PROactive study.
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Diabetes Mellitus, Type 2↗
Biomedical subjects
R Retnakaran
Publications and source records attributed to R Retnakaran.
Elevated C-reactive protein in Native Canadian children: an ominous early complication of childhood obesity.
AIM: Subclinical inflammation has been proposed as a pathophysiologic mechanism linking obesity with vascular and metabolic disease. Native North American populations are experiencing high prevalence rates of both (i) childhood obesity and (ii) adult cardiovascular disease (CVD) and type 2 diabetes. Thus, we sought to determine whether subclinical inflammation is an early complication of obesity in Native children. METHODS: Serum concentrations of the inflammatory biomarker C-reactive protein (CRP) were assessed in a population-based, cross-sectional study of the Sandy Lake Oji-Cree community of Northern Ontario, Canada, involving 228 children aged 10-19 years (mean age 14.8). RESULTS: Median CRP in this population was 0.5 mg/l (interquartile range 0.18-1.79 mg/l). CRP levels were higher than age-matched reference data from the Third National Health and Nutrition Examination Survey (NHANES III). Importantly, fully 15.8% of the children of this community had CRP concentrations between 3 and 10 mg/l, a range that identifies adults at high risk of CVD. Moreover, increasing CRP concentration in this paediatric population was associated with an enhanced CV risk profile, consisting of increased adiposity, higher insulin resistance, worsening lipid profile (higher total cholesterol, triglycerides, low-density lipoprotein cholesterol, apolipoprotein B and total cholesterol : high-density-lipoprotein cholesterol ratio), increased leptin and decreased adiponectin. On multivariate analysis, waist circumference and interleukin-6 (IL-6) emerged as independent determinants of CRP concentration. CONCLUSION: Subclinical inflammation is an early complication of childhood obesity in Native children and may foreshadow an increased burden of CVD and type 2 diabetes in the future.
Adolescent↗
Adiponectin and beta cell dysfunction in gestational diabetes: pathophysiological implications.
AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) identifies a population of young women at high risk of developing type 2 diabetes and thus provides an excellent model for studying early events in the natural history of this disease. Adiponectin, a novel adipocyte-derived protein with insulin-sensitising properties, has been proposed as a factor linking insulin resistance and beta cell dysfunction in the pathogenesis of type 2 diabetes. We conducted the current investigation to determine whether adiponectin is associated with beta cell dysfunction in GDM. METHODS: We studied 180 women undergoing OGTT in late pregnancy. Based on the OGTT results, participants were stratified into three groups: (1) NGT (n=93); (2) IGT (n=39); and (3) GDM (n=48). First-phase insulin secretion was determined using a validated index previously proposed by Stumvoll. Insulin sensitivity was assessed using the validated OGTT insulin sensitivity index of Matsuda and DeFronzo (IS(OGTT)). RESULTS: To evaluate beta cell function in relation to ambient insulin sensitivity, an insulin secretion-sensitivity index (ISSI) was derived from the product of the Stumvoll index and the IS(OGTT), based on the existence of the predicted hyperbolic relationship between these two measures. Mean ISSI was highest in the NGT group (6,731), followed by that in the IGT group (4,976) and then that in the GDM group (3,300) (overall p<0.0001), compatible with the notion of declining beta cell function across these glucose tolerance groups. Importantly, adiponectin was significantly correlated with ISSI (r=0.34, p<0.0001), with a stepwise increase in mean ISSI observed per tertile of adiponectin concentration (trend p<0.0001). In multivariate linear regression analysis, ISSI was positively correlated with adiponectin and negatively correlated with GDM, IGT and C-reactive protein (r(2)=0.54). CONCLUSIONS/INTERPRETATION: Adiponectin concentration is an independent correlate of beta cell function in late pregnancy. As such, adiponectin may play a key role in mediating insulin resistance and beta cell dysfunction in the pathogenesis of diabetes.
Adiponectin↗
Hypoadiponectinaemia in South Asian women during pregnancy: evidence of ethnic variation in adiponectin concentration.
