Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: results of a prospective, randomized, double-blind, cross-over study

Background & aims

Citrulline increases protein synthesis during refeeding in rodents with short bowel syndrome, aging and malnutrition, and improves nitrogen balance in fed healthy humans. The aim of the current study therefore was to determine whether citrulline had affected protein metabolism in healthy volunteers.

Methods

In a randomized, double-blind, cross-over study, 12 healthy adults received a 5-h intravenous infusion of L-[1-¹³C]-leucine in the post-absorptive state, after a 7-day oral supplementation with 0.18 g/kg/day citrulline, or an iso-nitrogenous placebo. Treatment order was randomized, treatment periods were separated by 13-day wash out. Leucine appearance rate (Ra) was determined from plasma [1-¹³C]-keto-iso-caproate enrichment and leucine oxidation from expired ¹³CO₂, and nitrogen balance was estimated from 6-h urinary urea excretion.

Results

Compared with placebo, oral citrulline supplementation increased plasma citrulline, arginine and ornithine concentrations, but failed to affect albumin, transthyretin, free insulin and insulin-like growth factor (IGF)-1 plasma concentrations, urinary nitrate excretion, or nitrogen balance. Citrulline supplementation did not alter leucine Ra, leucine oxidation, nor whole-body protein synthesis.

Conclusion

In healthy, well nourished volunteers, oral citrulline increases plasma citrulline and arginine availability but does not affect whole-body protein kinetics in the post-absorptive state.     

Oxidative stress, mitochondrial respiration, and glycemic control: Clues from chronic supplementation with Cr or As to male wistar rats

Multiple experiments in male Wistar rats were designed to clarify the role of mitochondrial dysfunction in the mechanisms of oxidative stress-related diseases and toxicity-induced pathologies. In this particular report, 21 male Wistar rats were supplemented ad libitum with either As³⁺ or Cr³⁺ salts in drinking water to assess insulin secretion patterns in vivo and in vitro, mitochondrial dysfunction, oxidative stress, liver damage, basal insulin, and glucose tolerance curves, among other parameters. Results were compared with a control group without any metal supplementation. The CrCl₃ supplements were more invasive of metabolism and had a stronger effect on mitochondrial dysfunction than As³⁺, despite that both seem to use similar mechanisms of toxicity; viz.: binding to thiol or -SS- group in enzymes and proteins, and releasing oxidant species during their redox-cycling and metabolic activation processes, e.g., by cytochrome P450 in liver. Results support our aim to prove the influence of oxidative stress-induced mitochondrial dysfunction on glycemic control.     

Nicotinamide Riboside Supplementation to Suckling Male Mice Improves Lipid and Energy Metabolism in Skeletal Muscle and Liver in Adulthood

Nicotinamide riboside, an NAD⁺ precursor, has been attracting a lot of attention in recent years due to its potential benefits against multiple metabolic complications and age-related disorders related to NAD⁺ decline in tissues. The metabolic programming activity of NR supplementation in early-life stages is much less known. Here, we studied the long-term programming effects of mild NR supplementation during the suckling period on lipid and oxidative metabolism in skeletal muscle and liver tissues using an animal model. Suckling male mice received a daily oral dose of NR or vehicle (water) from day 2 to 20 of age, were weaned at day 21 onto a chow diet, and at day 90 were distributed to either a high-fat diet (HFD) or a normal-fat diet for 10 weeks. Compared to controls, NR-treated mice were protected against HFD-induced triacylglycerol accumulation in skeletal muscle and displayed lower triacylglycerol levels and steatosis degree in the liver and distinct capacities for fat oxidation and decreased lipogenesis in both tissues, paralleling signs of enhanced sirtuin 1 and AMP-dependent protein kinase signaling. These pre-clinical findings suggest that mild NR supplementation in early postnatal life beneficially impacts lipid and energy metabolism in skeletal muscle and liver in adulthood, serving as a potential preventive strategy against obesity-related disorders characterized by ectopic lipid accumulation.     

