Searching for "monogenic diabetes" in dogs using a candidate gene approach

BACKGROUND: Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility. RESULTS: Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds. CONCLUSIONS: Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2052-6687-1-8) contains supplementary material, which is available to authorized users

Effects of diabetes and hypertension on glomerular transforming growth factor-β receptor expression

Effects of diabetes and hypertension on glomerular transforming growth factor-β receptor expression.BackgroundSeveral studies have suggested that transforming growth factor-β1 (TGF-β1) is an important determinant of diabetic glomerular injury. TGF-β1 forms a heteromeric complex with two cellular receptor subtypes, designated TGF-β RII and TGF-β RI, but the effects of diabetes mellitus on glomerular TGF-β receptor expression have not been completely elucidated. We first compared the effect of experimental type I diabetes mellitus and uninephrectomy on glomerular TGF-β receptor expression in spontaneously hypertensive rats (SHRs), and then sought to determine whether changes in TGF-β receptor expression were strain specific by studying normotensive Wistar-Kyoto (WKY) rats.MethodsFive groups of male SHRs were studied. The first group received streptozotocin (60 mg/kg IV) and was studied after one week. The second group received streptozotocin and was studied after two weeks. The third group received streptozotocin (60 mg/kg IV) but received insulin to maintain euglycemia. The fourth group of age-matched SHRs served as the control group, while a fifth group of SHRs underwent uninephrectomy. Four groups of male WKY rats were also studied. The first group of WKY rats served as the age-matched control group. The second group of WKY rats received streptozotocin, while a third group of WKY rats underwent uninephrectomy. The fourth group underwent uninephrectomy and received streptozotocin. At each time point, glomeruli were isolated for protein extraction, and the protein was subjected to Western blot analysis of TGF-β RII and TGF-β RI expression.ResultsBasal expression of both TGF-β receptors per microgram of glomerular protein was similar in normotensive WKY rats and hypertensive SHRs. Hyperglycemia (blood glucose level, 17.8 ± 2.9 mmol/L) led to an early twofold increase in TGF-β RII protein expression and a fourfold increase in TGF-β RI protein expression in the glomeruli of hypertensive diabetic SHRs compared with euglycemic SHRs (blood glucose level, 5.8 ± 0.8 mmol/L), which was sustained after two weeks. Insulin treatment (blood glucose level, 5.2 ± 0.9 mmol/L) normalized both TGF-β RII and TGF-β RI expression in the glomeruli of SHRs that received streptozotocin. Glomerular capillary hypertension in the uninephrectomized SHRs led to a twofold increase in glomerular TGF-β RII protein expression, but did not reproduce the effect of diabetes mellitus on TGF-β RI expression. In contrast to the findings in SHRs, neither hyperglycemia (blood glucose level, 15.5 ± 2.1 mmol/L), uninephrectomy, nor hyperglycemia (blood glucose level, 16.8 ± 3.0 mmol/L) and uninephrectomy altered TGF-β receptor expression in the glomeruli of normotensive WKY rats.ConclusionThese studies support the hypothesis that hemodynamic factors and metabolic factors influence glomerular TGF-β receptor in vivo in the SHRs