AIMS: People of South Asian descent face an increased risk of Type 2 diabetes mellitus (DM) and coronary artery disease (CAD) compared with other ethnic groups. One candidate factor underlying this risk may be adiponectin, as circulating levels of this adipocyte-derived protein are reduced in both Type 2 DM and CAD. In a recent study, we assessed the relationship between adiponectin and gestational diabetes (GDM), a potential model of early events in the natural history of Type 2 DM. Here, we report the impact of ethnicity on plasma adiponectin concentration in that study. METHODS: A cross-sectional study was performed in 180 women undergoing oral glucose tolerance testing in late second or early third trimester to investigate the relationship between adiponectin and glucose tolerance in pregnancy. Based on self-reported ethnicity, participants were stratified into three groups: (i) Caucasian (n = 116), (ii) South Asian (n = 31), and (iii) Asian (n = 28). RESULTS: Median adiponectin concentration was much lower in the South Asian group (9.7 micro g/ml) than in Caucasians (15.8 micro g/ml) or Asians (16.1 micro g/ml) (overall P < 0.0001). With adjustment for age, prepregnancy body mass index, weight gain in pregnancy, previous history of GDM, family history of DM, fasting insulin and glucose intolerance, mean adiponectin remained significantly lower among South Asians compared with either Caucasians (P < 0.0001) or Asians (P = 0.0034). CONCLUSIONS: Women of South Asian descent exhibit significantly reduced plasma concentrations of adiponectin in pregnancy compared with Caucasian and Asian counterparts. This observation raises the possibility of hypoadiponectinaemia as a potential factor contributing to the increased risk of diabetes and cardiovascular disease in South Asians.
Adiponectin↗
A family of cyclin-like proteins that interact with the Pho85 cyclin-dependent kinase.
In budding yeast, entry into the mitotic cell cycle, or Start, requires the Cdc28 cyclin-dependent kinase (Cdk) and one of its three associated G1 cyclins, Cln1, Cln2, or Cln3. In addition, two other G1 cyclins, Pcl1 and Pcl2, associate with a second Cdk, Pho85, to contribute to Start. Although Pho85 is not essential for viability, Pcl1,2-Pho85 kinase complexes become essential for Start in the absence of Cln1,2-Cdc28 kinases. In addition, Pho85 interacts with a third cyclin, Pho80, to regulate acid phosphatase gene expression. Other cellular roles for Pho85 cyclin-Cdk complexes are suggested by the multiple phenotypes associated with deletion of PHO85, in addition to Start defects and deregulated acid phosphatase gene expression. Strains with pho80, pcl1, and pcl2 deletions show only a subset of the pho85 mutant phenotypes, suggesting the existence of additional Pho85 cyclins (Pcls). We used two-hybrid screening and database searching to identify seven additional cyclin-related genes that may interact with Pho85. We found that all of the new genes encode proteins that interacted with Pho85 in an affinity chromatography assay. One of these genes, CLG1, was previously suggested to encode a cyclin, based on the protein's sequence homology to Pcl1 and Pcl2. We have named the other genes PCL5, PCL6, PCL7, PCL8, PCL9, and PCL10. On the basis of sequence similarities, the PCLs can be divided into two subfamilies: the Pcl1,2-like subfamily and the Pho80-like subfamily. We found that deletion of members of the Pcl1,2 class of genes resulted in pronounced morphological abnormalities. In addition, we found that expression of one member of the Pcl1,2 subfamily, PCL9, is cell cycle regulated and is decreased in cells arrested in G1 by pheromone treatment. Our studies suggest that Pho85 associates with multiple cyclins and that subsets of cyclins may direct Pho85 to perform distinct roles in cell growth and division.
Amino Acid Sequence↗
Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator.
A novel member of the steroid/thyroid/retinoid superfamily of nuclear receptors has been isolated as part of a screen to identify genes related to the recently characterized orphan receptor ROR alpha. This new orphan receptor, cloned from a mouse brain cDNA library, is closely related to the rat Rev-ErbA alpha gene product (97% and 68% identity in the DNA- and ligand-binding domains, respectively) and referred to as RVR. Northern blot analysis reveals that two RVR mRNA species are expressed during mouse embryogenesis and widely expressed in adult tissues. Studies with in vitro translated RVR protein show that it binds the DNA sequence ATAACTAGGTCA, a hormone response element composed of a 6-base pair AT-rich sequence preceding a single nuclear receptor recognition half-site core motif PuGGTCA. We show that RVR recognizes this hormone response element with a specificity similar to that of the orphan receptor ROR alpha 2. However, cotransfection studies indicate that RVR does not activate transcription when this hormone response element is linked to a reporter gene but rather acts as a potent competitive repressor of ROR alpha function. These results indicate the existence of an orphan nuclear receptor-based signaling pathway with the intrinsic ability to regulate the expression of specific gene networks through competition between transcriptional activators and repressors for the same recognition site.
Amino Acid Sequence↗