Effect of dietary protein status on glucose utilization by the pentose cycle in pig adipose tissue

We investigated the effects of three levels of dietary protein (12, 18 and 23%) on lipid metabolism in pig adipose tissue (PAT). Eight-week-old male pigs were fasted for 96 hr and then refed for the same period of time. Adipose tissue biopsy samples were obtained and incubated for 3 hr in Hanks' salts containing 5.5 mM [1-¹⁴C], [6-¹⁴C], [U-¹⁴C] and [3-³H] glucose as well as 10 mM [2-¹⁴C] acetate and pyruvate. Fatty acids, CO₂, lactate and glyceride-glycerol yields were determined. An increase in dietary protein decreased (P<.05) glucose utilization and subsequent in vitro lipogenesis in PAT. A calculation of the role of the pentose cycle (PC) revealed a capacity to provide 60 to 90% of the NADPH required to support the observed rates of de novo fatty acid synthesis when glucose was a substrate. Several algorithms used to model PC acitivity in rat adipose tissue appeared to be inadequate for PAT because of a severe lack of triose phosphate pool equilibration and because of an apparent lack of CO₂ evolvement from the Krebs' Cycle. Tritium incorporation into fatty acids from [3-³H]glucose was related to ¹⁴CO₂ production from [1-¹⁴C]glucose and may be used to estimate glucose metabolism through the PC.     

Effect of H<Subscript>2</Subscript>S on the circadian rhythm of mouse hepatocytes

Background  

Dysregulation of circadian rhythms can contribute to diseases of lipid metabolism. NAD-dependent deacetylase sirtuin-1(SIRT1) is an important hub which links lipid metabolism with circadian clock by its deacetylation activity depends on intracellular NAD⁺/NADH content ratio. Hydrogen sulfide (H₂S) is an endogenous reductant which can affect the intracellular redox state. Therefore, we hypothesized that exogenous H₂S can affect the expression of circadian clock genes mediated by sirt1 thereby affecting body's lipid metabolism. And also because the liver is a typical peripheral circadian clock oscillator that is intimately linked to lipid metabolism. Thus the effect of H₂S were observed on 24-hour dynamic expression of 4 central circadian clock genes and sirt1gene in primary cultured hepatocytes.     

A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD+ Metabolome in Healthy Middle-Aged Adults: A Randomized,Triple-Blind,Placebo-Controlled,Cross-Over Pilot Clinical Trial

Nicotinamide adenine dinucleotide (NAD⁺) is an essential cofactor required for proper functioning of all cells and its decline is correlated with advancing age and disease. This randomized, triple-blind, placebo-controlled, crossover pilot study assessed the efficacy and safety of a combination of nicotinamide with D-ribose (RiaGev) for NAD metabolome enhancement and related benefits in healthy middle-aged adults. Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD⁺ metabolome in blood, especially NADP⁺ by 27% compared to the placebo group (p = 0.033) and over the baseline (p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly (p = 0.013) reduced overall blood glucose without significant changes in insulin secretion (p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly decreased (p = 0.026) in the RiaGev group in contrast to the placebo. Subjects in the RiaGev group showed less fatigue, improved mental concentration and motivation over the baseline (p = 0.015, 0.018, and 0.012, respectively) as observed through the Checklist Individual Strength (CIS) questionnaire. There were no clinically relevant adverse events, or alterations in hematology, electrolytes, liver, and kidney markers pre- and post-supplementation. RiaGev appears to be safe and efficacious in increasing NAD⁺ metabolome in healthy middle-aged adults, as shown by this study.     

