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1.
Fluvastatin Reduces Glucose Tolerance in Healthy Young Individuals Independently of Cold Induced BAT Activity.
Felder, M, Maushart, CI, Gashi, G, Senn, JR, Becker, AS, Müller, J, Balaz, M, Wolfrum, C, Burger, IA, Betz, MJ
Frontiers in endocrinology. 2021;:765807
Abstract
BACKGROUND Statins are commonly prescribed for primary and secondary prevention of atherosclerotic disease. They reduce cholesterol biosynthesis by inhibiting hydroxymethylglutaryl-coenzyme A-reductase (HMG-CoA-reductase) and therefore mevalonate synthesis. Several studies reported a small, but significant increase in the diagnosis of diabetes mellitus with statin treatment. The molecular mechanisms behind this adverse effect are not yet fully understood. Brown adipose tissue (BAT), which plays a role in thermogenesis, has been associated with a reduced risk of insulin resistance. Statins inhibit adipose tissue browning and have been negatively linked to the presence of BAT in humans. We therefore speculated that inhibition of BAT by statins contributes to increased insulin resistance in humans. METHODS A prospective study was conducted in 17 young, healthy men. After screening whether significant cold-induced thermogenesis (CIT) was present, participants underwent glucose tolerance testing (oGTT) and assessment of BAT activity by FDG-PET/MRI after cold-exposure and treatment with a β3-agonist. Fluvastatin 2x40mg per day was then administered for two weeks and oGTT and FDG-PET/MRI were repeated. RESULTS Two weeks of fluvastatin treatment led to a significant increase in glucose area under the curve (AUC) during oGTT (p=0.02), reduction in total cholesterol and LDL cholesterol (both p<0.0001). Insulin AUC (p=0.26), resting energy expenditure (REE) (p=0.44) and diet induced thermogenesis (DIT) (p=0.27) did not change significantly. The Matsuda index, as an indicator of insulin sensitivity, was lower after fluvastatin intake, but the difference was not statistically significant (p=0.09). As parameters of BAT activity, mean standard uptake value (SUVmean) (p=0.12), volume (p=0.49) and total glycolysis (p=0.74) did not change significantly during the intervention. Matsuda index, was inversely related to SUVmean and the respiratory exchange ratio (RER) (both R2 = 0.44, p=0.005) at baseline, but not after administration of fluvastatin (R2 = 0.08, p=0.29, and R2 = 0.14, p=0.16, respectively). CONCLUSIONS Treatment with fluvastatin for two weeks reduced serum lipid levels but increased glucose AUC in young, healthy men, indicating reduced glucose tolerance. This was not associated with changes in cold-induced BAT activity.
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Treatment with Anaerobutyricum soehngenii: a pilot study of safety and dose-response effects on glucose metabolism in human subjects with metabolic syndrome.
Gilijamse, PW, Hartstra, AV, Levin, E, Wortelboer, K, Serlie, MJ, Ackermans, MT, Herrema, H, Nederveen, AJ, Imangaliyev, S, Aalvink, S, et al
NPJ biofilms and microbiomes. 2020;(1):16
Abstract
Dysbiosis of the intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic strain Anaerobutyricum soehngenii on glucose metabolism in 24 subjects with metabolic syndrome. We found that treatment with A. soehngenii was safe and observed a significant correlation between the measured fecal abundance of administered A. soehngenii and improvement in peripheral insulin sensitivity after 4 weeks of treatment. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehngenii (defined as improved insulin sensitivity 4 weeks after A. soehngenii intake) is dependent on microbiota composition at baseline. These data in humans are promising, but additional studies are needed to reproduce our findings and to investigate long-term effects, as well as other modes of delivery.
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Continuous Intragastric Dextrose: A Therapeutic Option for Refractory Hypoglycemia in Congenital Hyperinsulinism.
