Glucose Metabolism In Humans Research Articles

The relation between postprandial glucagon-like peptide-1 release and insulin sensitivity before and after bariatric surgery in humans with class II/III obesity.

Glucagon-like peptide-1 (GLP-1) receptor agonist treatment is beneficial for the human glucose metabolism, and GLP-1 secretion is greatly enhanced following Roux-en-Y gastric bypass (RYGB). To elucidate the relationship between GLP-1 concentrations and insulin sensitivity in subjects with class II/III obesity without diabetes and to assess the relation between GLP-1 and the improvements in glucose metabolism following RYGB. Clinical research facility in a university hospital. We recruited 35 patients scheduled for RYGB and assessed their plasma GLP-1, insulin, and glucose responses to a high-fat mixed meal. Basal and insulin-mediated glucose fluxes were determined during a 2-step hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracers. Out of 35 subjects, 10 were studied both before surgery and at 1 year of follow-up. Plasma GLP-1 increased following the high-fat mixed meal. Postprandial GLP-1 excursions correlated positively with hepatic and peripheral insulin sensitivity, but not with body mass index. At 1 year after RYGB, participants had lost 24% ± 6% of their body weight. Plasma GLP-1, insulin, and glucose levels peaked earlier and higher after the mixed meal. The positive association between the postprandial GLP-1 response and peripheral insulin sensitivity persisted. Postprandial GLP-1 concentrations correlate with insulin sensitivity in subjects with class II/III obesity without diabetes before and 1 year after RYGB. Increased GLP-1 signaling in postbariatric patients may, directly or indirectly, contribute to the observed improvements in insulin sensitivity and metabolic health.

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

Osteoporosis and diabetes mellitus represent global health problems due to their high, and increasing with aging, prevalence in the general population. Osteoporosis can be successfully treated with both antiresorptive and anabolic drugs. While these drugs are clearly effective in reducing the risk of fracture in patients with postmenopausal and male osteoporosis, it is still unclear whether they may have the same efficacy in patients with diabetic osteopathy. Furthermore, as bone-derived cytokines (osteokines) are able to influence glucose metabolism, it is conceivable that antiosteoporotic drugs may have an effect on glycemic control through their modulation of bone turnover that affects the osteokines’ release. These aspects are addressed in this narrative review by means of an unrestricted computerized literature search in the PubMed database. Our findings indicate a balance between good and bad news. Active bone therapies and their modulation of bone turnover do not appear to play a clinically significant role in glucose metabolism in humans. Moreover, there are insufficient data to clarify whether there are any differences in the efficacy of antiosteoporotic drugs on fracture incidence between diabetic and nondiabetic patients with osteoporosis. Although more studies are required for stronger recommendations to be issued, bisphosphonates appear to be the first-line drug for treatment of osteoporosis in diabetic patients, while denosumab seems preferable for older patients, particularly for those with impaired renal function, and osteoanabolic agents should be reserved for patients with more severe forms of osteoporosis.

A milk casein hydrolysate-derived peptide enhances glucose uptake through the AMP-activated protein kinase signalling pathway in skeletal muscle cells.

What is the central question of this study? How do common active ingredients contained in both Lactobacillus helveticus-fermented milk and milk casein hydrolysate (MCH) enhance glucose metabolism by skeletal muscle? What is the main finding and its importance? MCH enhanced glucose uptake in skeletal muscle cells by stimulating AMP-activated kinase, but not insulin, signalling. Moreover, the MCH-derived specific peptide Ile-Pro-Pro mimicked this effect, suggesting a mechanism for MCH-induced metabolic improvement. Improvement of glucose metabolism in the skeletal muscle has a key role in exercise performance and prevention of metabolic diseases. In our previous study, we showed that intake of milk casein hydrolysate improves glucose metabolism in humans, but the mechanism of action was not elucidated. In this study, we aimed to investigate the mechanism of action of milk casein hydrolysate and its derived peptides on glucose uptake and glucose metabolic signalling in cultured skeletal muscle cells. Differentiated C2C12 myotubes were used for the experiments. The differentiated cells were incubated with milk casein hydrolysate, valine-proline-proline and isoleucine-proline-proline. Subsequently, the rate of 2-deoxy-glucose uptake and the phosphorylation levels of insulin-dependent and -independent signalling factors were examined. We found that the rate of 2-deoxy-glucose uptake in both milk casein hydrolysate and isoleucine-proline-proline-treated cells was higher than that in the control cells. Immunoblotting assays showed that the phosphorylation levels of AMP-activated protein kinase, a rate-limiting factor in insulin-independent signalling, and of liver kinase B1, an upstream factor of AMP-activated protein kinase, in both milk casein hydrolysate and isoleucine-proline-proline-treated cells were higher than those in the control cells. Such significant effects were not observed after treatment with valine-proline-proline. Moreover, the insulin-dependent signalling was not significantly affected under the different conditions. The findings of our study suggest that milk casein hydrolysate enhances glucose uptake by activating insulin-independent AMP-activated protein kinase signalling in skeletal muscle cells, which might be mediated by a milk casein hydrolysate-derived peptide, namely, isoleucine-proline-proline.