ALTERATION OF ACETALDEHYDE METABOLISM IN CARBON TETRACHLORIDE-INTOXICATED RAT LIVER: ANALYSIS USING LIVER PERFUSION SYSTEM

The hepatic metabolism of acetaldehyde in carbon tetrachloride(CCl₄)-intoxicated rats was studied using a non-recirculatinghaemoglobin-free liver-perfusion system. Acetaldehyde uptakeby the liver from acutely CCl₄-treated animals (4.16 mmol/kg,i.p.) at 24 hr after the treatment was not significantly altered,whereas that by the liver from chronically CCl₄-treated animals(2.08 mmol/kg,i.p., twice a week, for 8–12 weeks) wasdecreased by approximately 50% when it was determined in thepresence of 0.01–5 mM acetaldehyde. In liver from ratschronically intoxicated with CCl₄, the following important biochemicalchanges were observed: (1) The activity of low K_m aldehyde dehydrogenase(ALDH) in hepatic mitochondria was decreased by approximately75%. (2) The basal levels of the lactate/pyruvate (cytosolic[NADH]/[NAD⁺]) ratio as well as the ß-hydroxybutyrate/acetoacetate(mitochondrial [NADH]/[NAD⁺]) ratio were elevated by more than2-fold. (3) Mitochondrial NADH oxidation was also reduced byapproximately 35% of the control level. (4) The basal levelof hepatic oxygen uptake was attenuated by approximately 50%,and the infusion of acetaldehyde (0.01–5.0 mM) causeda further decrease in the uptake. (5) The rate of ethanol productionfrom acetaldehyde by the catalytic action of alcohol dehydrogenasewas found to be unaltered when low concentrations of acetaldehyde(0.01–0.2 mM) were used, whereas a significant suppressionof the rate of ethanol production was detected in the presenceof high concentrations of acetaldehyde (0.6–5 mM). Thesedata suggest that the changes in activity of the lowK_m mitochondrialacetaldehyde dehydrogenase and those in mitochondrial NADH oxidationcoupled with mitochondrial respiration may, at least in part,play important roles in the decreased hepatic acetaldehyde metabolismobserved in chronically CCl₄-treated rats.     

Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts

The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD⁺) levels through supplementation with NAD⁺ precursors has been identified as a promising treatment strategy for a number of conditions; principally, age-related cognitive decline (including Alzheimer’s disease and vascular dementia), but also diabetes, stroke, and traumatic brain injury. Candidate factors have included NAD⁺ itself, its reduced form NADH, nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and niacin (or nicotinic acid). This review summarises the research findings for each source of cognitive impairment for which NAD⁺ precursor supplementation has been investigated as a therapy. The findings are mostly positive but have been made primarily in animal models, with some reports of null or adverse effects. Given the increasing popularity and availability of these factors as nutritional supplements, further properly controlled clinical research is needed to provide definitive answers regarding this strategy’s likely impact on human cognitive health when used to address different sources of impairment.     

Protein Redistribution From Skeletal Muscle to Splanchnic Tissue on Fasting and Refeeding in Young and Older Healthy Individuals

BackgroundDuring aging, a shift of protein metabolism from muscle to splanchnic tissue contributes to increased muscle protein loss after a period of metabolic stress (eg, fasting).ObjectiveTo study the adaptation of protein metabolism in the whole body and tissue (ie, skeletal muscle and splanchnic area) to metabolic stress, such as short-term fasting and refeeding, in aged people.Design and participantsWe studied splanchnic and muscle protein metabolism after 38 hours of fasting and refeeding in 7 young (5 men/2 women, 24.4 ± 2.0 years) and 8 elderly individuals (6 men/2 women, 70.6 ± 3.1 years).MeasurementsWe used intravenous (IV) L-[¹³C₆]phenylalanine, IV L-[²H₃]leucine, and oral L-[¹³C₁]leucine to obtain (1) whole-body protein kinetics, (2) muscle and albumin fractional synthesis rate (FSR, %/d; ¹³C₆-Phe, and ¹³C₁-Leu), and (3) splanchnic extraction during fasting and refeeding (%, ²H₃- and ¹³C₁-Leu).ResultsWhole-body protein breakdown was activated during fasting in young and older individuals (P < .01 vs fasted state). Muscle FSR remained unchanged in both groups and not stimulated by refeeding in either group with either IV ¹³C Phe or oral ¹³C Leu, probably because of high plasma levels of essential amino acids (EAAs) and branched-chain amino acids (BCAAs). Splanchnic extraction of leucine was 42% higher in the elderly individuals (P = .03 vs young) and was associated with an increased albumin synthesis rate in elderly individuals in the fed state (P < .05 vs young).ConclusionSplanchnic protein metabolism is modified by age, but this metabolic change is not associated with a lower synthesis rate of muscle protein, provided high plasma levels of essential EAAs are maintained. Our data also suggest that splanchnic protein synthesis is a metabolic priority during recovery after metabolic stress in healthy elderly persons and that it might be even more affected in polymedicated older individuals having chronic diseases.     

