Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency.
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SUBMITTER: Chen M
PROVIDER: S-EPMC1257533 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveGlycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disorder caused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemia, hepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin.MethodsTo evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L-G6pc-/-) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively.ResultsWe found that fasting-induced hypoglycemia in L-G6pc-/- mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L-G6pc-/- mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombin and activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L-G6pc-/- mice, ADP-induced platelet aggregation was disturbed.ConclusionsThese studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L-G6pc-/- mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia.
| S-EPMC8243524 | biostudies-literature
Project description:Insulin secretion from pancreatic ?-cells is critical for maintaining glucose homeostasis and deregulation of circulating insulin levels is associated with the development of metabolic diseases. While many factors have been implicated in the stimulation of insulin secretion, the mechanisms that subsequently reduce insulin secretion remain largely unexplored. Here we demonstrate that mice with ?-cell specific ablation of the Y1 receptor exhibit significantly upregulated serum insulin levels associated with increased body weight and adiposity. Interestingly, when challenged with a high fat diet these ?-cell specific Y1-deficient mice also develop hyperglycaemia and impaired glucose tolerance. This is most likely due to enhanced hepatic lipid synthesis, resulting in an increase of lipid accumulation in the liver. Together, our study demonstrates that Y1 receptor signaling negatively regulates insulin release, and pharmacological inhibition of Y1 receptor signalling for the treatment of non-insulin dependent diabetes should be taken into careful consideration.
| S-EPMC6120893 | biostudies-literature
Project description:ObjectiveDetermine the value of the combination of fasting glucose less than the 10th percentile (FG < p10) during 75 gram oral glucose tolerance test (75g OGTT) with maternal characteristics to predict low birth weight (LBW) established by Intergrowth-21st tables.MethodsProspective cohort study of pregnant women who was underwent 75g OGTT between 24 and 28.6 weeks. The 10th percentile fasting glucose of the population was determined at 65 mg/dL and women with risk factors that could modify fetal weight, including those related to intrauterine growth restriction, were excluded. Two groups were formed: group FG < p10 and group with normal fasting glucose. The main finding was the diagnosis of LBW. The association between FG < p10, maternal characteristics and LBW was established by multivariate logistic regression. The predictive performance of the models constructed was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis.Results349 women were eligible for study, of whom 66 (18.91%) had FG < p10; neonates in this group had lower birth weights (2947.28 g and 3138.26 g, p = 0.001), higher frequencies of LBW (25% and 6.81%, p < 0.001) and of weights < 2500 g in term births (8.6% and 2.3%, p = 0.034). The basal prediction model consisted of nulliparity by achieving an AUC of 60%, while the addition of FG < p10 resulted in the significant improvement of the previous model (AUC 72%, DeLong: p = 0.005).ConclusionsIn pregnant women without factors that could modify fetal weight, the predictive model created by combining FG < p10 during 75g OGTT with nulliparity was significantly associated with increased risk of LBW.RegistrationClinicalTrials.gov: NCT04144595.
| S-EPMC8102028 | biostudies-literature
Project description:AimAltered adipokine serum concentrations early reflect impaired adipose tissue function in obese patients with type 2 diabetes (T2D). It is not entirely clear whether these adipokine alterations are already present in prediabetic states and so far there is no comprehensive adipokine panel available. Therefore, the aim of this study was to assess distinct adipokine profiles in patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2D.MethodsBased on 75 g oral glucose tolerance tests, 124 individuals were divided into groups of IFG (n = 35), IGT (n = 45), or NGT (n = 43). Furthermore, 56 subjects with T2D were included. Serum concentrations of adiponectin, chemerin, fetuin-A, leptin, interleukin (IL)-6, retinol-binding protein 4 (RBP4), monocyte chemoattractant protein (MCP)-1, vaspin, progranulin, and soluble leptin receptor (sOBR) were measured by ELISAs.ResultsChemerin, progranulin, fetuin-A, and RBP4, IL-6, adiponectin and leptin serum concentrations were differentially regulated among the four investigated groups but only circulating chemerin was significantly different in patients with IGT compared to those with IFG. Compared to T2D the IFG subjects had higher serum chemerin, progranulin, fetuin-A and RBP4 levels which was not detectable in the comparison of the T2D and IGT group.ConclusionAlterations in adipokine serum concentrations are already detectable in prediabetic states, mainly for chemerin, and may reflect adipose tissue dysfunction as an early pathogenetic event in T2D development. In addition, distinct adipokine serum patterns in individuals with IFG and IGT suggest a specific role of adipose tissue in the pathogenesis of these prediabetic states.