Direct embryotoxicity of chromium (III) exposure during preimplantation development.

Chromium in its trivalent form (chromium (III)) is an essential component of a balanced diet, and its deficiency disturbs glucose and lipid metabolism in humans and animals. The prevailing view is that chromium (III) is notably less toxic than chromium (VI), which is genotoxic and carcinogenic. Thus, the biotransformation of environmental chromium (VI) to chromium (III) is a promising and environmentally friendly detoxification method. However, increasing evidence suggests that chromium (III) induces considerable cytotoxicity. However, the toxicity of chromium (III) to early embryos remains largely unknown. In the present study, we used in vitro fertilization (IVF) to produce mouse embryos and identified the direct embryotoxicity of chromium (III). On exposure to high concentrations of CrCl3, blastocyst formation almost completely failed and a large proportion of embryos were arrested at the 2- to 4-cell stage. At low concentrations of CrCl3, IVF embryos showed a significant decrease in blastocyst formation, reduced total cell numbers, aberrant lineage differentiation, increased oxidative stress, and apoptosis. We also found that chromium (III) exposure during the preimplantation stage, even at low concentrations, led to impaired post-implantation development. Thus, our study substantiates the direct embryotoxicity of chromium (III) during preimplantation development and prolonged impairment of development potential. The results further highlight the potential adverse effects of chromium (III) on public reproductive health with respect to increased environmental enrichment of and dietary supplementation with chromium (III) complexes.

Typical phthalic acid esters induce apoptosis by regulating the PI3K/Akt/Bcl-2 signaling pathway in rat insulinoma cells

Di-(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) are representative phthalic acid esters (PAEs), a class of environmental endocrine disruptors used as plasticizers. PAEs exposure is associated with glucose metabolism, insulin resistance, and glucose tolerance; however, the mechanism and various PAE effects on human glucose metabolism remain largely unknown. In this study, we investigated the effects of DEHP, DBP, and their mixture on rat insulinoma (INS-1) cell apoptosis and the mechanism involved in vitro. The INS-1 cells were cultured in RPMI-1640 + 10% fetal bovine serum for 24 h and pretreated with dimethyl sulfoxide (vehicle, <0.1%), DEHP (30 μM), DBP (30 μM), and their mixture (30 μM DEHP + 30 μM DBP). The methyl-thiazolyl tetrazolium bromide test was used to measure cell viability. Hoechst 33342/propidium iodide (PI) staining and Annexin V-FITC/PI staining, 2′,7′-dichlorofluorescein diacetate assay, and glucose-induced insulin secretion assay were used to detect cell apoptosis rates, intracellular reactive oxygen species (ROS), and insulin secretion in INS-1, respectively. The mRNA expression levels of Bcl-2, Bax, Caspase 9, Caspase 8, Caspase 3, phosphoinositide 3-kinase (PI3K), and Akt were detected using real-time quantitative reverse transcription PCR; their protein expression levels were detected using western blotting. To the best of our knowledge, this study was the first to show that the combined effect of the two PAEs promotes a ROS-mediated PI3K/Akt/Bcl-2 pathway-induced pancreatic β cell apoptosis that is significantly higher than the effects of each PAE. Thus, safety standards and studies do not consider this effect as a significant oversight when blending PAEs. We assert that this must be addressed and corrected for establishing more impactful and safer standards.

