny using bioinformatics analysis. We found that intrauterine exposure to hyperglycemia led to impaired glucose and insulin tolerance in the progeny, with a tendency toward increased fasting blood glucose in fat offspring at 16weeks (P = 0.0004). LncMeg3 expression was significantly upregulated (P = 0.0061), DNMT3B expression downregulated (P = 0.0226), and DNMT3A (P = 0.0026), TET2 (P = 0.0180) expression upregulated in the liver. Pyrophosphoric sequencing showed hypomethylation in Meg3-DMRs (P = 0.0005). Meg3 intervention by vein tail led to a decrease in the percentage of obese and emaciated offspring (emaciation: 44% vs. 23%; obesity: 25% vs. 15%) and attenuated glucose intolerance. Bioinformatics analysis revealed significant differences in the transcriptome of the progeny, particularly in circadian rhythm and PPAR signaling pathways. In conclusion, our study suggests that hypomethylation of Meg3-DMRs increases the expression of the imprinted gene Meg3 in the liver of males, which is associated with impaired glucose tolerance in GDM-F1. MEG3 interference may attenuate glucose intolerance, which may be related to transcriptional changes. Our findings provide new insights into the mechanisms underlying the long-term effects of intrauterine hyperglycemia on progeny health and highlight the potential of Meg3 as an intervention target for glucose intolerance.

Efficacy and safety of HIMABERB® Berberine on glycemic control in patients with prediabetes: double-blind, placebo-controlled, and randomized pilot trial

BackgroundPrediabetes and diabetes involve alterations in glucose homeostasis, including increased fasting blood glucose and impaired glucose tolerance. Berberine has been identified as a potential regulator of glucose homeostasis with implications on the management of type 2 diabetes mellitus (DM). Given a paucity of data on berberine in prediabetes, evaluation of its effect in individuals with prediabetes may prove clinically valuable.ObjectiveThe present pilot study aimed to investigate the effect of daily oral berberine on markers of glycemic control and insulin resistance among individuals with prediabetes.MethodsA randomized, double-blinded, placebo-controlled trial was conducted for 12 weeks among 34 individuals with prediabetes as defined by the American Diabetes Association (fasting plasma glucose (FPG) between 5.6 and 6.9 mmol/L, glycosylated hemoglobin (HbA1c) between 5.7% and 6.4%, or 2-hour 75-gram oral glucose tolerance test (2 h-OGTT) between 7.8 and 11.1 mmol/L). HIMABERB® 500 mg was given three times daily to the treatment group, and placebo was administered three times daily to the control group. Glycemic control markers and physical parameters were evaluated for both groups on days 0, 28, 56, and 84. The glycemic control markers assessed included FPG, fasting insulin (FI), 2 h-OGTT, HbA1c, and homeostatic model assessment-insulin resistance (HOMA-IR). The observed outcomes were analyzed using independent t-test statistics to determine the significance of differences over time after treatment initiation and between treatment and control groups.ResultsSignificant decreases in all markers of glycemic control were observed in the treatment group at intermediate time points and the endpoint of the study compared to baseline levels and to the control group. For the treatment group, FPG decreased from 6.75 ± 0.23 mmol/L to 5.33 ± 0.28 mmol/L, FI from 9.81 ± 0.36 to 7.88 ± 0.52 mmol/L, 2 h-OGTT from 10.44 ± 0.52 to 8.12 ± 0.40 mmol/L, HbA1c from 6.40% ± 0.20–5.43% ± 0.21%, and HOMA-IR from 3.61 ± 0.31 to 2.41 ± 0.14. The decreases in glycemic control markers compared to the control group were clinically and statistically significant (p<10− 5). No severe adverse effects, kidney or liver toxicity were detected.ConclusionAfter 12 weeks, berberine (HIMABERB®) intervention in individuals with prediabetes significantly reduced glycemic control markers, with mean FPG and 2 h-OTGG being reduced to below prediabetic thresholds, supporting the investigation of the use of HIMABERB® for delaying progression to diabetes mellitus.Trial registrationhttp://ctri.nic.in(CTRI/2021/12/038751) (20/12/2021).

Frequency and Association of Gamble Variables of Impaired Glucose Tolerance Among Medical Students

Objective: To find out the frequency and association of gamble variables of impaired glucose tolerance among medical students. Method: This cross-sectional study was conducted at Quaid-e-Azam Medical College Bahawalpur in month of March 2022 to assess the frequency of impaired glucose tolerance and the factors predisposing to the same. After necessary permissions, participants giving written informed consent were interviewed and participants were subjected to an oral glucose tolerance test (OGTT) and their heights, weights were measured. Results: None of the participants had increased fasting blood glucose but 60 min after OGTT serum glucose levelswere increased in 79(49.37%)subjects and 120min afterOGTTserumglucosewasincreased in 15 (9.3%) subjects. There was association of age, male gender, increased BMI, positive family history of diabetes, lack of physical activity, junk food intake and smoking with impaired glucose tolerance in medical students. Conclusions: Impaired glucose tolerance was found in a substantial number of non-diabetic medical students and had a statistically significant association with gamble variables high BMI, family foundation of diabetes middle financial class, scarce physical activity, high junk food intake and smoking

Bedding as a variable affecting fasting blood glucose and vascular physiology in mice.

