Abstract
Ketone bodies – 3-hydroxybutyrate (3-OHB), acetoacetate, and acetone – are ancient, evolutionarily preserved, small fuel substrates, which uniquely can substitute and alternate with glucose ...under conditions of fuel and food deficiency. Once canonized as a noxious, toxic pathogen leading to ketoacidosis in patients with diabetes, it is now becoming increasingly clear that 3-OHB possesses a large number of beneficial, life-preserving effects in the fields of clinical science and medicine. 3-OHB, the most prominent ketone body, binds to specific hydroxyl-carboxylic acid receptors and inhibits histone deacetylase enzymes, free fatty acid receptors, and the NOD-like receptor protein 3 inflammasome, tentatively inhibiting lipolysis, inflammation, oxidative stress, cancer growth, angiogenesis, and atherosclerosis, and perhaps contributing to the increased longevity associated with exercise and caloric restriction. Clinically ketone bodies/ketogenic diets have for a long time been used to reduce the incidence of seizures in epilepsy and may have a role in the treatment of other neurological diseases such as dementia. 3-OHB also acts to preserve muscle protein during systemic inflammation and is an important component of the metabolic defense against insulin-induced hypoglycemia. Most recently, a number of studies have reported that 3-OHB dramatically increases myocardial blood flow and cardiac output in control subjects and patients with heart failure. At the moment, scientific interest in ketone bodies, in particular 3-OHB, is in a hectic transit and, hopefully, future, much needed, controlled clinical studies will reveal and determine to which extent the diverse biological manifestations of 3-OHB should be introduced medically.
Animal studies suggest a positive role for nicotinamide riboside (NR) on insulin sensitivity and hepatic steatosis in models of obesity and type 2 diabetes. NR, an NAD+ precursor, is a member of the ...vitamin B-3 family now available as an over-the-counter supplement. Although data from preclinical trials appear consistent, potential effects and safety need to be evaluated in human clinical trials.
The aim of this study was to test the safety of dietary NR supplementation over a 12-wk period and potential to improve insulin sensitivity and other metabolic parameters in obese, insulin-resistant men.
In an investigator-initiated randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40–70 y were randomly assigned to 12 wk of NR (1000 mg twice daily) or placebo. We determined the effects of NR supplementation on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates of tritiated glucose and palmitate. Body composition and fat mass distribution were determined by whole-body dual-energy X-ray absorptiometry (DXA) and MRI scans, and measurements of intrahepatic lipid content were obtained by MR spectroscopy.
Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal.
12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registered at clinicaltrials.gov as NCT02303483.
Acute inflammation, and subsequent release of bacterial products (e.g. LPS), inflammatory cytokines, and stress hormones, is catabolic, and the loss of lean body mass predicts morbidity and ...mortality. Lipid intermediates may reduce protein loss, but the roles of free fatty acids (FFAs) and ketone bodies during acute inflammation are unclear.
We aimed to test whether infusions of 3-hydroxybutyrate (3OHB), FFAs, and saline reduce protein catabolism during exposure to LPS and Acipimox (to restrict and control endogenous lipolysis).
A total of 10 healthy male subjects were randomly tested 3 times, with: 1) LPS, Acipimox (Olbetam) and saline, 2) LPS, Acipimox, and nonesterified fatty acids (Intralipid), and 3) LPS, Acipimox, and 3OHB, during a 5-h basal period and a 2-h hyperinsulinemic, euglycemic clamp. Labeled phenylalanine, tyrosine, and urea tracers were used to estimate protein kinetics, and muscle biopsies were taken for Western blot analysis of protein metabolic signaling.
3OHB infusion increased 3OHB concentrations (P < 0.0005) to 3.5 mM and decreased whole-body phenylalanine-to-tyrosine degradation. Basal and insulin-stimulated net forearm phenylalanine release decreased by >70% (P < 0.005), with both appearance and phenylalanine disappearance being profoundly decreased. Phosphorylation of eukaryotic initiation factor 2α at Ser51 was increased in skeletal muscle, and S6 kinase phosphorylation at Ser235/236 tended (P = 0.074) to be decreased with 3OHB infusion (suggesting inhibition of protein synthesis), whereas no detectable effects were seen on markers of protein breakdown. Lipid infusion did not affect phenylalanine kinetics, and insulin sensitivity was unaffected by interventions.