Recombinant Antibodies with Unique Specificities Allow for Sensitive and Specific Detection of Uncarboxylated Osteocalcin in Human Circulation

Osteocalcin is a bone-specific protein which contains three glutamic acid residues (Glu) that undergo post-translational gamma-carboxylation. Uncarboxylated osteocalcin (ucOC) may participate in the regulation of glucose metabolism, thus measurement of ucOC could be useful in evaluating interactions between bone and glucose metabolism. We developed recombinant antibodies and immunoassay to specifically detect ucOC in human blood samples. ucOC-specific recombinant antibodies were selected from an antibody library by phage display. Four candidates were characterized, and one (Fab-AP13) was used to set up an immunoassay with a pre-existing MAb. Plasma ucOC levels were measured in subjects with normal fasting blood glucose (≤ 6 mmol/l, N = 46) or with hyperglycemia (≥ 7 mmol/l, N = 29). Further, we analyzed ucOC in age- and gender-matched patients with diagnosed type 2 diabetes (T2D, N = 49). Antibodies recognized ucOC without cross-reaction to carboxylated osteocalcin. Antibodies had unique binding sites at the carboxylation region, with Glu17 included in all epitopes. Immunoassay was set up and characterized. Immunoassay detected ucOC in serum and plasma, with on average 1.6-fold higher levels in plasma. ucOC concentrations were significantly lower in subjects with hyperglycemia (median 0.58 ng/ml, p = 0.008) or with T2D diagnosis (0.68 ng/ml, p = 0.015) than in subjects with normal blood glucose (1.01 ng/ml). ucOC negatively correlated with fasting plasma glucose in subjects without T2D (r = − 0.24, p = 0.035) but not in T2D patients (p = 0.41). Our immunoassay, based on the novel recombinant antibody, allows for specific and sensitive detection of ucOC in human circulation. Correlation between ucOC and plasma glucose suggests interactions between osteocalcin and glucose metabolism in humans.

The effect of exercise training on osteocalcin, adipocytokines, and insulin resistance: a systematic review and meta-analysis of randomized controlled trials.

Recently, it has been reported that osteocalcin (OC), in particular its undercarboxylated (ucOC) form, is not only a bone remodeling marker but also an active hormone that intercedes glucose metabolism in humans. This study aimed to determine the impact of an exercise intervention on ucOC, adiponectin, leptin, and insulin resistance (measured by HOMA-IR). PubMed, CINAHL, Medline, Google Scholar, and Scopus databases and reference lists of included studies were searched. Twenty-two randomized controlled trials (RCTs) of exercise training impact in adults were included in the analysis. Results showed an overall significant increase in serum ucOC (MD: 0.15ng/ml; 95% CI: 0.05 to 0.25) and adiponectin (MD: 2.83mg/ml; 95% CI: 1.67 to 3.98), a significant decline in leptin (MD: - 4.89pg/ml; 95% CI: - 6.94 to - 2.84), fasting glucose (MD: - 2.29mg/dl; 95% CI: - 4.04 to - 0.54), fasting insulin (MD, - 8.90μIU/ml; 95% CI: - 13.81 to - 3.98), and HOMA-IR (MD: - 1.96; 95% CI: - 3.11 to - 0.80). However, after removal of studies that had prescribed a balanced diet along with exercise intervention, total OC (TOC) levels also increased in the exercise group compared with the control group (MD: 0.36ng/ml; 95% CI: 0.07 to 0.65). Our findings demonstrate that exercise-induced increases in ucOC are the probable cause of increased adiponectin. Additionally, increases in ucOC itself are probably due to changes in leptin levels and other factors, rather than its direct impact on bone and its osteoblastic activity. Further studies are required to clarify the mechanisms underlying the impact of exercise training on ucOC, adipocytokines, and insulin resistance.

Passive exposure to heat improves glucose metabolism in overweight humans.

