Bas Havekes

Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus

Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14–15 °C) increased peripheral insulin sensitivity by ∼43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation markedly increased, without effects on insulin signaling or AMP-activated protein kinase (AMPK) activation and only a minor increase in BAT glucose uptake.

The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity

The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans.

Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients

CONTEXT The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose. OBJECTIVE The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1. DESIGN This was a diagnostic study. SETTING The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population. PATIENTS AND METHODS Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up. MAIN OUTCOME MEASURES The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker. RESULTS For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes. CONCLUSION The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.

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/m2) 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 μmol/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.

Long-Term Natural Course of Pituitary Tumors in Patients With MEN1: Results From the DutchMEN1 Study Group (DMSG).

CONTEXT Guidelines advise lifelong radiological followup for asymptomatic pituitary adenomas (PITs) because of the risk for growth and subsequent visual field defects. In the context of multiple endocrine neoplasia type 1 (MEN1) an even more comprehensive screening is advised because PITs are presumed to manifest more aggressive behavior. We studied the long-term course of MEN1-related PITs, which may be used as a model for sporadically occurring PITs. OBJECTIVE The aim of our study is to assess the results of systematic pre-symptomatic PIT screening and subsequent long-term followup of PITs with emphasis on nonfunctioning microadenomas diagnosed by screening. PATIENTS AND METHODS A cohort study was performed using the Dutch national MEN1 database, including greater than 90% of the Dutch MEN1 population older than 16 years (n = 323). MAIN OUTCOME MEASURES Screening results, natural course, and effects of treatment of PIT were assessed. RESULTS PIT was diagnosed in 123 patients with MEN1 (38.1 %), of whom 66 were diagnosed by MEN1-related screening. Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas (n = 52) responded well to treatment with dopamine agonists. CONCLUSION Systematic presymptomatic screening for PIT in patients with MEN1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable.

Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients

CONTEXT The natural course and survival of neuroendocrine tumors (NETs) of thymus (Th) and lung in multiple endocrine neoplasia type 1 (MEN1) patients are still unknown. OBJECTIVE Our objective was to assess prevalence, tumor growth, and survival of Th and lung NETs in an unselected MEN1 population with long-term follow-up. DESIGN This was an observational study. PATIENTS AND METHODS A longitudinal study was performed using the Dutch national MEN1 database, including >90% of the Dutch MEN1 population >16 years of age. Patients under care of the Dutch University Medical Centers (1990-2011) (n = 323) were included. MAIN OUTCOME MEASURES The prevalence and survival of Th and lung NETs were assessed. Linear mixed-models analysis was applied to assess tumor growth with age as a possible confounder and gender, genotype and baseline tumor size as possible effect modifiers. RESULTS Th NETs occurred in 3.4% of patients, almost exclusively in males with a 10-year survival of 25% (95% confidence interval = 8%-80%). A thoracic computed tomography scan was available in 188 patients (58.2%). A lung NET was identified in 42 patients (13.0%) with a 10-year survival of 71.1% (95% confidence interval = 51%-100%). Tumor volume of lung NETs increased 17% per year (P < .001) (tumor doubling time 4.5 years). Tumor doubling time in males was 2.5 vs 5.5 years in females (P = .05). Lung NET growth was not associated with genotype or with baseline tumor size (<1 vs ≥1 cm). CONCLUSION In MEN1 patients, Th NETs almost exclusively occurred in males and had a very low prevalence and a high mortality. Lung NETs occurred more often than previously thought, had an indolent course, and occurred equally in both sexes. Tumor growth in males was double compared with female patients.

Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis - A Cohort Study in a Group of Thyroid Carcinoma Patients

Background/Objectives Thyroid hormone receptors are present on brown adipose tissue (BAT), indicating a role for thyroid hormone in the regulation of BAT activation. The objective of this study was to examine the effect of thyroid hormone withdrawal followed by thyroid hormone in TSH-suppressive dosages, on energy expenditure and brown adipose tissue activity. Subjects/Methods This study was a longitudinal study in an academic center, with a follow-up period of 6 months. Ten patients with well-differentiated thyroid carcinoma eligible for surgical treatment and subsequent radioactive iodine ablation therapy were studied in a hypothyroid state after thyroidectomy and in a subclinical hyperthyroid state (TSH-suppression according to treatment protocol). Paired two-tailed t-tests and linear regression analyses were used. Results Basal metabolic rate (BMR) was significantly higher after treatment with synthetic thyroid hormone (levothyroxine) than in the hypothyroid state (BMR 3.8 ± 0.5 kJ/min versus 4.4 ± 0.6 kJ/min, P = 0.012), and non-shivering thermogenesis (NST) significantly increased from 15 ± 10% to 25 ± 6% (P = 0.009). Mean BAT activity was significantly higher in the subclinical hyperthyroid state than in the hypothyroid state (BAT standard uptake value (SUVMean) 4.0 ± 2.9 versus 2.4 ± 1.8, P = 0.039). Conclusions Our study shows that higher levels of thyroid hormone are associated with a higher level of cold-activated BAT. Trial Registration ClinicalTrials.gov NCT02499471

Diabetes: impaired damage control.