A Theacrine-Based Supplement Increases Cellular NAD+ Levels and Affects Biomarkers Related to Sirtuin Activity in C2C12 Muscle Cells In Vitro

There is evidence in rodents to suggest that theacrine-based supplements modulate tissue sirtuin activity as well as other biological processes associated with aging. Herein, we examined if a theacrine-based supplement (termed NAD3) altered sirtuin activity in vitro while also affecting markers of mitochondrial biogenesis. The murine C2C12 myoblast cell line was used for experimentation. Following 7 days of differentiation, myotubes were treated with 0.45 mg/mL of NAD3 (containing ~2 mM theacrine) for 3 and 24 h (n = 6 treatment wells per time point). Relative to control (CTL)-treated cells, NAD3 treatments increased (p < 0.05) Sirt1 mRNA levels at 3 h, as well as global sirtuin activity at 3 and 24 h. Follow-up experiments comparing 24 h NAD3 or CTL treatments indicated that NAD3 increased nicotinamide phosphoribosyltransferase (NAMPT) and SIRT1 protein levels (p < 0.05). Cellular nicotinamide adenine dinucleotide (NAD⁺) levels were also elevated nearly two-fold after 24 h of NAD3 versus CTL treatments (p < 0.001). Markers of mitochondrial biogenesis were minimally affected. Although these data are limited to select biomarkers in vitro, these preliminary findings suggest that a theacrine-based supplement can modulate select biomarkers related to NAD⁺ biogenesis and sirtuin activity. However, these changes did not drive increases in mitochondrial biogenesis. While promising, these data are limited to a rodent cell line and human muscle biopsy studies are needed to validate and elucidate the significance of these findings.     

Potential of Polyphenols to Restore SIRT1 and NAD+ Metabolism in Renal Disease

SIRT1 is an NAD⁺-dependent class III histone deacetylase that is abundantly expressed in the kidney, where it modulates gene expression, apoptosis, energy homeostasis, autophagy, acute stress responses, and mitochondrial biogenesis. Alterations in SIRT1 activity and NAD⁺ metabolism are frequently observed in acute and chronic kidney diseases of diverse origins, including obesity and diabetes. Nevertheless, in vitro and in vivo studies and clinical trials with humans show that the SIRT1-activating compounds derived from natural sources, such as polyphenols found in fruits, vegetables, and plants, including resveratrol, quercetin, and isoflavones, can prevent disease and be part of treatments for a wide variety of diseases. Here, we summarize the roles of SIRT1 and NAD⁺ metabolism in renal pathophysiology and provide an overview of polyphenols that have the potential to restore SIRT1 and NAD⁺ metabolism in renal diseases.     

Fish oil positively regulates anabolic signalling alongside an increase in whole-body gluconeogenesis in ageing skeletal muscle

Purpose

Fish oil, containing mainly long-chain n-3 polyunsaturated fatty acids (LCn-3PUFA), has been found to acutely stimulate protein synthesis and insulin-mediated glucose metabolism. However, the underlying mechanism and more prolonged effect of fish oil during ageing remain to be determined.