AimHeat exposure has been indicated to positively affect glucose metabolism. An involvement of heat shock protein 72 (HSP72) in the enhancement of insulin sensitivity upon heat exposure has been previously suggested. Here, we performed an intervention study exploring the effect of passive heat acclimation (PHA) on glucose metabolism and intracellular (a) HSP72 concentrations in overweight humans.MethodsEleven non‐diabetic overweight (BMI 27‐35 kg/m2) participants underwent 10 consecutive days of PHA (4‐6 h/day, 34.4 ± 0.2°C, 22.8 ± 2.7%RH). Before and after PHA, whole‐body insulin sensitivity was assessed using a one‐step hyperinsulinaemic‐euglycaemic clamp, skeletal muscle biopsies were taken to measure intracellular iHSP72, energy expenditure and substrate oxidation were measured using indirect calorimetry and blood samples were drawn to assess markers of metabolic health. Thermophysiological adaptations were measured during a temperature ramp protocol before and after PHA.ResultsDespite a lack of change in iHSP72, 10 days of PHA reduced basal (9.7 ± 1.4 pre‐ vs 8.4 ± 2.1 μmol · kg–1 · min–1 post‐PHA, P = .038) and insulin‐stimulated (2.1 ± 0.9 pre‐ vs 1.5 ± 0.8 μmol · kg–1 · min–1 post‐PHA, P = .005) endogenous glucose production (EGP) and increased insulin suppression of EGP (78.5 ± 9.7% pre‐ vs 83.0 ± 7.9% post‐PHA, P = .028). Consistently, fasting plasma glucose (6.0 ± 0.5 pre‐ vs 5.8 ± 0.4 mmol/L post‐PHA, P = .013) and insulin concentrations (97 ± 55 pre‐ vs 84 ± 49 pmol/L post‐PHA, P = .026) decreased significantly. Moreover, fat oxidation increased, and free fatty acids as well as cholesterol concentrations and mean arterial pressure decreased after PHA.ConclusionOur results show that PHA for 10 days improves glucose metabolism and enhances fat metabolism, without changes in iHSP72. Further exploration of the therapeutic role of heat in cardio‐metabolic disorders should be considered.

134-OR: Effects of PCSK9 Inhibitors on Glucose Metabolism and ß-Cell Function in Humans

PCSK9 inhibitors are monoclonal antibodies effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. Since PCSK9 is also expressed in other organs, including pancreas, studies on PCSK9 KO mice, have shown impaired insulin secretion. Other murine models in which PCSK9 was silenced only in the liver (mimicking the action of PCSK9i) had normal glucose metabolism. The aim of our study was to evaluate the effect of PCSK9 inhibitors on glucose metabolism and beta cell function in humans. 11 nondiabetic subjects candidate for PCSK9i therapy were enrolled in the study. All subjects underwent an OGTT at baseline and after 6 months of therapy, at which point surrogate insulin sensitivity indices were obtained (Matsuda; OGIS). During OGTT, insulin secretion parameters were derived from C-peptide levels by deconvolution; we evaluated basal insulin secretion rate, total insulin secretion rate and β-cell glucose sensitivity, for 6 of the 11 enrolled subjects. All patients showed a 53.3% reduction in LDL cholesterol after 6 months of therapy; the mean LDL-C baseline level (B) was 202.5 ± 45 mg/dl, while mean LDL-C post therapy (PT) value was 94.6 ± 27 mg/dl. Glycemic and insulinemic curves showed no significant differences between baseline and follow-up. Matsuda index (B 4.1 ± 1, PT 3.4 ± 0.7 mL min-1kg-1) and OGIS (B 396.9 ± 32, PT 386.2 ± 28 ml min-1m-2), showed no differences between baseline and post-therapy evaluation. There were no significant differences in insulin secretion parameters: basal insulin secretion rate (B 63.7 ± 34, PT 66.4 ± 23 pmol min-1m-2), total insulin secretion rate (B 48.7 ± 17, PT 46.9 ± 16, nmol m-2) and β-cell glucose sensitivity (B 117.5 ± 69, PT 141.2 ± 47 pmol min-1m-2mM-1) obtained from c-peptide deconvolution. Our study, although preliminary and in a small sample of patients, suggests that PCSK9is does not cause alterations in glucose metabolism and beta cell function. Further studies and a longer follow-up may provide us with further data to confirm our observations. Disclosure S. Moffa: None. T. Mezza: None. C. Cefalo: None. F. Cinti: None. G. Sorice: None. F. Impronta: None. U. Capece: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis.

