OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users

Substrates for the Organic Cation Transporter 1, encoded by the SLC22A1 gene, are metformin, amantadine, pramipexole, and, possibly, levodopa. Recently, we identified that the rs622342 A > C polymorphism is associated with the HbA1c lowering effect in metformin users. In the Rotterdam Study, we associated this polymorphism with higher prescribed doses of all anti-Parkinsonian drugs. Between the first and fifth prescriptions for levodopa, for each minor rs622342 C allele, the prescribed doses were 0.34 defined daily dose higher (95% CI 0.064, 0.62; p = 0.017). The mortality ratio after start of levodopa therapy was 1.47 times higher (95% CI 1.01, 2.13; p = 0.045)

The Chemerin/ChemR23 System Does Not Affect the Pro-Inflammatory Response of Mouse and Human Macrophages Ex Vivo

Macrophages constitute a major component of innate immunity and play an essential role in defense mechanisms against external aggressions and in inflammatory responses. Chemerin, a chemoattractant protein, is generated in inflammatory conditions, and recruits cells expressing the G protein-coupled receptor ChemR23, including macrophages. Chemerin was initially expected to behave as a pro-inflammatory agent. However, recent data described more complex activities that are either pro- or anti-inflammatory, according to the disease model investigated. In the present study, peritoneal macrophages were generated from WT or ChemR23−/− mice, stimulated with lipopolyssaccharide in combination or not with IFN-γ and the production of pro- (TNF-α, IL-1β and IL-6) and anti-inflammatory (IL-10) cytokines was evaluated using qRT-PCR and ELISA. Human macrophages generated from peripheral blood monocytes were also tested in parallel. Peritoneal macrophages from WT mice, recruited by thioglycolate or polyacrylamide beads, functionally expressed ChemR23, as assessed by flow cytometry, binding and chemotaxis assays. However, chemerin had no effect on the strong upregulation of cytokine release by these cells upon stimulation by LPS or LPS/IFN-γ, whatever the concentration tested. Similar data were obtained with human macrophages. In conclusion, our results rule out the direct anti-inflammatory effect of chemerin on macrophages ex vivo, described previously in the literature, despite the expression of a functional ChemR23 receptor in these cells

Chemerin and Adiponectin Contribute Reciprocally to Metabolic Syndrome

Obesity and metabolic syndrome (MetS) are considered chronic inflammatory states. Chemerin, a novel adipokine, may play an important role in linking MetS and inflammation. We investigated the association of chemerin with inflammatory markers and with characteristics of MetS in apparently healthy overweight and obese adults. We studied 92 adults; 59 men and 33 women whose average body mass index (BMI) was 28.15±5.08 kg/m2. Anthropometric parameters, insulin resistance indices, lipid profiles, and inflammatory markers including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), adiponectin, and chemerin were measured. Controlling for age, gender, and BMI, serum chemerin level was positively correlated with body fat and serum triglyceride, and negatively correlated with adiponectin and high density lipoprotein cholesterol (HDL- C), and was not correlated with altered hsCRP or PTX3 levels. Among the low, moderate and high chemerin groups, high chemerin individuals are more likely to have lower HDL-C. Conversely, individuals in the low adiponectin group are more likely to have lower HDL-C and show more MetS phenotypic traits than moderate and high adiponectin subjects. To determine the relationships of chemerin and adiponectin to MetS and its components, participants were stratified into four groups based on their chemerin and adiponectin levels (high chemerin/high adiponectin, high chemerin/low adiponectin, low chemerin/high adiponectin, or low chemerin/low adiponectin). Participants who were in the high chemerin/low adiponectin group more likely to have dyslipidemia and MetS (OR: 5.79, 95% CI:1.00–33.70) compared to the other three group. Our findings suggest that chemerin and adiponectin may reciprocally participate in the development of MetS

Chemerin regulates β-cell function in mice

Although various function of chemerin have been suggested, its physiological role remains to be elucidated. Here we show that chemerin-deficient mice are glucose intolerant irrespective of exhibiting reduced macrophage accumulation in adipose tissue. The glucose intolerance was mainly due to increased hepatic glucose production and impaired insulin secretion. Chemerin and its receptor ChemR23 were expressed in β-cell. Studies using isolated islets and perfused pancreas revealed impaired glucose-dependent insulin secretion (GSIS) in chemerin-deficient mice. Conversely, chemerin transgenic mice revealed enhanced GSIS and improved glucose tolerance. Expression of MafA, a pivotal transcriptional factor for β-cell function, was downregulated in chemerin-deficient islets and a chemerin-ablated β-cell line and rescue of MafA expression restored GSIS, indicating that chemerin regulates β-cell function via maintaining MafA expression. These results indicate that chemerin regulates β-cell function and plays an important role in glucose homeostasis in a tissue-dependent manner

Perturbation of rat renal tubule transport of the organic cation amantadine in recent onset streptozotocin-induced diabetes and in uninephrectomy

The effects of early-stage diabetes mellitus and uninephrectomy on the renal tubule transport of amantadine were investigated. Kidney tubules were isolated from streptozotocin-induced diabetic (+/- insulin treatment), uninephrectomized, and control male Sprague-Dawley rats. There were no differences in the K-m of amantadine uptake in renal proximal and distal tubules for the imposed treatments compared with control values. V-max for amantadine uptake in the proximal tubules of diabetic and uninephrectomized rats was higher than the respective control (P < 0.05). V-max for insulin-treated diabetic rats was similar to control values but was lower than that for untreated diabetic rats (P < 0.05). V-max for distal tubule uptake was not altered by any treatment. Structure-activity studies demonstrated that bicarbonate-dependent amantadine uptake was inhibited by glycolate and lactate, but not by propionate or alpha-, beta-, or gamma -hydroxybutyrate. Early stage streptozotocin-induced diabetes mellitus and uninephrectomy induced changes in the kidney that resulted in a similar selective increase in proximal tubule amantadine uptake. These data represent the first description that experimentally induced diabetes mellitus and uninephrectomy modulate the function of the renal tubule organic cation (amantadine) transport system. Both interventions represent potential models in which phenotypic modulation of the renal elimination of organic cationic drugs may be achieved and studied.https://www.ingentaconnect.com/content/cndscipub/cjpp/2001/00000079/00000001/art0000