Methods

Fish oil (EPAX6000; 49.6 % eicosapentaenoic acid, 50.4 % docosahexaenoic acid) or control oil (60 % olive, 40 % soy) supplementation was delivered, via chocolate-derived sweets, to rats for 8 weeks. Throughout the study, food intake and body weight were recorded and body composition was investigated using EchoMRI. During the last 40 min of a 6 h infusion, with labelled dextrose ([U-¹³C]glucose) and amino acids ([1-¹³C]phenylalanine), blood samples were collected to assess glucose and phenylalanine kinetics. Soleus and longissimus dorsi muscles were extracted for protein and mRNA analyses.

Results

Fish oil had no effect on food intake or body composition. An increased whole-body glucose turnover, mainly accounted for via an increase in endogenous glucose production, was observed with fish oil feeding. No effects on whole-body phenylalanine turnover were observed. In longissimus dorsi, fish oil augmented the phosphorylation of phosphoinositide 3-kinase (PI3K)^[Tyr458] (P = 0.04) and 70 kDa ribosomal protein S6 kinase (p70s6k)^[Thr389] (P = 0.04). There were no differences in protein kinase B (Akt)^[Ser473], mammalian target of rapamycin (mTOR)^[Ser2448], protein phosphatase 2A (PP2A) 56 kDa regulatory B subunit γ (PP2A-B56-γ), forkhead box containing proteins O-subclass 3a (FOX03a)^[Ser253] or inflammatory markers (Interleukin-6, Interleukin-1 β, tumour necrosis factor-α, and cyclooxygenase-2).

Conclusions

Our data suggest that the fish oil may stimulate endogenous glucose production and increase anabolic signalling in ageing rats.     

Pinitol supplementation does not affect insulin-mediated glucose metabolism and muscle insulin receptor content and phosphorylation in older humans

This study assessed the effect of oral pinitol supplementation on oral and intravenous glucose tolerances and on skeletal muscle insulin receptor content and phosphorylation in older people. Fifteen people (6 men, 9 women; age 66 +/- 8 y; BMI 27.9 +/- 3.3 kg/m(2); hemoglobin A1c 5.39 +/- 0.46%, mean +/- SD) completed a 7-wk protocol. Subjects were randomly assigned to groups that during wk 2-7 consumed twice daily either a non-nutritive beverage (Placebo group, n = 8) or the same beverage with 1000 mg pinitol dissolved into it (Pinitol group, n = 7, total dose = 2000 mg pinitol/d). Testing was done at wk 1 and wk 7. In the Pinitol group with supplementation, 24-h urinary pinitol excretion increased 17-fold. The fasting concentrations of glucose, insulin, and C-peptide, and the 180-min area under the curve for these compounds, in response to oral (75 g) and intravenous (300 mg/kg) glucose tolerance challenges, were unchanged from wk 1 to wk 7 and were not influenced by pinitol. Also, pinitol did not affect indices of hepatic and whole-body insulin sensitivity from the oral glucose tolerance test and indices of insulin sensitivity, acute insulin response to glucose, and glucose effectiveness from the intravenous glucose tolerance test, estimated using minimal modeling. Pinitol did not differentially affect total insulin receptor content and insulin receptor phosphotyrosine 1158 and insulin receptor phosphotyrosine 1162/1163 activation in vastus lateralis samples taken during an oral-glucose-induced hyperglycemic and hyperinsulinemic state. These data suggest that pinitol supplementation does not influence whole-body insulin-mediated glucose metabolism and muscle insulin receptor content and phosphorylation in nondiabetic, older people.     