| S-EPMC2976690 | biostudies-literature
Project description:The glucose-6-phosphatase catalytic subunit 2 (G6PC2) gene encodes an islet-specific glucose-6-phosphatase catalytic subunit. G6PC2 forms a substrate cycle with glucokinase that determines the glucose sensitivity of insulin secretion. Consequently, deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin. Although chronic elevation of FBG is detrimental to health, glucocorticoids induce G6PC2 expression, suggesting that G6PC2 evolved to transiently modulate FBG under conditions of glucocorticoid-related stress. We show, using competition and mutagenesis experiments, that the synthetic glucocorticoid dexamethasone (Dex) induces G6PC2 promoter activity through a mechanism involving displacement of the islet-enriched transcription factor MafA by the glucocorticoid receptor. The induction of G6PC2 promoter activity by Dex is modulated by a single nucleotide polymorphism, previously linked to altered FBG in humans, that affects FOXA2 binding. A 5-day repeated injection paradigm was used to examine the chronic effect of Dex on FBG and glucose tolerance in wild-type (WT) and G6pc2 knockout mice. Acute Dex treatment only induces G6pc2 expression in 129SvEv but not C57BL/6J mice, but this chronic treatment induced G6pc2 expression in both. In 6-hour fasted C57BL/6J WT mice, Dex treatment lowered FBG and improved glucose tolerance, with G6pc2 deletion exacerbating the decrease in FBG and enhancing the improvement in glucose tolerance. In contrast, in 24-hour fasted C57BL/6J WT mice, Dex treatment raised FBG but still improved glucose tolerance, with G6pc2 deletion limiting the increase in FBG and enhancing the improvement in glucose tolerance. These observations demonstrate that G6pc2 modulates the complex effects of Dex on both FBG and glucose tolerance.
| S-EPMC5086534 | biostudies-literature
Project description:BACKGROUND:Around 308 million people worldwide are estimated to have impaired glucose tolerance (IGT); 25% to 75% of these will develop diabetes within a decade of initial diagnosis. At diagnosis, half will have tissue-related damage and all have an increased risk for coronary heart disease. OBJECTIVES:The objective of this review was to assess the effects and safety of Chinese herbal medicines for the treatment of people with impaired glucose tolerance or impaired fasting glucose (IFG). SEARCH STRATEGY:We searched the following databases: The Cochrane Library, PubMed, EMBASE, AMED, a range of Chinese language databases, SIGLE and databases of ongoing trials. SELECTION CRITERIA:Randomised clinical trials comparing Chinese herbal medicines with placebo, no treatment, pharmacological or non-pharmacological interventions in people with IGT or IFG were considered. DATA COLLECTION AND ANALYSIS:Two authors independently extracted data. Trials were assessed for risk of bias against key criteria: random sequence generation, allocation concealment, blinding of participants, outcome assessors and intervention providers, incomplete outcome data, selective outcome reporting and other sources of bias. MAIN RESULTS:This review examined 16 trials lasting four weeks to two years involving 1391 participants receiving 15 different Chinese herbal medicines in eight different comparisons. No trial reported on mortality, morbidity or costs. No serious adverse events like severe hypoglycaemia were observed. Meta-analysis of eight trials showed that those receiving Chinese herbal medicines combined with lifestyle modification were more than twice as likely to have their fasting plasma glucose levels return to normal levels (i.e. fasting plasma glucose <7.8 mmol/L and 2hr blood glucose <11.1 mmol/L) compared to lifestyle modification alone (RR 2.07; 95% confidence intervall (CI) 1.52 to 2.82). Those receiving Chinese herbs were less likely to progress to diabetes over the duration of the trial (RR 0.33; 95% CI 0.19 to 0.58). However, all trials had a considerable risk of bias and none of the specific herbal medicines comparison data was available from more than one study. Moreover, results could have been confounded by rates of natural reversion to normal glucose levels. AUTHORS' CONCLUSIONS:The positive evidence in favour of Chinese herbal medicines for the treatment of IGT or IFG is constrained by the following factors: lack of trials that tested the same herbal medicine, lack of details on co-interventions, unclear methods of randomisation, poor reporting and other risks of bias.
| S-EPMC3191296 | biostudies-literature
Project description:Purpose:The study aims to assess current practices of patients with diabetes to control blood glucose levels during Ramadan. Patients and Methods:A cross-sectional approach has been used for collecting data through a structured and interview-based questionnaire to assess the association between self-monitoring of blood glucose (SMBG) and hypoglycemia. The questionnaire has recorded information about demographics, duration of diabetes, and treatment of diabetes, and hypoglycemia complications faced during Ramadan. The primary outcomes of this study include frequency of SMBG during fasting in Ramadan and association of SMBG and hypoglycemia and break of fasting. However, the secondary outcomes include medications, glycemic control, and other influencing factors. The data was analyzed using Statistical Package of Social Sciences (SPSS) version 20. Results:The findings have shown that the majority of the patients used a combination of metformin+sulphonylurea (23.02%) following metformin+insulin (20.86%), insulin (12.94%), and metformin (8.63%). Whereas diet control, high or low blood sugar, insulin dose adjustment in fasting conditions were the most influential factors during Ramadan when the blood sugar levels were tested. Majority of the patients monitored their blood glucose level during pre-iftar (56.8%) following to hypoglycemia (30.2%), post-iftar (29.4%), and rarely monitored in afternoon (3.5%) despite that only 10.1% monitored their blood glucose on a daily basis. Patients who had symptoms of hypoglycemia and had to break their fasting at least once were 41% and 27.2%, respectively. There is a significant association between age and gender with symptoms of low blood sugar level. Additionally, a significant association between blood sugar monitoring and high blood sugar level has been shown (p=0.041), indicating that lack in daily blood sugar monitoring can increase the blood sugar level of a patient during Ramadan. Conclusion:The present study has helped in providing better understanding about the self-monitoring of blood glucose level and hypoglycemia. Furthermore, it also emphasizes the pre-Ramadan education about when to break their fasting along with frequency and timing of SMBG.