Vajravelu, ME, Congdon, M, Mitteer, L, Koh, J, Givler, S, Shults, J, De León, DD
Hormone research in paediatrics. 2019;(1):62-68
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Abstract
UNLABELLED Feeding problems are frequent in infants with congenital hyperinsulinism (HI) and may be exacerbated by continuous enteral nutrition (EN) used to maintain euglycemia. Our center's HI team uses dextrose solution given continuously via gastric tube (intrasgastric dextrose, IGD) for infants not fully responsive to conventional medical therapy or pancreatectomy. Here, we describe our practice as well as growth, feeding, and adverse events in infants with HI exposed to IGD. METHODS This was a retrospective cohort of infants with HI treated with IGD from 2009-2017. Primary outcomes were weight-for-length and body mass index Z-scores (WFL-Z and BMI-Z) in the year following IGD initiation. Secondary outcomes included EN use and adverse events. We used multivariable regression to assess covariates of interest. RESULTS We studied 32 subjects (13 female) with a median age at IGD initiation of 73 days (range 17-367); median follow-up was 11.2 months (range 5.0-14.2). WFL-Z did not change significantly over time (p > 0.05). EN use decreased significantly over time, i.e., at 0 months: 72% (95% CI 53-85) vs. at 12 months 39% (95% CI 22-59). No potential adverse events led to discontinuation of IGD. CONCLUSIONS Over a median follow-up of nearly 1 year, IGD was well-tolerated, with no change in WFL-Z or BMI-Z from baseline.
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H. pylori eradication with antibiotic treatment causes changes in glucose homeostasis related to modifications in the gut microbiota.
Martín-Núñez, GM, Cornejo-Pareja, I, Coin-Aragüez, L, Roca-Rodríguez, MDM, Muñoz-Garach, A, Clemente-Postigo, M, Cardona, F, Moreno-Indias, I, Tinahones, FJ
PloS one. 2019;(3):e0213548
Abstract
BACKGROUND H. pylori infection and eradication cause perturbations of the gut microbiome. The gut microbiota has been identified as a potential contributor to metabolic diseases. We evaluate whether these alterations in intestinal microbiota composition produced by H. pylori infection and its posterior eradication with antibiotic treatment could be associated with glucose homeostasis in metabolically healthy subjects. METHODS Forty adult patients infected with H. pylori and 20 control subjects were recruited. The infected subjects were evaluated before and two months after eradication treatment (omeprazole, clarithromycin, amoxicillin). The microbiota composition in fecal samples was determined by 16S rRNA gene (V3-V4) sequencing using Illumina Miseq. RESULTS Patients (pre- and post-H. pylori eradication) showed a decreased bacterial richness and diversity with respect to controls. There was an improvement in glucose homeostasis in subjects two months after H. pylori eradication treatment. Changes in the amount of Rikenellaceae, Butyricimonas, E. biforme, B. fragilis, and Megamonas were inversely associated with changes in the glucose level or related parameters (Hb1ac) in H. pylori eradication subjects. CONCLUSIONS H. pylori infection and eradication with antibiotic treatment causes alteration of the human gut microbiome. The increase in SCFA-producing bacteria and glucose-removing bacteria, specifically members of Megamonas, Rikenellaceae and Butyricimonas, has been related with an improvement in glucose homeostasis after H. pylori eradication with antibiotic treatment.
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Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients.
Margerie, D, Lefebvre, P, Raverdy, V, Schwahn, U, Ruetten, H, Larsen, P, Duhamel, A, Labreuche, J, Thuillier, D, Derudas, B, et al
BMC medical genomics. 2019;(1):80
Abstract
BACKGROUND Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. METHODS An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. RESULTS We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60-4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. CONCLUSIONS A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. TRIAL REGISTRATION NCT01129297 . Registered May 242,010 (retrospectively registered).
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Hepatitis C Direct Acting Antivirals and Ribavirin Modify Lipid but not Glucose Parameters.
Doyle, MA, Galanakis, C, Mulvihill, E, Crawley, A, Cooper, CL
Cells. 2019;(3)
Abstract
Chronic hepatitis C (HCV) infection perturbs lipid and glucose metabolism. The influenceof direct acting antiviral (DAA) treatment and ribavirin on these measures was evaluated.Furthermore, the effect of HCV cure on these parameters was assessed. Participants were allocatedto one of three 12-week treatment groups: non-cirrhotic genotype 1aparitaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) plus ribavirin; non-cirrhotic 1b-PrOD;compensated cirrhotic 1a or 1b-PrOD plus ribavirin. Fasting insulin, glucose, lipid andapolipoprotein measures were assessed at baseline, Treatment Weeks 4 and 12, and 12 and 24 weekspost-dosing. Twenty-three of 24 participants achieved SVR (PP= 23/24, 96% SVR). Overall, totalcholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels all increased intreatment and post-dosing. However, LDL-C levels decreased during treatment in ribavirinrecipients. Fasting glucose, insulin, and HOMA-IR were unchanged during treatment and 12 weekspost-treatment. By 12 weeks post-treatment, controlled attenuation parameter (CAP) scores, ameasure of steatosis, increased from baseline (mean 30.3 ± 63.5, p = 0.05). This regimen was safe andhighly effective and did not influence glucose metabolism. Ribavirin exposure may mitigate someon-treatment lipid changes. Further mechanistic studies are needed to understand how ribavirinimpacts lipid pathways, as there could be therapeutic implications. The metabolic pathophysiologyof increased CAP score with HCV treatment requires explanation.