Dietary nitrate does not modify blood pressure and cardiac output at rest and during exercise in older adults: a randomised cross-over study

Dietary nitrate (NO₃^-) supplementation has been associated with improved vascular and metabolic health. We conducted a double-blind, cross-over, placebo-controlled RCT to investigate the effects of 7-d consumption of beetroot juice compared with placebo on (1) blood pressure (BP) measured in resting conditions and during exercise, (2) cardiac and peripheral vascular function and (3) biomarkers of inflammation, oxidative stress and endothelial integrity. Twenty non-smoking healthy participants aged 60–75 years and BMI 20.0–29.9?kg/m² were recruited. Measurement was conducted before and after each 7-d intervention period. Consumption of NO₃^- had no effect on resting systolic and diastolic BP. NO₃^- consumption did not improve indexes of central and peripheral cardiac function responses during cardiopulmonary exercise testing. Dietary NO₃^- supplementation did not modify biomarkers of inflammation, oxidative stress and endothelial integrity. This study does not support the short-term benefits of dietary NO₃^- supplementation on physiological and biochemical markers of vascular health in older healthy adults.     

Marine Oil from C. finmarchicus Enhances Glucose Homeostasis and Liver Insulin Resistance in Obese Prediabetic Individuals

The intermediate state between normal glucose tolerance and overt type 2 diabetes mellitus is associated with micro- and macrovascular diseases, requiring safe and cost-effective treatment measures interventions. A novel source of LC n-3 FAs is Calanus finmarchicus Oil, which showed promising effects on glucose homeostasis in preclinical studies due to anti-obesity effects and/or anti-inflammatory properties. In total, 43 obese patients (BMI: 31.7 ± 5.2 kg/m²) were allocated in the following two groups: (1) Calanus oil group (2 g CO/day) and (2) placebo group (2 g paraffin oil/day). Markers of glucose metabolism, body composition and energy intake were measured at the beginning (t0), after 12 weeks (t₁₂) and 16 weeks (t₁₆). Overall, parameters reflecting abnormal glucose homeostasis and insulin resistance in the liver, including fasting insulin (−2.9 mU/L ± 4.10, p < 0.05), HOMA-IR (−0.9 ± 1.28, p < 0.05) and hepatic insulin resistance index (−1.06 ± 1.72 × 10⁶, p < 0.05) significantly enhanced after a 12-week CO-intervention, while no differences were observed in HbA1c, AUC_0–2h Glucose, AUC_0–2h Insulin, 2 h plasma glucose and muscle insulin sensitivity index. Our results indicate that Calanus oil causes beneficial effects on glucose metabolism and insulin resistance in obese patients, with clinical relevance to be verified in further studies. In addition, the possible active compounds and their mechanisms of action should be elucidated.     

Preoperative Glucose and Protein Metabolism: The Influence of Diabetes Mellitus Type 2 in Patients With Colorectal Tumors

Hypermetabolism, abnormal plasma amino acid profiles, increased gluconeogenesis, and changes in liver and muscle protein turnover are well-described undesirable effects in patients with cancer and diabetes mellitus type 2 (DM2) The aim of the present study was to analyze the specific impact and interaction of these 2 disease patterns on patients’ preoperative glucose and protein metabolism. Eight nondiabetic and 8 diabetic patients devoid of cachexia underwent a stable isotope infusion study on the day before surgery for colorectal cancer or adenoma with high-grade dysplasia. Protein and glucose kinetics were assessed in a fasted state by L-[1-¹³C]leucine and [6,6²H₂]glucose. In diabetic patients, glucose metabolism was found to be elevated as the plasma glucose level increased (P = 0.013) and endogenous rate of appearance of glucose tended to be higher compared to nondiabetic patients (P = 0.083). Protein metabolism was not affected by the metabolic state of the 2 groups. Resting energy expenditure was higher in diabetic patients (P = 0.028). Under postabsorptive conditions, noncachectic patients with DM2 suffering from colorectal tumors showed an elevated turnover in glucose metabolism whereas the nondiabetic counterparts failed to demonstrate any metabolic changes due solely to malignancy.     

