217 research outputs found
Positional Cloning of a Type 2 Diabetes Quantitative Trait Locus; Tomosyn-2, a Negative Regulator of Insulin Secretion
We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lepob/ob and C57BL/6 (B6) Lepob/ob mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congenic mice and narrowed the diabetes susceptibility locus to a 1.6 Mb region. Introgression of this 1.6 Mb fragment of the BTBR Chr 16 into lean B6 mice (B6.16BT36â38) replicated the phenotypes of the consomic mice. Pancreatic islets from the B6.16BT36â38 mice were defective in the second phase of the insulin secretion, suggesting that the 1.6 Mb region encodes a regulator of insulin secretion. Within this region, syntaxin-binding protein 5-like (Stxbp5l) or tomosyn-2 was the only gene with an expression difference and a non-synonymous coding single nucleotide polymorphism (SNP) between the B6 and BTBR alleles. Overexpression of the b-tomosyn-2 isoform in the pancreatic β-cell line, INS1 (832/13), resulted in an inhibition of insulin secretion in response to 3 mM 8-bromo cAMP at 7 mM glucose. In vitro binding experiments showed that tomosyn-2 binds recombinant syntaxin-1A and syntaxin-4, key proteins that are involved in insulin secretion via formation of the SNARE complex. The B6 form of tomosyn-2 is more susceptible to proteasomal degradation than the BTBR form, establishing a functional role for the coding SNP in tomosyn-2. We conclude that tomosyn-2 is the major gene responsible for the T2D Chr 16 quantitative trait locus (QTL) we mapped in our mouse cross. Our findings suggest that tomosyn-2 is a key negative regulator of insulin secretion
Why Are Nigeria-Cameroon Chimpanzees (Pan troglodytes ellioti) Free of SIVcpz Infection?
Abstract Simian immunodeficiency virus (SIV) naturally infects two subspecies of chimpanzee: Pan troglodytes troglodytes from Central Africa (SIVcpzPtt) and P. t. schweinfurtii from East Africa (SIVcpzPts), but is absent in P. t. verus from West Africa and appears to be absent in P. t. ellioti inhabiting Nigeria and western Cameroon. One explanation for this pattern is that P. t. troglodytes and P. t schweinfurthii may have acquired SIVcpz after their divergence from P. t. verus and P. t. ellioti. However, all of the subspecies, except P. t. verus, still occasionally exchange migrants making the absence of SIVcpz in P. t. ellioti puzzling. Sampling of P. t. ellioti has been minimal to date, particularly along the banks of the Sanaga River, where its range abuts that of P. t. troglodytes. This study had three objectives. First, we extended the sampling of SIVcpz across the range of chimpanzees north of the Sanaga River to address whether under-sampling might account for the absence of evidence for SIVcpz infection in P. t. ellioti. Second, we investigated how environmental variation is associated with the spread and prevalence of SIVcpz in the two chimpanzee subspecies inhabiting Cameroon since environmental variation has been shown to contribute to their divergence from one another. Finally, we compared the prevalence and distribution of SIVcpz with that of Simian Foamy Virus (SFV) to examine the role of ecology and behavior in shaping the distribution of diseases in wild host populations. The dataset includes previously published results on SIVcpz infection and SFVcpz as well as newly collected data, and represents over 1000 chimpanzee fecal samples from 41 locations across Cameroon. Results revealed that none of the 181 P. t. ellioti fecal samples collected across the range of P. t. ellioti tested positive for SIVcpz. In addition, species distribution models suggest that environmental variation contributes to differences in the distribution and prevalence of SIVcpz and SFVcpz. The ecological niches of these two viruses are largely non-overlapping, although stronger statistical support for this conclusion will require more sampling
The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice
AIMS/HYPOTHESIS: Zfp69 was previously identified by positional cloning as a candidate gene for obesity-associated diabetes. C57BL/6J and New Zealand obese (NZO) mice carry a loss-of-function mutation due to the integration of a retrotransposon. On the NZO background, the Zfp69 locus caused severe hyperglycaemia and loss of beta cells. To provide direct evidence for a causal role of Zfp69, we investigated the effects of its overexpression on both a lean [B6-Tg(Zfp69)] and an obese [NZO/B6-Tg(Zfp69)] background. METHODS: Zfp69 transgenic mice were generated by integrating the cDNA into the ROSA locus of the C57BL/6 genome and characterised. RESULTS: B6-Tg(Zfp69) mice were normoglycaemic, developed hyperinsulinaemia, and exhibited increased expression of G6pc and Pck1 and slightly reduced phospho-Akt levels in the liver. During OGTTs, glucose clearance was normal but insulin levels were significantly higher in the B6-Tg(Zfp69) than in control mice. The liver fat content and plasma triacylglycerol levels were significantly increased in B6-Tg(Zfp69) and NZO/B6-Tg(Zfp69) mice on a high-fat diet compared with controls. Liver transcriptome analysis of B6-Tg(Zfp69) mice revealed a downregulation of genes involved in glucose and lipid metabolism. Specifically, expression of Nampt, Lpin2, Map2k6, Gys2, Bnip3, Fitm2, Slc2a2, Ppargc1Îą and Insr was significantly decreased in the liver of B6-Tg(Zfp69) mice compared with wild-type animals. However, overexpression of Zfp69 did not induce overt diabetes with hyperglycaemia and beta cell loss. CONCLUSIONS/INTERPRETATION: Zfp69 mediates hyperlipidaemia, liver fat accumulation and mild insulin resistance. However, it does not induce type 2 diabetes, suggesting that the diabetogenic effect of the Zfp69 locus requires synergy with other as yet unidentified genes
Early detection and intervention for young children with early developmental disabilities in Western Uganda: a mixed-methods evaluation.