A coordinated response by the innate immune system, (micro)circulation and nervous system is needed to limit tissue destruction and to initiate reparative processes after tissue damage. Alterations in danger signals in diabetes can be an important cause of the excessive tissue loss and defective tissue repair after injury and can contribute to the higher rates of cardiac failure after myocardial infarction, more severe tissue loss in the case of peripheral ischaemia and impaired wound healing. Here we discuss the mechanisms underlying this impaired damage control in diabetes, with an emphasis on the proinflammatory cytokine high mobility group box 1 and the potential role of dipeptidyl peptidase IV inhibition in improving repair responses.

Effects of Bezafibrate Treatment in a Patient and a Carrier With Mutations in the PNPLA2 Gene, Causing Neutral Lipid Storage Disease With Myopathy

Neutral lipid storage disease with myopathy (NLSDM) is a rare but severe genetic disorder characterized by excessive lipid accumulation in tissues including skin, bone marrow, heart, liver, and muscles. Clinically, NLSDM patients present with severe dilated cardiomyopathy, skeletal muscle myopathy, and insulin resistance.1 NLSDM is caused by a defect in the PNPLA2 gene encoding the enzyme adipose triglyceride lipase (ATGL),2 which catalyzes the breakdown of triglycerides in multiple tissues and is the rate-limiting step of lipolysis. Although heterozygous carriers and homozygous patients both present with similar clinical symptoms, the severity of these symptoms in homozygous patients is more dramatic, leading to premature death attributed to dilated cardiomyopathy in some patients.1,2 To date, the only available treatment is strict dietary guidelines and is focused on treating the comorbidities rather than targeting the primary defect. To investigate cardiac lipotoxicity in NLSDM, ATGL-deficient mice have been investigated. Just like NLSDM patients, ATGL-deficient mice are also characterized by excessive lipid storage in skeletal muscle, liver, and heart, and they develop cardiomyopathy at a young age, resulting in premature death.3 Interestingly, we reported recently that a lack of ATGL resulted in a diminished cardiac peroxisome proliferator-activated receptor (PPAR) activity and mitochondrial function, suggesting that lipolysis-derived fatty acids or fatty acid byproducts serve as transcriptional activators of PPARs.4 Subsequently, pharmacological treatment of ATGL-deficient mice with PPAR agonists completely reversed the mitochondrial defects, restored cardiac function, and prevented premature death. These promising findings inspired us to investigate whether PPAR agonist treatment in patients and carriers of a PNPLA2 gene defect could also have beneficial effects. Although NSLDM is a very rare disease, we had the opportunity to study 2 sisters with PNPLA2 gene mutations. Patient 1 is a 37-year-old woman with a body mass index of 21.4 kg/m2. …

Demonstration of a day-night rhythm in human skeletal muscle oxidative capacity

Objective A disturbed day-night rhythm is associated with metabolic perturbations that can lead to obesity and type 2 diabetes mellitus (T2DM). In skeletal muscle, a reduced oxidative capacity is also associated with the development of T2DM. However, whether oxidative capacity in skeletal muscle displays a day-night rhythm in humans has so far not been investigated. Methods Lean, healthy subjects were enrolled in a standardized living protocol with regular meals, physical activity and sleep to reflect our everyday lifestyle. Mitochondrial oxidative capacity was examined in skeletal muscle biopsies taken at five time points within a 24-hour period. Results Core-body temperature was lower during the early night, confirming a normal day-night rhythm. Skeletal muscle oxidative capacity demonstrated a robust day-night rhythm, with a significant time effect in ADP-stimulated respiration (state 3 MO, state 3 MOG and state 3 MOGS, p < 0.05). Respiration was lowest at 1 PM and highest at 11 PM (state 3 MOGS: 80.6 ± 4.0 vs. 95.8 ± 4.7 pmol/mg/s). Interestingly, the fluctuation in mitochondrial function was also observed in whole-body energy expenditure, with peak energy expenditure at 11 PM and lowest energy expenditure at 4 AM (p < 0.001). In addition, we demonstrate rhythmicity in mRNA expression of molecular clock genes in human skeletal muscle. Conclusions Our results suggest that the biological clock drives robust rhythms in human skeletal muscle oxidative metabolism. It is tempting to speculate that disruption of these rhythms contribute to the deterioration of metabolic health associated with circadian misalignment.