Diurnal Regulation of Peripheral Glucose Metabolism: Potential Effects of Exercise Timing.

Diurnal oscillations in energy metabolism are linked to the activity of biological clocks and contribute to whole‐body glucose homeostasis. Postprandially, skeletal muscle takes up approximately 80% of circulatory glucose and hence is a key organ in maintenance of glucose homeostasis. Dysregulation of molecular clock components in skeletal muscle disrupts whole‐body glucose homeostasis. Next to light‐dark cycles, nonphotic cues such as nutrient intake and physical activity are also potent cues to (re)set (dys)regulated clocks. Physical exercise is one of the most potent ways to improve myocellular insulin sensitivity. Given the role of the biological clock in glucose homeostasis and the power of exercise to improve insulin sensitivity, one can hypothesize that there might be an optimal time for exercise to maximally improve insulin sensitivity and glucose homeostasis. In this review, we aim to summarize the available information related to the interaction of diurnal rhythm, glucose homeostasis, and physical exercise as a nonphotic cue to correct dysregulation of human glucose metabolism.

0033 Recurrent Circadian Disruption While Minimizing Sleep Loss in Humans Impairs Glucose Tolerance Only in The Presence of High-Fat Diet

Abstract Introduction Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity and cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods. Here we used a forced desynchrony protocol to investigate the effect of 3 weeks of recurrent circadian disruption (RCD) with minimal sleep loss on glucose metabolism in humans on a lower or higher fat diet (LFD and HFD, respectively). Methods Six healthy adults (38-69yrs; 3f) participated in a 37-day inpatient protocol with LFD (25–27% fat) and 15.67-hr fasting duration, or HFD (45–50% fat) and 13-hr fasting duration. The protocol included three weeks of RCD consisting of 28-hr “days” with 11.67-hr sleep opportunities (=10hrs/24hr). Glucose and insulin responses to a standardized breakfast were conducted at baseline, at an aligned circadian phase after 2–3 weeks of exposure to RCD, and after 1 week of recovery. Frequent blood samples were assayed for glucose and insulin; the Area-Under-Curve was calculated from start of breakfast through postprandial minute 180. Results Total Sleep Time was similar in Baseline and RCD in both groups. Participants on the LFD showed no change in glucose AUC during RCD compared to Baseline. Insulin AUC was lower during RCD (p=0.0269) and Recovery (p=0.0443) than Baseline. In contrast, participants on the HFD showed a significant increase in glucose AUC during RCD compared to Baseline (p&amp;lt;0.0001); AUC returned to Baseline during Recovery. There was no significant change in insulin AUC on the HFD. Conclusion RCD (in the absence of sleep loss) led to impaired glucose tolerance when combined with HFD, but not when combined with LFD. These results suggest that LFD may be part of healthy strategies for people experiencing RCD. Support Study supported by P01AG009975 and conducted in the Brigham and Women’s Hospital Center for Clinical Investigation, part of Harvard Clinical and Translational Science Center supported by UL1TR001102. Authors supported by a fellowship from the Finnish Cultural Foundation (KMZ); T32HL007901 and F32HL143893 (RKY); T32HL007901 and F32AG051325 (NV); K24HL105664 (EBK); R01HL118601 (FAJLS).

Effects of Timing of Acute and Consecutive Catechin Ingestion on Postprandial Glucose Metabolism in Mice and Humans.

We examined the effects of the timing of acute and consecutive epigallocatechin gallate (EGCG) and catechin-rich green tea ingestion on postprandial glucose in mice and human adults. In mouse experiments, we compared the effects of EGCG administration early (morning) and late (evening) in the active period on postprandial glucose. In human experiments, participants were randomly assigned to the morning-placebo (MP, n = 10), morning-green tea (MGT, n = 10), evening-placebo (EP, n = 9), and evening-green tea (EGT, n = 9) groups, and consumed either catechin-rich green tea or a placebo beverage for 1 week. At baseline and after 1 week, participants consumed their designated beverages with breakfast (MP and MGT) or supper (EP and EGT). Venous blood samples were collected in the fasted state and 30, 60, 120, and 180 min after each meal. Consecutive administration of EGCG in the evening, but not in the morning, reduced postprandial glucose at 30 (p = 0.006) and 60 (p = 0.037) min in the evening trials in mice. In humans, ingestion of catechin-rich green tea in the evening decreased postprandial glucose (three-factor analysis of variance, p < 0.05). Thus, catechin intake in the evening more effectively suppressed elevation of postprandial glucose.