BACKGROUND: Early support for children with developmental disabilities is crucial but frequently unavailable in low-resource settings. We conducted a mixed-methods evaluation to assess the feasibility, acceptability, and impact of a programme of early detection and intervention for young children with developmental disabilities in Western Uganda. METHODS: Early child development training for healthcare workers (HCWs) was implemented in three rural districts, and attendance was tracked. HCW knowledge and confidence were assessed pre-/post-intervention, and referral numbers tracked to evaluate impact. Facilitators were trained and mentored to deliver a participatory, group, early intervention programme (EIP) for young children with developmental disabilities and their families. Facilitators were tracked as they were identified, trained, and delivered the intervention, and attendance of families was tracked. Pre-/post-intervention assessments evaluated changes in family quality of life (PedsQL 2.0, Family Impact Module), and child nutritional outcomes. Focus group discussions with stakeholders also assessed feasibility, acceptability and impact. RESULTS: Overall, 93 HCWs from 45 healthcare facilities received training. In the pre-/post-evaluation, median knowledge and confidence scores increased significantly (from 4.0 to 7.0 and from 2.7 to 4.7, respectively (p < 0.001)). HCWs reported feeling empowered to refer and offer care for families with a young child with disability. Referral rates increased significantly from 148 to 251 per annum (70%; p = 0.03). Eleven EIP facilitators were trained, and all delivered the intervention; 84 families were enrolled, of which 78% attended at least 6 out of 10 modules. Amongst those with paired pre-/post-intervention data (n = 48), total family quality of life scores increased significantly (21%, p < 0.001). Improvements were seen across all domains of quality of life, with the largest impacts on emotional functioning and social functioning (p < 0.001). The programme was acceptable to caregivers and facilitators. Caregivers reported improved knowledge, family relationships, hope, emotional wellbeing, and reduced self-stigma. CONCLUSIONS: A programme of early detection and intervention for children with early developmental disabilities and their families was feasible and acceptable in a rural community-based Ugandan setting. HCW training positively impacted knowledge, confidence, attitudes, and referral rates. Families enrolled to the EIP reported significant improvements in quality of life. Important programmatic barriers identified included geographical spread, poverty, gender inequality, and stigma
Pancreatic islet expression profiling in diabetes-prone C57BLKS/J mice reveals transcriptional differences contributed by DBA loci, including Plagl1 and Nnt
Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure
Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study)
<p>Abstract</p> <p>Background</p> <p>Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes.</p> <p>Methods</p> <p>We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the <it>BNC2</it>, <it>SORCS1</it>, <it>GSC </it>and <it>WDR72 </it>loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model.</p> <p>Results</p> <p>No significant associations with HbA1c or glucose levels were found for the <it>SORCS1</it>, <it>BNC2</it>, <it>GSC </it>or <it>WDR72 </it>variants (all <it>P</it>-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the <it>SORCS1 </it>risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (<it>P </it>= 0.13) and 0.13 mmol/l (<it>P </it>= 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the <it>WDR72 </it>risk variant showed a borderline association with reduced HbA1c levels (<it>β </it>= -0.21, <it>P </it>= 0.06), and direction consistent with decreased glucose levels (<it>β </it>= -0.29, <it>P </it>= 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (<it>β </it>= 0.04, <it>P </it>= 0.38).</p> <p>Conclusions</p> <p>The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the <it>SORCS1 </it>SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the <it>SORCS1 </it>locus, affect glycemic control in type 2 diabetes.</p
A wild derived quantitative trait locus on mouse chromosome 2 prevents obesity
