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1.
Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism.
Li-Gao, R, Hughes, DA, van Klinken, JB, de Mutsert, R, Rosendaal, FR, Mook-Kanamori, DO, Timpson, NJ, Willems van Dijk, K
Diabetes. 2021;(12):2932-2946
Abstract
Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (β [SE] -0.23 [0.03], P = 2.15 × 10-19). In addition, the ANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: β [SE] 0.17 [0.03], P = 5.76 × 10-10; XXLVLDL cholesterol ester: β [SE] 0.17 [0.03], P = 9.74 × 10-10), which also revealed strong associations with body composition and diabetes in the UK Biobank (P < 5 × 10-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, Matsuda insulin sensitivity index, and HbA1c in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected q <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the ANKRD55 locus underlying diabetes.
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2.
The effect of intestinal glucose load on neural regulation of food craving.
Stopyra, MA, Friederich, HC, Sailer, S, Pauen, S, Bendszus, M, Herzog, W, Simon, JJ
Nutritional neuroscience. 2021;(2):109-118
Abstract
Objectives: Excess sugar consumption, particularly in the form of sweetened beverages, has been identified as a pivotal contributor to the epidemic of obesity and associated metabolic disorders. However, the impact of sugar-sweetened beverages on food craving is still inconclusive. Therefore, the present study aimed to specifically investigate the effects of an intestinal glucose load on neural processing of food cues. Methods: Using a single-blind fMRI design, 26 normal-weight women were scanned on two occasions, after receiving either a glucose or water infusion directly into the stomach using a nasogastric tube, without being aware of the type of infusion. Participants had to either view neutral and food images, or were asked to distract themselves from these images by solving an arithmetic task. Results: In response to viewing high-caloric food cues, we observed increased activation in reward-related brain areas. During food distraction, fronto-parietal brain regions were recruited, which are commonly related to attentional deployment and hedonic valuation. Furthermore, activity in the dorsolateral prefrontal cortex showed increased functional connectivity with the insula and was correlated with subjective craving levels to food cues. Despite an increase of blood glucose levels in response to the glucose compared to the water infusion, neither subjective food craving nor neural regulation of food craving showed significant differences. Conclusions: These findings support a decreased satiation effect of sweet beverages, as intestinal glucose ingestion and signalling showed no significant effect on cortical brain circuits associated with food craving. This trial was registered at clinicaltrials.gov as NCT03075371.
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3.
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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4.
A Phase I Study on the Pharmacokinetics and Pharmacodynamics of DJT1116PG, a Novel Selective Inhibitor of Sodium-glucose Cotransporter Type 2, in Healthy Individuals at Steady State.
Zhang, H, Liu, J, Zhu, X, Li, X, Chen, H, Wu, M, Li, C, Ding, Y
Clinical therapeutics. 2020;(5):892-905.e3
Abstract
PURPOSE DJT1116PG, which selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter type 2, was developed as an insulin-independent treatment for type 2 diabetes mellitus. This Phase I trial evaluated the pharmacokinetic and pharmacodynamic properties of DJT1116PG at steady state in healthy Chinese individuals. METHODS This was a multiple ascending dose study of DJT1116PG (20, 50, and 100 mg once daily for 7 days) that included 36 healthy individuals. FINDINGS There were no serious adverse events or deaths in these studies, and no adverse event led to study discontinuation. Oral DJT1116PG was rapidly absorbed with a Tmax of 0.75-1.5 h and a t½ of 12-16.2 h. Systemic exposure (Cmax and AUC) of DJT1116PG and its inactive metabolites (T1444, T1454, and T1830) increased in a dose-dependent manner. Urinary glucose excretion (UGE) plateaued at 50 mg of DJT1116PG in a previous single ascending dose study and on day 1 of this study. UGE plateaued at 20 mg of DJT1116PG on day 7 of this study. Serum glucose parameters were similar in individuals who received DJT1116PG or placebo. IMPLICATIONS DJT1116PG was well tolerated in healthy Chinese individuals. At steady state, UGE plateaued at 20 mg of DJT1116PG in these individuals. These findings will inform the selection of doses for further early-stage clinical trials of DJT1116PG. Chinese Drug Trial Identifier: CTR20160986.
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5.
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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6.
Effects of acute intake of grape/pomegranate pomace dietary supplement on glucose metabolism and oxidative stress in adults with abdominal obesity.
Pérez-Ramírez, IF, de Diego, EH, Riomoros-Arranz, M, Reynoso-Camacho, R, Saura-Calixto, F, Pérez-Jiménez, J
International journal of food sciences and nutrition. 2020;(1):94-105
Abstract
A controlled acute, cross-over clinical study (NCT02710461) was performed in order to evaluate the effects on glucose metabolism of a grape/pomegranate pomace dietary supplement in subjects with abdominal obesity (aged 40-60, n = 20). A standard 75 g oral glucose tolerance test (OGTT) was administered alone, together with or 10 h after the consumption of 10 g of the dietary supplement, rich in both extractable (0.4 g) and non-extractable (1.4 g) polyphenols. The dietary supplement did not ameliorate glucose or insulin at any sampling time. No improvement in antioxidant capacity was observed in plasma or urine, concordant with no increased urine polyphenol excretion. A tendency towards improved insulin sensitivity was observed when the product was consumed 10 h before glucose solution. These results suggest that a single realistic dose of grape/pomegranate pomace is not able to clearly improve glucose metabolism; chronic intake remains to be evaluated.
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7.
Mechanistic evaluation of the effect of sodium-dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics.