Yerba mate may prevent diabetes according to a crossover, randomized, controlled study in humans

AbstractYerba mate (Ilex paraguariensis) infusions have been shown to reduce plasma glucose in animals and serum lipids in humans. However, the effects of regularly consuming yerba mate on glucose metabolism in humans has been less studied. The objective of the study was to evaluate the effects of regularly consuming yerba mate on diabetes related biomarkers in healthy and moderately hypercholesterolemic people.A randomized, crossover, controlled study was carried out in normocholesterolemic (NC, n = 25) and hypercholesterolemic (HC, n = 27), non-smoker and non-vegetarian, men and women, with BMI 18–25 kg/m2. After a run-in stage, the effects of consuming three servings/day of yerba mate in boiled water during 8 weeks (mate stage) were compared with an isotonic drink during the same time (control stage). Along the study, polyphenol rich foods were restricted. At the beginning and the end of each intervention, urine and blood samples were collected. Dietary records and physical activity questionnaires were completed in each stage. Glucose was analyzed using a colorimetric kit (Sprinreact), and insulin, glucagon, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), plasminogen activator inhibitor-1 (PAI-1), resistin and visfatin were analyzed using Bio-Rad Multiplex Diabetes kits on Bio-Plex MAGPIX system. Results were statistically studied using a mix model with repeated measures and a Bonferroni test within each group (SPSS 23.0).Nutrient intake and physical activitiy did not show changes along the study. In contrast, fasting levels of glucose, insulin, glucagon, and GLP-1 significantly decreased after the mate stage, showing glucagon a significant yerba mate*group interaction. Attending to these results, it may be concluded that sustained consumption of yerba mate may prevent type 2 diabetes. These outcomes indicate that the effects of yerba mate in pre-diabetes and T2DM subjects are worth further studying.Funded by the Spanish State Research Agency, projects AGL2010-18269 and AGL2015-69986-R

Machine learning derived input-function in a dynamic 18F-FDG PET study of mice

Tracer kinetic modelling, based on dynamic 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used to quantify glucose metabolism in humans and animals. Knowledge of the arterial input-function (AIF) is required for such measurements. Our aim was to explore two non-invasive machine learning-based models, for AIF prediction in a small-animal dynamic FDG PET study. 7 tissue regions were delineated in images from 68 FDG PET/computed tomography mouse scans. Two machine learning-based models were trained for AIF prediction, based on Gaussian processes (GP) and a long short-term memory (LSTM) recurrent neural network, respectively. Because blood data were unavailable, a reference AIF was formed by fitting an established AIF model to vena cava and left ventricle image data. The predicted and reference AIFs were compared by the area under curve (AUC) and root mean square error (RMSE). Net-influx rate constants, Ki, were calculated with a two-tissue compartment model, using both predicted and reference AIFs for three tissue regions in each mouse scan, and compared by means of error, ratio, correlation coefficient, P value and Bland-Altman analysis. The impact of different tissue regions on AIF prediction was evaluated by training a GP and an LSTM model on subsets of tissue regions, and calculating the RMSE between the reference and the predicted AIF curve. Both models generated AIFs with AUCs similar to reference. The LSTM models resulted in lower AIF RMSE, compared to GP. Ki from both models agreed well with reference values, with no significant differences. Myocardium was highlighted as important for AIF prediction, but AIFs with similar RMSE were obtained also without myocardium in the input data. Machine learning can be used for accurate and non-invasive prediction of an image-derived reference AIF in FDG studies of mice. We recommend the LSTM approach, as this model predicts AIFs with lower errors, compared to GP.