Rodent husbandry requires careful consideration of environmental factors that may impact colony performance and subsequent physiological studies. Of note, recent reports have suggested corncob bedding may affect a broad range of organ systems. As corncob bedding may contain digestible hemicelluloses, trace sugars, and fiber, we hypothesized that corncob bedding impacts overnight fasting blood glucose and murine vascular function. Here, we compared mice housed on corncob bedding, which were then fasted overnight on either corncob or ALPHA-dri bedding, a virgin paper pulp cellulose alternative. Male and female mice were used from two noninduced, endothelial-specific conditional knockout strains [Cadherin 5-cre/ERT2, floxed hemoglobin-α1 (Hba1fl/fl) or Cadherin 5-cre/ERT2, floxed cytochrome-B5 reductase 3 (CyB5R3fl/fl)] on a C57BL/6J genetic background. After fasting overnight, initial fasting blood glucose was measured, and mice were anesthetized with isoflurane for measurement of blood perfusion via laser speckle contrast analysis using a PeriMed PeriCam PSI NR system. After a 15-min equilibration, the mice were injected intraperitoneally with the α1-adrenergic receptor agonist, phenylephrine (5 mg/kg), or saline, and monitored for changes in blood perfusion. After a 15-min response period, blood glucose was remeasured postprocedure. In both strains, mice fasted on corncob bedding had higher blood glucose than the pulp cellulose group. In the CyB5R3fl/fl strain, mice housed on corncob bedding displayed a significant reduction in phenylephrine-mediated change in perfusion. In the Hba1fl/fl strain, phenylephrine-induced change in perfusion was not different in the corncob group. This work suggests that corncob bedding, in part due to its ingestion by mice, could impact vascular measurements and fasting blood glucose. To promote scientific rigor and improve reproducibility, bedding type should be routinely included in published methods.NEW & NOTEWORTHY This study demonstrates real-time measurement of changes in perfusion to pharmacological treatment using laser speckle contrast analysis. Furthermore, this investigation revealed that fasting mice overnight on corncob bedding has differential effects on vascular function and that there was increased fasting blood glucose in mice fasted on corncob bedding compared with paper pulp cellulose bedding. This highlights the impact that bedding type can have on outcomes in vascular and metabolic research and reinforces the need for thorough and robust reporting of animal husbandry practices.

1787-PUB: An Increased Risk of Metabolic Syndrome in Type 2 Diabetes Mellitus Patients Is Suggested by a High TG/HDL Ratio—A Retrospective Study

Background: The prevalence of cardiovascular events and the risk of mortality are higher among patients with Metabolic syndrome (MetS), and the risk factors include central obesity, increased blood pressure, increased fasting blood glucose (FBG) levels and abnormal blood lipids. Early diagnosis of MetS and timely intervention can prevent unnecessary complications related to its progression and help reduce the risk of Cardiovascular disorders (CVD). Purpose: The purpose of this EHR-based real-world study was to identify the relationship between Triglyceride/High-density lipoprotein cholesterol (TG/HDL-C) ratio and metabolic syndrome. Methods: Participants in the trial must have had type 2 diabetes mellitus for at least six months and must be presenting for routine treatment in one of 14 centres around the nation. Data on medical history, diabetes complications, medications, and laboratory values were gathered using an EMR (MEDEVA) integrated research proforma, and the study period was for six months (March-August 2022). Clinical and statistical professionals at MEDEVA combined anonymized data and conducted analyses using Python 3.6 (pandas, scikit-learn, SciPy for exploratory data analysis, and Matplotlib for exploratory visualisation), SPSS version 26 (statistical analysis). Results: Of the 372 patients with Type 2 Diabetes Mellitus, 278 had Metabolic Syndrome (MetS), and 94 did not have MetS. The TG/HDL ratio was significantly higher for the group with MetS (5.1) than the group without MetS (2.7). As a next step, to avoid potential confounding, the sample was adjusted for BMI and age, i.e., covariate matching was done. The TG/HDL ratio continued to be higher for the group with MetS (5.4) than the group without MetS (2.7). Conclusion: We discovered a strong link between metabolic syndrome and the TG/HDL-C ratio. A high TG/HDL ratio indicates an increased risk of developing metabolic syndrome. Disclosure A.K.Saxena: None. S.S.Dariya: None. A.Patil: None. S.K.Patra: None. D.Kumar: None. R.Regulla: None. M.Gupta: None. M.Lakshmanan: None. R.Sheohare: None. B.Patni: None. M.Aslam: None. A.Maheshwari: None. N.K.Singh: None. V.S.Hiremath: None.