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Short-Term Isocaloric Intake of a Fructose- but not Glucose-Rich Diet Affects Bacterial Endotoxin Concentrations and Markers of Metabolic Health in Normal Weight Healthy Subjects.
Nier, A, Brandt, A, Rajcic, D, Bruns, T, Bergheim, I
Molecular nutrition & food research. 2019;(6):e1800868
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Abstract
SCOPE Dietary pattern and impairments of intestinal barrier function are discussed to be critical in the development of metabolic impairments. Here, it is determined if an isocaloric exchange of complex carbohydrates with monosaccharides affects markers of intestinal permeability and metabolic health in healthy subjects. METHODS AND RESULTS After a dietary standardization for 4 days, all 12 subjects aged 21-33 years receive an isocaloric fructose- and glucose-enriched diet for 3 days separated by a wash-out phase. Anthropometry, blood pressure, markers of intestinal permeability and metabolic as well as inflammatory parameters are determined in blood samples or isolated peripheral blood mononuclear cells collected at baseline, after standardizations and the monosaccharide interventions, respectively. While anthropometric and inflammatory parameters are not changed, the intake of an isocaloric fructose- but not glucose-enriched diet is associated with a significant increase of bacterial endotoxin plasma levels and alanine aminotransferase activity in serum, while total plasma nitrate/nitrite concentrations are significantly decreased. In peripheral blood mononuclear cells, Toll like receptors 4, 2, and MYD88 mRNA expressions are significantly induced after the fructose-rich but not the glucose-rich diet. CONCLUSION In metabolically healthy subjects, even a short-term intake of a fructose-rich diet can elevate bacterial endotoxin levels and change markers of liver health and vascular endothelial function.
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Classical monocytes from older adults maintain capacity for metabolic compensation during glucose deprivation and lipopolysaccharide stimulation.
Yarbro, JR, Pence, BD
Mechanisms of ageing and development. 2019;:111146
Abstract
Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that classical monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged classical monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged classical monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.
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Morning Mastication Enhances Postprandial Glucose Metabolism in Healthy Young Subjects.
Sato, A, Ohtsuka, Y, Yamanaka, Y
The Tohoku journal of experimental medicine. 2019;(3):193-201
Abstract
Postprandial glucose concentration is dependent on the time of day and its concentration in the morning is lower than in the evening. However, whether it is dependent on mastication at different times of the day has not been studied before. We hypothesized that mastication affects insulin-mediated glucose metabolism differently in the morning and evening in healthy individuals. Firstly, nine healthy male volunteers (22.0 ± 0.7 SEM years, body mass index 22.0 ± 1.0 kg/m2) performed a 75-g oral glucose tolerance test (OGTT). One week after the OGTT, they participated in a high-carbohydrate food (rice) consumption test with 10 or 40 chews per mouthful. Each experiment was conducted in the morning (0800 h) and evening (2000 h) on the same day. Blood samples were collected before and at 30-min intervals for 120 min after glucose or rice consumption. The incremental area under the curve (iAUC) for glucose in the OGTT was significantly lower in the morning than in the evening, whereas the iAUC for insulin was similar at both times. In participants who chewed 40 times, the iAUC for glucose after rice consumption was significantly lower in the morning than in the evening but was similar at both times in individuals who chewed 10 times. Chewing 40 times in the morning (but not the evening) significantly increased insulin secretion at 30 min. This suggests that morning mastication improves early-phase insulin secretion after rice consumption. This novel finding may aid in reducing the incidence of obesity and type 2 diabetes mellitus.
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10.
Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans.
Page, LC, Gastaldelli, A, Gray, SM, D'Alessio, DA, Tong, J
Diabetes. 2018;(10):1976-1985
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Abstract
Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of 1) saline, 2) ghrelin, 3) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or 4) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired β-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.