Investigation of the Relationship between MR-Based Supraclavicular Fat Fraction and Thyroid Hormones

Purpose: Brown adipose tissue (BAT) plays a potential role in energy and glucose metabolism in humans. Thyroid hormones (TH) are main regulators of BAT development and function. However, it remains unknown how the magnetic resonance (MR)-based proton density fat fraction (PDFF) of supraclavicular adipose tissue used as a surrogate marker for BAT presence relates to TH. Therefore, the purpose of this analysis was to investigate the relationship between supraclavicular PDFF and serum levels of TH. Methods: In total, 96 adult volunteers from a large cross-sectional study who underwent additional MR examination of the neck and pelvis were included in this analysis. Segmented PDFF maps of the supraclavicular and gluteal subcutaneous adipose tissue were generated. Delta PDFF was calculated as the difference between gluteal and supraclavicular PDFF and grouped as high (≥12%) or low (<12%) based on the median and the clinical rationale of a high versus low probability of BAT being present. Thyroid-stimulating hormone (mIU/L), free triiodothyronine (FT3, pg/mL) and free thyroxine (FT4, ng/dL) levels were determined in blood samples. Body mass index (BMI) was calculated as weight (kg)/height (m)². Statistical analyses included the use of paired samples ttest, simple linear regression analysis and a multivariable linear regression analysis. Results: The median age of the subjects (77% female) was 33 years, BMI ranged from 17.2 to 43.1 kg/m². Supraclavicular and gluteal PDFF differed significantly (76.5 ± 4.8 vs. 89.4 ± 3.5 %, p < 0.01). Supraclavicular PDFF was associated with FT3 in subjects with high delta PDFF (R² = 0.17, p < 0.01), with higher FT3 being associated with lower supraclavicular PDFF (y = 85.2 + –3.6 x). In a multivariable linear regression analysis considering further potential prognostic factors, the interaction between the delta PDFF group and FT3 remained a predictor for supraclavicular PDFF (B = –4.65, p < 0.01). Discussion/Conclusions: Supraclavicular PDFF corresponds to the presence of BAT. In the present analysis, supraclavicular PDFF is correlated with FT3 in subjects with high delta PDFF. Therefore, the present findings suggest that biologically active T3 may be involved in the development of supraclavicular BAT.

Unexpected roles for ADH1 and SORD in catalyzing the final step of erythritol biosynthesis

The low-calorie sweetener erythritol is endogenously produced from glucose through the pentose phosphate pathway in humans. Erythritol is of medical interest because elevated plasma levels of this polyol are predictive for visceral adiposity gain and development of type 2 diabetes. However, the mechanisms behind these associations remain unknown because the erythritol biosynthesis pathway, particularly the enzyme catalyzing the final step of erythritol synthesis (reduction of erythrose to erythritol), is not characterized. In this study, we purified two enzymes from rabbit liver capable of catalyzing the conversion of erythrose to erythritol: alcohol dehydrogenase 1 (ADH1) and sorbitol dehydrogenase (SORD). Both recombinant human ADH1 and SORD reduce erythrose to erythritol, using NADPH as a co-factor, and cell culture studies indicate that this activity is primarily NADPH-dependent. We found that ADH1 variants vary markedly in both their affinity for erythrose and their catalytic capacity (turnover number). Interestingly, the recombinant protein produced from the ADH1B2 variant, common in Asian populations, is not active when NADPH is used as a co-factor in vitro We also confirmed SORD contributes to intracellular erythritol production in human A549 lung cancer cells, where ADH1 is minimally expressed. In summary, human ADH1 and SORD catalyze the conversion of erythrose to erythritol, pointing to novel roles for two dehydrogenase proteins in human glucose metabolism that may contribute to individual responses to diet. Proteomics data are available via ProteomeXchange with identifier PXD015178.

Effects Phytosomal Curcumin On Anthropometric Parameters, Insulin-Resistance, Cortisolemia And Non-Alcoholic Fatty Liver Disease Indexes: A Double-Blind, Placebo-Controlled Clinical Trial

Background and Aims: Curcumin has shown to exert a positive impact on human glucose metabolism, even if its bioavailability is usually very low. The present study aimed to explore the effect of phosphatidylserine -and piperine- containing curcumin phytosomes on a large number of metabolic parameters related to insulin-resistance, in the context of a randomized double-blind placebo-controlled trial involving 80 overweight subjects with suboptimal fasting plasma glucose.

