Bart Van Der Schueren

Decreased miR-181a Expression in Monocytes of Obese Patients Is Associated with the Occurrence of Metabolic Syndrome and Coronary Artery Disease

CONTEXT Inflammation during obesity is associated with higher risk of metabolic syndrome and coronary artery disease (CAD). Activation of the inflammatory toll-like receptor (TLR)/nuclear factor κB (NFκB) signaling in monocytes contributes to inflammation. Weight loss after bariatric surgery leads to significant improvement of obesity-related comorbidities. MicroRNA (miR), a class of small noncoding RNA, have been implicated as negative regulators of inflammatory processes. OBJECTIVE This study sought to identify dysregulated miR in monocytes of obese patients associated with TLR/NFκB signaling, metabolic syndrome, and CAD. DESIGN, SETTING, AND PATIENTS This retrospective study included two independent cohorts of 21 morbidly obese and 125 high-risk obese and nonobese patients in a hospitalized care setting. INTERVENTION INTERVENTION included bariatric surgery (n = 21) with a 3-month follow-up. MAIN OUTCOME MEASURES miR expressions in CD14(+) monocytes were determined by microarray analysis. TLR/NFκB-related miR were identified by an in silico target prediction analysis. Their expression was validated by quantitative RT-PCR. Their association with metabolic syndrome and angiographically documented CAD was assessed. RESULTS miR-181a, -181b, and -181d, identified as possible regulators of the TLR/NFκB signaling, were decreased in obese monocytes, and weight loss normalized their expression to levels observed in monocytes of lean persons. miR-181a but not miR-181b and miR-181d was associated with a higher number of metabolic syndrome components and with CAD even after adjustment for traditional risk factors, obesity and the metabolic syndrome. CONCLUSION This study demonstrates that the TLR/NFκB-related miR-181a is down-regulated in monocytes of obese patients and suggests that it is a putative biomarker of metabolic syndrome and CAD.

A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia

Background  Inactivating mutations of the calcium‐sensing receptor (CaSR), a G‐protein‐coupled receptor with extracellular (ECD), transmembrane (TMD) and intracellular (ICD) domains, cause familial hypocalciuric hypercalcaemia, neonatal severe primary hyperparathyroidism and occasionally primary hyperparathyroidism in adults.

The microRNA-29 Family Dictates the Balance Between Homeostatic and Pathological Glucose Handling in Diabetes and Obesity

The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)-deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing β-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.

Maternal Micronutrient Deficiencies and Related Adverse Neonatal Outcomes after Bariatric Surgery: A Systematic Review

Pregnant and postpartum women with a history of bariatric surgery are at risk of micronutrient deficiencies as a result of the combination of physiologic changes related to pregnancy and iatrogenic postoperative alterations in the absorption and metabolism of crucial nutrients. This systematic review investigates micronutrient deficiencies and related adverse clinical outcomes in pregnant and postpartum women after bariatric surgery. A systematic approach involving critical appraisal was conducted independently by 2 researchers to examine deficiencies of phylloquinone, folate, iron, calcium, zinc, magnesium, iodide, copper, and vitamins A, D, and B-12 in pregnant and postpartum women after bariatric surgery, together with subsequent outcomes in the neonates. The search identified 29 relevant cases and 8 cohort studies. The quality of reporting among the case reports was weak according to the criteria based on the CARE (CAse REporting) guidelines as was that for the cohort studies based on the criteria from the Cohort Study Quality Assessment list of the Dutch Cochrane Center. The most common adverse neonatal outcomes related to maternal micronutrient deficiencies include visual complications (vitamin A), intracranial hemorrhage (phylloquinone), neurological and developmental impairment (vitamin B-12), and neural tube defects (folate). On the basis of the systematically collected information, we conclude that the evidence on micronutrient deficiencies in pregnant and postpartum women after bariatric surgery and subsequent adverse neonatal outcomes remains weak and inconclusive.

GLP1 and cancer: friend or foe?

The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1s trophic effects. While increased β cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.

Magnitude and variability of the glucagon-like peptide-1 response in patients with type 2 diabetes up to 2 years following gastric bypass surgery.

OBJECTIVE To characterize the magnitude and variance of the change of glucose and glucagon-like peptide-1 (GLP-1) concentrations, and to identify determinants of glucose control up to 2 years after gastric bypass (GBP). RESEARCH DESIGN AND METHODS Glucose and GLP-1 concentrations were measured during an oral glucose challenge before and 1, 12, and 24 months after GBP in 15 severely obese patients with type 2 diabetes. RESULTS Glucose area under the curve from 0 to 180 min (AUC0–180) started decreasing in magnitude (P < 0.05) 1 month after surgery. GLP-1 AUC0–180 increased in magnitude 1 month after GBP (P < 0.05), with increased variance only after 1 year (Pσ2 ≤ 0.001). GLP-1 AUC0–180 was positively associated with insulin AUC0–180 (P = 0.025). CONCLUSIONS The increase in variance of GLP-1 at 1 and 2 years after GBP suggests mechanisms other than proximal gut bypass to explain the enhancement of GLP-1 secretion. The association between GLP-1 and insulin concentrations supports the idea that the incretins are involved in glucose control after GBP.

Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men

AIMS To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). METHODS Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI). RESULTS The aortic AIx following NTG decreased by -18.50 (-21.02, -15.98) % after telcagepant vs. -17.28 (-19.80, -14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated. CONCLUSIONS Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.

Bariatric Surgery Induces Weight Loss but Does Not Improve Glycemic Control in Patients With Type 1 Diabetes

Brethauer et al. (1) report an improvement of glycemic control following bariatric surgery in patients with type 1 diabetes. However, the small sample size and limited time of follow-up of this latest and other previous reports preclude drawing firm conclusions (1–3). We collected data from 22 patients with confirmed type 1 diabetes and BMI ≥35 kg/m2 from three Belgian bariatric surgery centers. Six patients underwent sleeve gastrectomy and 16 had Roux-en-Y gastric bypass surgery. Overall, we compared BMI, glycemic control (as assessed by A1C), and daily insulin dose between pre- and postsurgery using a linear mixed model with a random patient and a fixed period effect. P values < 0.05 are considered significant. At each time point, mean ± SEM is given in Fig. 1. …

Interictal Type 1 Cannabinoid Receptor Binding is Increased in Female Migraine Patients

Objective.— To compare binding of the type 1 cannabinoid receptor (CB1R) between migraine patients and healthy volunteers