Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mumol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans

Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (H-1-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our H-1-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity. Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use H-1-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.Peer reviewe

Long-term quality of life in adult survivors of pediatric differentiated thyroid carcinoma

Context: Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer–specific HRQoL in survivors only. Design: Survivors diagnosed between 1970 and 2013 at age #18 years, were included. Exclusion criteria were a follow-up ,5 years, attained age ,18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer–specific HRQoL questionnaire. Results: Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer–specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL. Conclusions: Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer–specific complaints). Factors possibly affecting QoL need further exploration

Psychosocial development in survivors of childhood differentiated thyroid carcinoma: A cross-sectional study

Objective: The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC. Design and methods: Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age 35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n=30

The wish to leave ethnically concentrated neighbourhoods: The role of perceived social cohesion and interethnic attitudes

This paper aims to investigate the motives behind people's wishes to move out of ethnically concentrated neighbourhoods. We focus on the impact of perceived social cohesion and negative interethnic attitudes and hypothesise on moving wishes of ethnic majority and minority residents in the Netherlands (i.e. Turks and Moroccans). Data were derived from the first wave of the 2009 Netherlands Longitudinal Lifecourse Study, collected in 35 municipalities covering 800 neighbourhoods. Taking into account household, housing and other neighbourhood attributes, multilevel logistic regression models show that ethnic majority residents are more likely to have a wish to move when they live in neighbourhoods with a large percentage of ethnic minorities. This can be explained by a lack of perceived social cohesion, but not by their negative attitudes towards ethnic minorities. Controlling for housing and neighbourhood conditions, the percentage of ethnic minorities neither increases nor decreases minority residents' moving wishes

The wish to leave ethnically concentrated neighbourhoods: The role of perceived social cohesion and interethnic attitudes

This paper aims to investigate the motives behind people's wishes to move out of ethnically concentrated neighbourhoods. We focus on the impact of perceived social cohesion and negative interethnic attitudes and hypothesise on moving wishes of ethnic majority and minority residents in the Netherlands (i.e. Turks and Moroccans). Data were derived from the first wave of the 2009 Netherlands Longitudinal Lifecourse Study, collected in 35 municipalities covering 800 neighbourhoods. Taking into account household, housing and other neighbourhood attributes, multilevel logistic regression models show that ethnic majority residents are more likely to have a wish to move when they live in neighbourhoods with a large percentage of ethnic minorities. This can be explained by a lack of perceived social cohesion, but not by their negative attitudes towards ethnic minorities. Controlling for housing and neighbourhood conditions, the percentage of ethnic minorities neither increases nor decreases minority residents' moving wishes

Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice

Fasting readily induces hepatic steatosis. Hepatic steatosis is associated with hepatic insulin resistance. The purpose of the present study was to document the effects of 16 h of fasting in wild-type mice on insulin sensitivity in liver and skeletal muscle in relation to 1) tissue accumulation of triglycerides (TGs) and 2) changes in mRNA expression of metabolically relevant genes. Sixteen hours of fasting did not show an effect on hepatic insulin sensitivity in terms of glucose production in the presence of increased hepatic TG content. In muscle, however, fasting resulted in increased insulin sensitivity, with increased muscle glucose uptake without changes in muscle TG content. In liver, fasting resulted in increased mRNA expression of genes promoting gluconeogenesis and TG synthesis but in decreased mRNA expression of genes involved in glycogenolysis and fatty acid synthesis. In muscle, increased mRNA expression of genes promoting glucose uptake, as well as lipogenesis and β-oxidation, was found. In conclusion, 16 h of fasting does not induce hepatic insulin resistance, although it causes liver steatosis, whereas muscle insulin sensitivity increases without changes in muscle TG content. Therefore, fasting induces differential changes in tissue-specific insulin sensitivity, and liver and muscle TG contents are unlikely to be involved in these changes

L-carnitine infusion does not alleviate lipid-induced insulin resistance and metabolic inflexibility

BackgroundLow carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility.MethodsIn a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis.ResultsL-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this.ConclusionAcute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this