Cereal B-Glucans: The Impact of Processing and How It Affects Physiological Responses.

Cereal β-glucans are dietary fibres primarily found in oats and barley, and have several positive effects on health, including lowering the postprandial glucose response and the improvement of blood cholesterol levels. Cereal β-glucans have a specific combination of β-(1→4) and β-(1→3) linkages into linear long-chain polysaccharides of high molecular weight. Due to their particular structure, cereal β-glucans generate viscosity within the intestinal tract, which is thought to be the main mechanism of action responsible for their positive health effects. However, cereal grains are rarely consumed raw; at least one cooking step is generally required before they can be safely eaten. Cooking and processing methods more generally will modify the physicochemical characteristics of β-glucans, such as molecular weight, extractability and the resulting viscosity. Therefore, the health impact of β-glucans will depend not only on the dose administered, but also on the ways they are processed or converted into food products. This review aims at summarizing the different parameters that can affect β-glucans efficacy to improve glucose and lipid metabolism in humans.

Propionate suppresses hepatic gluconeogenesis via GPR43/AMPK signaling pathway

Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are generated by gut microbial fermentation of dietary fiber. SCFAs may exert multiple beneficial effects on human lipid and glucose metabolism. However, their actions and underlying mechanisms are not fully elucidated. In this study, we examined the direct effects of propionate on hepatic glucose and lipid metabolism using human HepG2 hepatocytes. Here, we demonstrate that propionate at a physiologically-relevant concentration effectively suppresses palmitate-enhanced glucose production in HepG2 cells but does not affect intracellular neutral lipid levels. Our results indicated that propionate can decline in gluconeogenesis by down-regulation of glucose‐6‐phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) through activation of AMP-activated protein kinase (AMPK), which is a major regulator of the hepatic glucose metabolism. Mechanistic studies also revealed that propionate-stimulated AMPK phosphorylation can be ascribed to Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) activation in response to an increase in intracellular Ca2+ concentration. Moreover, siRNA-mediated knockdown of the propionate receptor GPR43 prevented propionate-inducible activation of AMPK and abrogates the gluconeogenesis-inhibitory action. Thus, our data indicate that the binding of propionate to hepatic GPR43 elicits CaMKKβ-dependent activation of AMPK through intracellular Ca2+ increase, leading to suppression of gluconeogenesis. The present study suggests the potential efficacy of propionate in preventive and therapeutic management of diabetes.

Brown adipose tissue estimated with the magnetic resonance imaging fat fraction is associated with glucose metabolism in adolescents.

SummaryBackgroundDespite therapeutic potential against obesity and diabetes, the associations of brown adipose tissue (BAT) with glucose metabolism in young humans are relatively unexplored.ObjectivesTo investigate possible associations between magnetic resonance imaging (MRI) estimates of BAT and glucose metabolism, whilst considering sex, age, and adiposity, in adolescents with normal and overweight/obese phenotypes.MethodsIn 143 subjects (10‐20 years), MRI estimates of BAT were assessed as cervical‐supraclavicular adipose tissue (sBAT) fat fraction (FF) and T2* from water‐fat MRI. FF and T2* of neighbouring subcutaneous adipose tissue (SAT) were also assessed. Adiposity was estimated with a standardized body mass index, the waist‐to‐height ratio, and abdominal visceral and subcutaneous adipose tissue volumes. Glucose metabolism was represented by the 2h plasma glucose concentration, the Matsuda index, the homeostatic model assessment of insulin resistance, and the oral disposition index; obtained from oral glucose tolerance tests.ResultssBAT FF and T2* correlated positively with adiposity before and after adjustment for sex and age. sBAT FF, but not T2*, correlated with 2h glucose and Matsuda index, also after adjustment for sex, age, and adiposity. The association with 2h glucose persisted after additional adjustment for SAT FF.ConclusionsThe association between sBAT FF and 2h glucose, observed independently of sex, age, adiposity, and SAT FF, indicates a role for BAT in glucose metabolism, which potentially could influence the risk of developing diabetes. The lacking association with sBAT T2* might be due to FF being a superior biomarker for BAT and/or to methodological limitations in the T2* quantification.