During acute inflammation, 3OHB has potent anticatabolic actions in muscle and at the whole-body level; in muscle, reduction of protein breakdown overrides inhibition of synthesis. This trial was registered at clinicaltrials.gov as NCT01752348.
In evolutionary terms, GH and intracellular STAT 5 signaling is a very old regulatory system. Whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress ...and fasting. GH exerts anabolic effects directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When subjects are well nourished, the GH-induced stimulation of IGF-I and insulin is important for anabolic storage and growth of lean body mass (LBM), adipose tissue, and glycogen reserves. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of FFA, which leads to decreased glucose and protein oxidation and preservation of LBM and glycogen stores. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the basal state, the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress, the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50%, with a similar increase in muscle protein breakdown. GH is a counterregulatory hormone that antagonizes the hepatic and peripheral effects of insulin on glucose metabolism via mechanisms involving the concomitant increase in FFA flux and uptake. This ability of GH to induce insulin resistance is significant for the defense against hypoglycemia, for the development of “stress” diabetes during fasting and inflammatory illness, and perhaps for the “Dawn” phenomenon (the increase in insulin requirements in the early morning hours). Adult patients with GH deficiency are insulin resistant—probably related to increased adiposity, reduced LBM, and impaired physical performance—which temporarily worsens when GH treatment is initiated. Conversely, despite increased LBM and decreased fat mass, patients with acromegaly are consistently insulin resistant and become more sensitive after appropriate treatment.
Lipolysis is the process by which triglycerides (TGs) are hydrolyzed to free fatty acids (FFAs) and glycerol. In adipocytes, this is achieved by sequential action of adipose TG lipase (ATGL), ...hormone-sensitive lipase (HSL), and monoglyceride lipase. The activity in the lipolytic pathway is tightly regulated by hormonal and nutritional factors. Under conditions of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a profound increase in FFA release from adipose tissue (AT). This response is crucial in order to provide the organism with a sufficient supply of substrate for oxidative metabolism. However, failure to efficiently suppress lipolysis when FFA demands are low can have serious metabolic consequences and is believed to be a key mechanism in the development of type 2 diabetes in obesity. As the discovery of ATGL in 2004, substantial progress has been made in the delineation of the remarkable complexity of the regulatory network controlling adipocyte lipolysis. Notably, regulatory mechanisms have been identified on multiple levels of the lipolytic pathway, including gene transcription and translation, post-translational modifications, intracellular localization, protein–protein interactions, and protein stability/degradation. Here, we provide an overview of the recent advances in the field of AT lipolysis with particular focus on the molecular regulation of the two main lipases, ATGL and HSL, and the intracellular and extracellular signals affecting their activity.
The antimicrobial agent nitrofurantoin is becoming increasingly important for treatment of urinary tract infections (UTIs) due to widespread occurrence of multidrug‐resistant Escherichia coli. ...Despite many years of use, little data on nitrofurantoin pharmacokinetics (PK) or ‐dynamics (PD) exist. The objective of this study was to (i) evaluate the pharmacokinetics of nitrofurantoin in a mouse model and (ii) use that data to design an in vivo dose fractionation study in an experimental model of UTI with E. coli for determination of the most predictive PK/PD index. Nitrofurantoin concentrations in urine were approximately 100‐fold larger than concentrations in plasma after oral administration of 5, 10, and 20 mg/kg nitrofurantoin. The area under the curve over the minimum inhibitory concentration (AUC/MIC) was weakly correlated to bacterial reduction in urine (r2 = 0.24), while no such correlation was found for the time that nitrofurantoin stayed above the MIC (T > MIC). Increasing size of single‐dose treatment was significantly correlated to eradication of bacteria in the urine, while this was not apparent when the same doses were divided in 2 or 3 doses 8 or 12 h apart. In conclusion, the results indicate that nitrofurantoin activity against E. coli in urine is driven by AUC/MIC.
Primarily, this study aims to examine whether children attending sports schools are more active than their counterpart attending normal schools. Secondary, the study aims to examine if physical ...activity (PA) levels in specific domains differ across school types. Finally, potential modifications by status of overweight/obesity and poor cardio-respiratory fitness are examined.