Changes in response to insulin and the effects of varying glucose tolerance on whole-body protein metabolism in patients with cystic fibrosis

BACKGROUND: Diabetes mellitus has been reported to increase whole-body protein breakdown and thus loss of lean body mass. Cystic fibrosis-related diabetes (CFRD) is associated with undernutrition and increased mortality. OBJECTIVE: We hypothesized that CFRD is associated with increased whole-body protein breakdown, which results in negative protein balance, and that correction of the glucose intolerance with insulin therapy would normalize whole-body protein metabolism. DESIGN: Rates of whole-body protein turnover and protein balance were measured in 28 adults with cystic fibrosis (17 M, 11 F). Subjects were assessed with a modified oral-glucose-tolerance test and categorized as having normal glucose tolerance, impaired glucose tolerance, or CFRD with and without fasting hyperglycemia; then they were compared with previously diagnosed CFRD adults already receiving insulin therapy. Indexes of protein turnover were calculated from [15N]glycine and 15N in urinary urea. RESULTS: Analysis of variance for the 28 subjects showed that whole-body protein breakdown was highest (P<0.05) in patients with CFRD. Whole-body protein synthesis was not significantly affected by impaired glucose tolerance. Significant (P<0.05) improvement in net protein synthesis occurred in the CFRD group 3 mo after insulin therapy was administered. Follow-up studies of 3 subjects with CFRD showed significant improvement in net protein synthesis after insulin therapy. Monitoring of the protein homeostasis of the impaired glucose tolerance group gave clues to the progression of their metabolic homeostasis. CONCLUSION: CFRD has an adverse effect on protein homeostasis by increasing net protein synthesis.     

Circadian Clock Component BMAL1 in the Paraventricular Nucleus Regulates Glucose Metabolism

It is suggested that clock genes link the circadian rhythm to glucose and lipid metabolism. In this study, we explored the role of the clock gene Bmal1 in the hypothalamic paraventricular nucleus (PVN) in glucose metabolism. The Sim1-Cre-mediated deletion of Bmal1 markedly reduced insulin secretion, resulting in impaired glucose tolerance. The pancreatic islets’ responses to glucose, sulfonylureas (SUs) and arginine vasopressin (AVP) were well maintained. To specify the PVN neuron subpopulation targeted by Bmal1, the expression of neuropeptides was examined. In these knockout (KO) mice, the mRNA expression of Avp in the PVN was selectively decreased, and the plasma AVP concentration was also decreased. However, fasting suppressed Avp expression in both KO and Cre mice. These results demonstrate that PVN BMAL1 maintains Avp expression in the PVN and release to the circulation, possibly providing islet β-cells with more AVP. This action helps enhance insulin release and, consequently, glucose tolerance. In contrast, the circadian variation of Avp expression is regulated by feeding, but not by PVN BMAL1.     

Effect of the consumption of β-lactoglobulin and epigallocatechin-3-gallate with or without calcium on glucose tolerance in C57BL/6 mice

Interactions between β-lactoglobulin (β-lg) and epigallocatechin-3-gallate (EGCG) may modulate their health benefits. The objective of this study was therefore to investigate the synergistic effect of consuming β-lg and EGCG complexes on glucose tolerance of C57BL/6 male mice given an oral glucose tolerance test (OGTT) and randomized to one of the following treatments administered prior to the OGTT: 1) simulated milk ultrafiltrate (SMUF^-), 2) SMUF^-?+?EGCG, 3) SMUF^-?+?β-lg, 4) SMUF^-?+?EGCG?+?β-lg, 5) SMUF?+?calcium (SMUF⁺) and 6) SMUF⁺?+?EGCG?+?β-lg. We found no significant between-group difference in postprandial glucose response. However, when mice were separated in those who received β-lg from those who did not, we found that the latter displayed significantly higher postprandial glucose concentrations. Our results support the beneficial impact of β-lg on glycemic control and suggest that concomitant EGCG or calcium consumption does not improve this effect.