<p>Abstract</p> <p>Background</p> <p>The genetic architecture of multifactorial traits such as obesity has been poorly understood. Quantitative trait locus (QTL) analysis is widely used to localize loci affecting multifactorial traits on chromosomal regions. However, large confidence intervals and small phenotypic effects of identified QTLs and closely linked loci are impeding the identification of causative genes that underlie the QTLs. Here we developed five subcongenic mouse strains with overlapping and non-overlapping wild-derived genomic regions from an F2 intercross of a previously developed congenic strain, B6.Cg-<it>Pbwg1</it>, and its genetic background strain, C57BL/6J (B6). The subcongenic strains developed were phenotyped on low-fat standard chow and a high-fat diet to fine-map a previously identified obesity QTL. Microarray analysis was performed with Affymetrix GeneChips to search for candidate genes of the QTL.</p> <p>Results</p> <p>The obesity QTL was physically mapped to an 8.8-Mb region of mouse chromosome 2. The wild-derived allele significantly decreased white fat pad weight, body weight and serum levels of glucose and triglyceride. It was also resistant to the high-fat diet. Among 29 genes residing within the 8.8-Mb region, <it>Gpd2, Upp2, Acvr1c, March7 </it>and <it>Rbms1 </it>showed great differential expression in livers and/or gonadal fat pads between B6.Cg-<it>Pbwg1 </it>and B6 mice.</p> <p>Conclusions</p> <p>The wild-derived QTL allele prevented obesity in both mice fed a low-fat standard diet and mice fed a high-fat diet. This finding will pave the way for identification of causative genes for obesity. A further understanding of this unique QTL effect at genetic and molecular levels may lead to the discovery of new biological and pathologic pathways associated with obesity.</p
The effect of ABCA1 gene polymorphisms on ischaemic stroke risk and relationship with lipid profile
<p>Abstract</p> <p>Background</p> <p>Ischaemic stroke is a common disorder with genetic and environmental components contributing to overall risk. Atherothromboembolic abnormalities, which play a crucial role in the pathogenesis of ischaemic stroke, are often the end result of dysregulation of lipid metabolism. The ATP Binding Cassette Transporter (<it>ABCA1</it>) is a key gene involved in lipid metabolism. It encodes the cholesterol regulatory efflux protein which mediates the transfer of cellular phospholipids and cholesterol to acceptor apolipoproteins such as apolipoprotein A-I (ApoA-I). Common polymorphisms in this gene affect High Density Lipoprotein Cholesterol (HDL-C) and Apolipoprotein A-I levels and so influence the risk of atherosclerosis. This study has assessed the distribution of <it>ABCA1 </it>polymorphisms and haplotype arrangements in patients with ischaemic stroke and compared them to an appropriate control group. It also examined the relationship of these polymorphisms with serum lipid profiles in cases and controls.</p> <p>Methods</p> <p>We studied four common polymorphisms in <it>ABCA1 </it>gene: G/A-L158L, G/A-R219K, G/A-G316G and G/A-R1587K in 400 Caucasian ischaemic stroke patients and 487 controls. Dynamic Allele Specific Hybridisation (DASH) was used as the genotyping assay.</p> <p>Results</p> <p>Genotype and allele frequencies of all polymorphisms were similar in cases and controls, except for a modest difference in the <it>ABCA1 </it>R219K allele frequency (P-value = 0.05). Using the PHASE2 program, haplotype frequencies for the four loci (158, 219, 316, and 1587) were estimated in cases and controls. There was no significant difference in overall haplotypes arrangement in patients group compared to controls (p = 0.27). 2211 and 1211 haplotypes (1 = common allele, 2 = rare allele) were more frequent in cases (p = 0.05). Adjusted ORs indicated 40% and 46% excess risk of stroke for these haplotypes respectively. However, none of the adjusted ORs were statistically significant. Individuals who had R219K "22" genotype had a higher LDL level (p = 0.001).</p> <p>Conclusion</p> <p>Our study does not support a major role for the <it>ABCA1 </it>gene as a risk factor for ischaemic stroke. Some haplotypes may confer a minor amount of increased risk or protection. Polymorphisms in this gene may influence serum lipid profile.</p
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