Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

Summary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. Introduction: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. Methods: We performed nested case–control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800–829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). Results: Meta-analysis of the two nested case–control studies showed pooled odds ratios of 0.98 (0.91–1.05, p = 0.52), 1.04 (0.97–1.12, p = 0.28), and 1.16 (0.83–1.62, p = 0.38) for the associations betwee

Dipeptidyl peptidase IV inhibitors in diabetes: more than inhibition of glucagon-like peptide-1 metabolism?

Inhibitors of the protease dipeptidyl peptidase IV (DPP-IV) are promising new drugs for the treatment of type 2 diabetes. They are thought to act by inhibiting the breakdown of glucagon-like peptide-1 and, thereby, selectively enhancing insulin release under conditions when it is physiologically required. These drugs are selective for DPP-IV, but the enzyme itself has a broad range of substrates other than glucagon-like peptide-1. Other high affinity substrates of DPP-IV including peptide YY may also play a role in the regulation of energy homeostasis. Moreover, DPP-IV is also known as CD26 and considered to be a moonlighting protein because it has a wide range of other functions unrelated to energy homeostasis, e.g. in immunity. The potential role of DPP-IV inhibition on substrates other than glucagon-like peptide-1 in diabetes patients remains to be elucidated

Mutations in IRS4 are associated with central hypothyroidism

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutatio

Memory-guided force output is associated with self-reported ADHD symptoms in young adults

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental health disorder in childhood and persists into adulthood in up to 65 % of cases. ADHD is associated with adverse outcomes such as the ability to gain and maintain employment and is associated with an increased risk for substance abuse obesity workplace injuries and traffic accidents A majority of diagnosed children have motor deficits; however, few studies have examined motor deficits in young adults. This study provides a novel examination of visuomotor control of grip force in young adults with and without ADHD. Participants were instructed to maintain force production over a 20-second trial with and without real-time visual feedback about their performance. The results demonstrated that when visual feedback was available, adults with ADHD produced slightly higher grip force than controls. However, when visual feedback was removed, adults with ADHD had a faster rate of decay of force, which was associated with ADHD symptom severity and trait impulsivity. These findings suggest that there may be important differences in the way that adults with ADHD integrate visual feedback during continuous motor tasks. These may account for some of the motor impairments reported in children with ADHD. These deficits could result from (1) dysfunctional sensory motor integration and/or (2) deficits in short-term visuomotor memory

Hypothalamic control of hepatic lipid metabolism via the autonomic nervous system

Our body is well designed to store energy in times of nutrient excess, and release energy in times of food deprivation. This adaptation to the external environment is achieved by humoral factors and the autonomic nervous system. Claude Bernard, in the 19th century, showed the importance of the autonomic nervous system in the control of glucose metabolism. In the 20th century, the discovery of insulin and the development of techniques to measure hormone concentrations shifted the focus from the neural control of metabolism to the secretion of hormones, thus functionally "decapitating" the body. Just before the end of the 20th century, starting with the discovery of leptin in 1994, the control of energy metabolism went back to our heads. Since the start of 21st century, numerous studies have reported the involvement of hypothalamic pathways in the control of hepatic insulin sensitivity and glucose production. The autonomic nervous system is, therefore, acknowledged to be one of the important determinants of liver metabolism and a possible treatment target. In this chapter, we review research to date on the hypothalamic control of hepatic lipid metabolism

The hypothalamic clock and its control of glucose homeostasis

The everyday life of mammals, including humans, exhibits many behavioral, physiological and endocrine oscillations. The major timekeeping mechanism for these rhythms is contained in the central nervous system (CNS). The output of the CNS clock not only controls daily rhythms in sleep/wake (or feeding/fasting) behavior but also exerts a direct control over glucose metabolism. Here, we show how the biological clock plays an important role in determining early morning (fasting) plasma glucose concentrations by affecting hepatic glucose production and glucose uptake, as well as glucose tolerance, by determining feeding-induced insulin responses. Recently, large-scale genetic studies in humans provided the first evidence for the involvement of disrupted (clock gene) rhythms in the pathogenesis of type 2 diabete