Participants were from the first part of the CHAMPS-study DK, which included approximately 1200 children attending the 0th - 6th grade. At the sports schools, the mandatory physical education (PE) program was increased from 2 to 6 weekly lessons over a 3-year period. Children attending normal schools were offered the standard 2 PE lessons. PA was assessed at two different occasions with the GT3X ActiGraph accelerometer, once during winter in 2009/10 and once during summer/fall in 2010. Leisure time organized sports participation was quantified by SMS track. Based on baseline values in 2008, we generated a high-BMI and a low-cardio-respiratory fitness for age and sex group variable.
There were no significant differences in PA levels during total time, PE, or recess between children attending sports schools and normal schools, respectively. However, children, especially boys, attending sports schools were more active during school time than children attending normal schools (girls: β=51, p=0.065; boys: β=113, p<0.001). However, in the leisure time during weekdays children who attended sports schools were less active (girls: β=-41, p=0.004; boys: β=-72, p<0.001) and less involved in leisure time organized sports participation (girls: β=-0.4, p=0.016; boys: β=-0.2, p=0.236) than children who attended normal schools. Examination of modification by baseline status of overweight/obesity and low cardio-respiratory fitness indicated that during PE low fit girls in particular were more active at sports schools.
No differences were revealed in overall PA levels between children attending sports schools and normal schools. Sports schools children were more active than normal schools children during school time, but less active during leisure time. In girls, less organized sports participation at least partly explained the observed differences in PA levels during leisure time across school types. Baseline status of cardio-respiratory fitness modified school type differences in PA levels during PE in girls.
More studies include multiple generations of the Actigraph activity monitor. So far no studies have compared the output including the newest generation and investigated the impact on the output of ...the activity monitor when enabling the low frequency extension (LFE) option. The aims were to study the responses of four generations (AM7164, GT1M, GT3X and GT3X+) of the Actigraph activity monitor in a mechanical setup and a free living environment with and without enabling the LFE option.
The monitors were oscillated in a mechanical setup using two radii in the frequency range 0.25-3.0 Hz. Following the mechanical study a convenience sample (N = 20) wore three monitors (one AM7164 and two GT3X) for 24 hours.
The AM7164 differed from the newer generations across frequencies (p < 0.05) in the mechanical setup. The AM7164 produced a higher output at the lower and at the highest intensities, whereas the output was lower at the middle intensities in the mid-range compared to the newer generations. The LFE option decreased the differences at the lower frequencies, but increased differences at the higher. In free living, the mean physical activity level (PA) of the GT3X was 18 counts per minute (CPM) (8%) lower compared to the AM7164 (p < 0.001). Time spent in sedentary intensity was 26.6 minutes (95% CI 15.6 to 35.3) higher when assessed by the GT3X compared to the AM7164 (p < 0.001). Time spend in light and vigorous PA were 23.3 minutes (95% CI 31.8 to 14.8) and 11.7 minutes (95% CI 2.8 to 0.7) lower when assessed by the GT3X compared to the AM7164 (p < 0.05). When enabling the LFE the differences in the sedentary and light PA intensity (<333 counts*10 sec-1) were attenuated (p > 0.05 for differences between generations) thus attenuated the difference in mean PA (p > 0.05) when the LFE option was enabled. However, it did not attenuate the difference in time spend in vigorous PA and it introduced a difference in time spend in moderate PA (+ 3.0 min (95% CI 0.4 to 5.6)) between the generations.
We observed significant differences between the AM7164 and the newer Actigraph GT-generations (GT1M, GT3X and GT3X+) in a mechanical setup and in free-living. Enabling the LFE option attenuated the differences in mean PA completely, but induced a bias in the moderate PA intensities.
Escherichia coli is the leading cause of urinary tract infection, one of the most common bacterial infections in humans. Despite this, a genomic perspective is lacking regarding the phylogenetic ...distribution of isolates associated with different clinical syndromes. Here, we present a large-scale phylogenomic analysis of a spatiotemporally and clinically diverse set of 907 E. coli isolates, including 722 uropathogenic E. coli (UPEC) isolates. A genome-wide association approach identifies the (P-fimbriae-encoding) papGII locus as the key feature distinguishing invasive UPEC, defined as isolates associated with severe UTI, i.e., kidney infection (pyelonephritis) or urinary-source bacteremia, from non-invasive UPEC, defined as isolates associated with asymptomatic bacteriuria or bladder infection (cystitis). Within the E. coli population, distinct invasive UPEC lineages emerged through repeated horizontal acquisition of diverse papGII-containing pathogenicity islands. Our findings elucidate the molecular determinants of severe UTI and have implications for the early detection of this pathogen.
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