Mori-Anai, K, Tashima, Y, Nakada, T, Nakamaru, Y, Takahata, T, Saito, R
Biopharmaceutics & drug disposition. 2020;(8-9):352-366
Abstract
Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration-time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (Tmax,glc ) to reach maximum concentration of glucose (Cmax,glc ), and the delay of Tmax,glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in Cmax,glc was estimated to be 23%-28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.
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8.
Fructose vs glucose decreased liking/wanting and subsequent intake of high-energy foods in young women.
Ao, H, Li, J, Li, O, Su, M, Gao, X
Nutrition research (New York, N.Y.). 2020;:60-71
Abstract
Recent research on the health impacts of added sugar has prompted the comparison of the effects of its 2 major components: glucose and fructose. Fructose was identified as a risk factor for obesity and metabolic syndrome. However, because of the differences in metabolic responses and responsivity of reward circuitry to palatable food, it is unknown if glucose and fructose induce similar appetite-related responses in humans with varying weights. This study compared the behavioral responses to food in young women of a healthy weight (n = 31) and with excess weight (n = 28). We hypothesized that (1) the inhibitory effect of glucose (vs fructose) on food-related responses would be greater in subjects of a healthy weight than in those with overweight/obesity and (2) subjects with overweight/obesity would exhibit a stronger preference for food than subjects with a healthy weight. After an overnight fast, the subjects ingested a glucose or equienergetic fructose beverage on 2 separate days, respectively. Then, they completed liking and wanting ratings and 2 decision-making tasks followed by ad libitum food intake. The results revealed that fructose reduced both liking and wanting for food in subjects with overweight/obesity and also decreased energy intake in all subjects. Relative to the healthy-weight group, subjects with overweight/obesity preferred the immediate reward. Moreover, only in the healthy-weight group were liking and wanting scores for food positively associated with actual food consumption. Overall, fructose (vs glucose) showed an acute inhibitory effect on appetite-related responses in subjects with excess weight.
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9.
Postprandial Aminogenic Insulin and Glucagon Secretion Can Stimulate Glucose Flux in Humans.
Ang, T, Bruce, CR, Kowalski, GM
Diabetes. 2019;(5):939-946
Abstract
Insulin and glucagon exert opposing actions on glucose metabolism, and their secretion is classically viewed as being inversely regulated. This is, however, context specific as protein ingestion concomitantly stimulates euglycemic insulin and glucagon secretion. It remains enigmatic how euglycemia is preserved under these conditions. Accordingly, we examined the systems-level mechanisms governing such endocrine control of glucose homeostasis. Eight healthy participants completed a water (control) and multidose whey protein ingestion trial designed to augment the protein-induced endocrine response. Glucose kinetics were measured using stable isotope tracer methodology. Protein ingestion induced marked hyperaminoacidemia, hyperinsulinemia (approximately sixfold basal), and unprecedented hyperglucagonemia (approximately eightfold basal) while suppressing free fatty acids. Both glucose disposal (Rd) and endogenous glucose production (EGP) increased by ∼25%, thereby maintaining euglycemia. This demonstrates 1) that protein ingestion can stimulate glucose Rd and EGP, 2) that postprandial inhibition of adipose lipolysis does not suppress EGP, and 3) that physiological hyperglucagonemia can override the hepatic actions of insulin, rendering the liver unresponsive to insulin-mediated EGP suppression. Finally, we argue that glucagon is a bona fide postprandial hormone that evolved to concurrently and synergistically work with insulin to regulate glucose, amino acid, and nitrogen metabolism. These findings may have implications for glucagon receptor antagonist or agonist-based therapies.
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10.
Bifidobacterium bifidum TMC3115 Can Characteristically Influence Glucose and Lipid Profile and Intestinal Microbiota in the Middle-Aged and Elderly.
Wang, K, Yu, X, Li, Y, Guo, Y, Ge, L, Pu, F, Ma, X, Cui, W, Marrota, F, He, F, et al
Probiotics and antimicrobial proteins. 2019;(4):1182-1194
Abstract
Bifidobacterium bifidum TMC3115 strain (TMC3115) was orally administrated to 47 subjects with mild hyperglycaemia and dyslipidaemia aged 45 to 75 years for 3 weeks. Blood samples were collected before and after intervention for profiling plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol and triglyceride concentrations, as well as fasting blood glucose. Before and 3 and 4 weeks after intervention, the faecal samples were collected to analyse faecal microbiota using the sequencing of 16S rRNA genes with a next-generation sequencer. TMC3115 significantly decreased plasma TC and LDL-C levels of the tested subjects after intervention (P < 0.05). The frequencies of defaecation and faecal odour after the intervention and 1 week later were significantly better than at pre-intervention, respectively. TMC3115 administration increased Firmicutes, Bacteroides and Actinobacteria and decreases in Proteobacteria and Fusobacteria. There were significant increases in the proportions of Dorea and Lachnospira after the intervention (P < 0.05). TMC3115 also increased the level of Firmicutes and decreased that of Bacteroidetes 1 week after the intervention (P < 0.05). Serum triglycerides correlated negatively with the proportions of Bacteroidetes (R = - 0.21, P = 0.047) and Bacteroides (R = - 0.23, P = 0.029), while the relative abundance of Dialister of Firmicutes correlated negatively and significantly with the serum LDL-C (R = - 0.24, P = 0.022) and TC levels (R = - 0.22, P = 0.030). These results indicate that TMC3115 might exhibit beneficial effects on the serum cholesterol metabolism of subjects with dyslipidaemia through modulation of their intestinal microbiota. Trial registration: ChiCTR-OOC-16010271.