| S-EPMC7147609 | biostudies-literature
Project description:AimsTo identify socioeconomic, behavioral and clinical factors that are associated with prediabetes according to different prediabetes definition criteria.MethodsAnalyses use pooled data of the population-based Cooperative Health Research in the Region of Augsburg (KORA) studies (n = 5312 observations aged ≥ 38 years without diabetes). Prediabetes was defined through either impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or elevated HbA1c according to thresholds of the American Diabetes Association. Explanatory variables were regressed on prediabetes using generalized estimating equations.ResultsMean age was 58.4 years; 50% had prediabetes (33% had IFG, 16% IGT, and 26% elevated HbA1c, 10% fulfilled all three criteria). Age, obesity, hypertension, low education, unemployment, statutory health insurance, urban residence and physical inactivity were associated with prediabetes. Male sex was a stronger risk factor for IFG (OR = 2.5; 95%-CI: 2.2-2.9) than for IGT or elevated HbA1c, and being unemployed was a stronger risk factor for IGT (OR = 3.2 95%-CI: 2.6-4.0) than for IFG or elevated HbA1c.ConclusionsThe overlap of people with IFG, IGT and elevated HbA1c is small, and some factors are associated with only one criterion. Knowledge on sociodemographic and socioeconomic risk factors can be used to effectively target interventions to people at high risk for type 2 diabetes.
| S-EPMC7591423 | biostudies-literature
Project description:ObjectiveIn human studies, new model systems are needed for improved mechanistic investigation of developmental predisposition for metabolic disease but also to serve as benchmarks in early life prevention or intervention efforts. In this regard, human infant umbilical cord-derived mesenchymal stem cells (MSCs) are an emerging tool. However, long-term clinical relevance to in vivo markers of metabolic disease is unknown.MethodsIn a cohort of 124 mother/child dyads, this study tested the hypothesis that triglyceride content (TG) of infant MSCs undergoing adipogenesis in vitro (MSC-TG) is associated with in vivo adiposity (percent fat mass) from birth to early childhood and with fasting glucose and insulin in early childhood.ResultsMSC-TG was positively associated with in vivo child adiposity at birth, age 4 to 6 months, and age 4 to 6 years. MSC-TG was associated with fasting glucose, but not insulin, at 4 to 6 years. Importantly, MSC-TG explained an additional 13% variance in child adiposity at 4 to 6 years, after accounting for other established birth predictors (weight and percent fat mass at birth) and other established covariates related to child adiposity (e.g., breastfeeding exposure, physical activity).ConclusionsThis work demonstrates the strength of the MSC model for predicting offspring metabolic phenotype into childhood, even when considering the important contribution of other early life risk factors.
| S-EPMC9782692 | biostudies-literature
Project description:AIM: To investigate the impact of chronic ingestion of sebacic acid (SA), a 10-carbon medium-chain dicarboxylic acid, on glycaemic control in a mouse model of type 2 diabetes (T2D). METHODS: Three groups of 15 db/db mice were fed for 6 weeks either a chow diet (Ctrl) or a chow diet supplemented with 1.5 or 15% (SA(1.5%) and SA(15%) , respectively) energy from SA. Fasting glycaemia was measured once a week and HbA1c before and after supplementation. An oral glucose tolerance test (OGTT) was performed at the end of the supplementation. Gene expression was determined by transcriptomic analysis on the liver of the Ctrl and SA(15%) groups. RESULTS: After 42 days of supplementation, fasting glycaemia and HbA1c were ?70 and 25% lower in the SA(15%) group compared with the other groups showing a beneficial effect of SA on hyperglycaemia. During OGTT, plasma glucose area under the curve was reduced after SA(15%) compared with the other groups. This effect was associated with a tendency for an improved insulin response. In the liver, Pck1 and FBP mRNA were statistically decreased in the SA(15%) compared with Ctrl suggesting a reduced hepatic glucose output induced by SA. CONCLUSION: Dietary supplementation of SA largely improves glycaemic control in a mouse model of T2D. This beneficial effect may be due to (i) an improved glucose-induced insulin secretion and (ii) a reduced hepatic glucose output.
| S-EPMC2997326 | biostudies-literature