The role of the autonomic nervous liver innervation in the control of energy metabolism

Despite a longstanding research interest ever since the early work by Claude Bernard, the functional significance of autonomic liver innervation, either sympathetic or parasympathetic, is still ill defined. This scarcity of information not only holds for the brain control of hepatic metabolism, but also for the metabolic sensing function of the liver and the way in which this metabolic information from the liver affects the brain. Clinical information from the bedside suggests that successful human liver transplantation (implying a complete autonomic liver denervation) causes no life threatening metabolic derangements, at least in the absence of severe metabolic challenges such as hypoglycemia. However, from the benchside, data are accumulating that interference with the neuronal brain-liver connection does cause pronounced changes in liver metabolism. This review provides an extensive overview on how metabolic information is sensed by the liver, and how this information is processed via neuronal pathways to the brain. With this information the brain controls liver metabolism and that of other organs and tissues. We will pay special attention to the hypothalamic pathways involved in these liver-brain-liver circuits. At this stage, we still do not know the final destination and processing of the metabolic information that is transferred from the liver to the brain. On the other hand, in recent years, there has been a considerable increase in the understanding which brain areas are involved in the control of liver metabolism via its autonomic innervation. However, in view of the ever rising prevalence of type 2 diabetes, this potentially highly relevant knowledge is still by far too limited. Thus the autonomic innervation of the liver and its role in the control of metabolism needs our continued and devoted attention. (C) 2010 Elsevier B.V. All rights reserve

Assessing the Optimal Time Point for the Measurement of Extrastriatal Serotonin Transporter Binding with I-123-FP-CIT SPECT in Healthy, Male Subjects

I-123-N-omega-fluoropropyl-2 beta-carboxymethoxy-3 beta-(4-iodophenyl) nortropane (I-123-FP-CIT) is commonly used to assess the dopamine transporter in the striatum. However, recent studies suggest that this tracer may be used also to assess binding to monoamine transporters in the midbrain or diencephalon, which may reflect predominantly serotonin transporter (SEAT) binding. However, it is still unclear at what time point after injection SPECT should be performed for optimal assessment of SERT with I-123-FP-CIT. Therefore, we examined the time course of extrastriatal I-123-FP-CIT binding. Methods: Nineteen healthy, male subjects were included, and SPECT images were acquired up to 3 h after I-123-FP-CIT injection. Region-of-interest analysis was performed, and specific-to-nonspecific binding ratios were calculated. Results: Specific-to-nonspecific I-123-FP-CIT binding ratios in the midbrain and diencephalon were significantly higher 2 h after injection than 1 h after injection and remained stable between 2 and 3 h after injection. Conclusion: The optimal time frame for assessing I-123-FP-CIT binding to extrastriatal SEAT is between 2 and 3 h after injection of the trace

Daily Gene Expression Rhythms in Rat White Adipose Tissue Do Not Differ Between Subcutaneous and Intra-Abdominal Depots

White adipose tissue (WAT) is present in different depots throughout the body. Although all depots are exposed to systemic humoral signals, they are not functionally identical. Studies in clock gene knockout animals and in shift workers suggest that daily rhythmicity may play an important role in lipid metabolism. Differences in rhythmicity between fat depots might explain differences in depot function; therefore, we measured mRNA expression of clock genes and metabolic genes on a 3-h interval over a 24-h period in the subcutaneous inguinal depot and in the intra-abdominal perirenal, epididymal, and mesenteric depots of male Wistar rats. We analyzed rhythmicity using CircWave software. Additionally, we measured plasma concentrations of glucose, insulin, corticosterone, and leptin. The clock genes (Bmal1/Per2/Cry1/Cry2/RevErbα/DBP) showed robust daily gene expression rhythms, which did not vary between WAT depots. Metabolic gene expression rhythms (SREBP1c/PPARα/PPARγ/FAS/LPL/Glut4/HSL/CPT1b/leptin/visfatin/resistin) were more variable between depots. However, no distinct differences between intra-abdominal and subcutaneous rhythms were found. Concluding, specific fat depots are not associated with differences in clock gene expression rhythms and, therefore, do not provide a likely explanation for the differences in metabolic function between different fat depots