1793-PUB: Effects of Nonnutritive Sweeteners on Glycemic Indices in Healthy Persons, with Overweight or Obesity, or Diabetes—A Systematic Review and Meta-analysis of Randomized Controlled Trials

Evidence on nonnutritive sweeteners (NNS) and glycemia is controversial due to possible mechanisms promoting glucose intolerance. No study had systematically assessed variations in glycemic outcomes based on NNS type and dose, length of exposure, and nature of the comparator in trials evaluating subjects undergoing different clinical conditions. We conducted a systematic review and meta-analysis summarizing trials contrasting NNS consumers vs. non-consumers to assess the effect on eight glycemic indices. In participants without any major disease at baseline, NNS intake significantly increased fasting blood glucose (FBG). FBG and fasting insulin (FI) were higher among NNS consumers with hyperglycemia, those who followed for &amp;gt; 8wk, consumers of ≤ 350 mg/d, and participants receiving sucralose. Sucralose also increased 2h-glucose and 2h-insulin but reduced HbA1c. Aspartame increased HbA1c. Participants with obesity consuming NNS displayed significantly less FBG, FI, and HOMA. Results were consistent when clustering those with controlled baseline glycemia, subjects followed for ≤ 8wk, consumers of &amp;gt; 350 mg/d, and those replacing sugar with NNS. NNS consumers with baseline hyperglycemia exhibited less FI and HOMA. Participants consuming ≤ 350 mg/d displayed reductions in FBG and HOMA. Trials evaluating stevia consumers reported less FBG and FI levels. We found no overall effect on persons with diabetes. Subgroup assessments revealed that persons with diabetes with uncontrolled glycemia at baseline or who were followed for &amp;gt; 10wk displayed higher FI. In summary, the effect of NNS in glycemia varies across indices and between persons with inequivalent clinical conditions. Higher doses of NNS or longer interventions do not necessarily improve glycemic indices. Better-designed trials evaluating glycemic metabolism are needed to elucidate if NNS can be used as an alternative to sugar. Disclosure S.Golzan: None. A.Espinosa: None. M.Abbasi: None. M.Movahedian: None. M.Fathi: None. A.Hekmatdoost: None.

Glucocorticoid excess and insulin resistance in aged spontaneously hypertensive rats/stroke-prone

Vascular diseases cause chronic cerebral hypoperfusion and neuronal injury and are the second most common cause of dementia. A significant cause of chronic cerebral hypoperfusion is hypertension. Insulin resistance is an important risk factor for hypertension. Aside from age, insulin resistance is also the most important risk factor for the development of dementia. While Insulin resistance is considered an important risk factor for the development of hypertension and dementia, little consideration has been given to the idea that hypertension could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We hypothesized that hypertension initiates insulin resistance through sustained activation of the hypothalamic-pituitary-adrenal axis. To test this hypothesis, we measured corticosterone and the expression of steroid biosynthetic genes in six-month-old spontaneously hypertensive rat/stroke-prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To measure glycemic control, rats were subjected to glucose tolerance and insulin tolerance tests. SHRSP were hypertensive and cognitively impaired. SHRSPs had increased corticosterone compared to SD (Male SD vs. SHRSP: 167±29 pg/g vs.1091±166 pg/g, P&lt;0.0001; Female SD vs. SHRSP: 134±19 pg/g vs. 376±47 pg/g, P=0.0017). Adrenal CYP11B1 mRNA expression was increased in SHRSP (Males 14.44±1.44, P=0.0009; Females 710±59, P=0.0016). STARD1 mRNA expression provided a marker of HPA negative feedback. Male SHRSPs had decreased STARD1 mRNA expression (0.56±0.09, P = 0.0217). However, female SHRSPs had increased STARD1 mRNA expression (12.5± 2.25, P=0.0028). Female, but not male, SHRSPs had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (SD vs. SHRSP: 73±6 vs. 92±4 mg/dL glucose, P=0.0045; 33±2.0 vs. 12±5 pmol/L insulin, P=0.0111; AUC 185±37 vs. 279±27 mg/dL/h, P=0.0368). When fasting rats were challenged with insulin, both male and female SHRSPs had decreased clearance of glucose compared to SDs (Male SD vs. SHRSP AUC 87 ± 2 vs. 58 ± 4 mg/dL/h, P&lt; 0.0001, Female SD vs. SHRSP AUC 82 ± 2 vs. 68 ± 3 mg/dL/h, P=0.0007). These results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female SHRSP succumbing faster to hyperglycemia than males. Alzheimer's Association Research Fellowship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.