Activation of mesangial cell MAPK in responseto homocysteine

Activation of mesangial cell MAPK in response to homocysteine.BackgroundAlteration in mesangial cell function is central to the progression of glomerular disease in numerous models of chronic renal failure (CRF). Animal models of chronic glomerular disease are characterized by mesangial cell proliferation and elaboration of extracellular matrix protein (ECM), resulting in glomerulosclerosis. Elevated plasma levels of homocysteine (Hcy) are seen in both animal models and humans with CRF, and have been proposed to contribute to the high prevalence of vascular disease in this group. Some of the pathogenetic effects of Hcy are thought to be mediated via the induction of endoplasmic reticulum stress. Thus, Hcy effects on mesangial cells could contribute to the progression of CRF. Previous work has shown Hcy- mediated induction of Erk mitogen-activated protein kinase (MAPK) in vascular smooth muscle cells (VSMCs). Erk induces increases in activator protein-1 (AP-1) transcription factor activity which may augment mesangial cell proliferation and ECM protein production. Consequently, we studied the effect of Hcy on mesangial cell Erk signaling.MethodsMesangial cells were exposed to Hcy after 24 hours of serum starvation and Erk activity assessed. Nuclear translocation of phospho-Erk was visualized by confocal microscopy. AP-1 nuclear protein binding was measured in response to Hcy by mobility shift assay. Hcy-induced mesangial cell calcium flux was measured in Fura-2 loaded cells. Mesangial cell DNA synthesis in response to Hcy was assessed by [3H]-thymidine incorporation and proliferation by Western blotting for proliferating cell nuclear antigen (PCNA). Expression of endoplasmic reticulum stress response genes were determined by Northern and Western analysis.ResultsHcy led to an increase in Erk activity that was maximal at 50 μmol/L and 20 minutes of treatment. Subsequent experiments used this concentration and time point. Erk activity in response to Hcy was insensitive to n-acetylcysteine and catalase, indicating oxidative stress did not play a role. However, Hcy50 μmol/L induced a brief increase in intracellular mesangial cell calcium within 5 minutes, and the calcium ionophores A23187 and ionomycin increased Erk activity while chelation of intracellular calcium with BAPTA-AM abrogated the Erk response to Hcy. Confocal microscopy of activated Erk nuclear translocation mirrored these results as did mesangial cell nuclear protein binding to AP-1 consensus sequences. Hcy- induced increases in thymidine incorporation and PCNA expression at 24 hours were Erk dependent. The expression of endoplasmic reticulum stress response genes was significantly elevated by Hcy in an Erk-dependent manner.ConclusionHcy increases Erk activity in mesangial cells via a calcium-dependent mechanism, resulting in increased AP-1 nuclear protein binding, cell DNA synthesis and proliferation and induction of endoplasmic reticulum stress. These observations suggest potential mechanisms by which Hcy may contribute to progressive glomerular injury

The effect of a 24-hour photoperiod on the survival, growth and swim bladder inflation of pre-flexion yellowfin tuna (Thunnus albacares) larvae

The effects of two different continuous photoperiod regimes on survival, growth and swim bladder inflation of pre-flexion yellowfin tuna (Thunnus albacares) larvae were investigated. Each photoperiod regime was tested twice with a different larval cohort to confirm the observed results. Trials 1 and 2 tested the effect of a reduced night-time light intensity (10-molesm-2s-1=30% of the daytime intensity) and found that those larvae reared for 8days under the 24h lighting (24-L) photoperiod exhibited a slight improvement in survival compared to those reared under the control photoperiod of 12h light (12-L), however these improvements were not significant. In addition, those larvae reared under this photoperiod regime were equal in length to those in the control. Trials 3 and 4 compared the same variables in larvae reared under a continuous photoperiod (24-L) with a constant light intensity of 30-molesm-2s-1, against those reared under the aforementioned 12-L photoperiod. Survival of larvae under the continuous photoperiods were 9±1% (n=2) and 10±2% (n=3) for Trials 3 and 4, respectively, compared to less than 1% in both control treatments; differences that in both cases were highly significant. In addition, in both trials larvae cultured under the 24-L photoperiod were significantly larger and exhibited more advanced development than those reared under the 12-L photoperiod, however swim bladder inflation was significantly lower. We suggest that the improved survival and growth achieved under a continuous photoperiod is due to the extended foraging time combined with the prevention of mortality caused by night-time sinking

Effect of Protein Kinase Cβ Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study

OBJECTIVE—The aim of this study was to examine the effect of protein kinase Cβ inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects

Publishing and sharing multi-dimensional image data with OMERO

Imaging data are used in the life and biomedical sciences to measure the molecular and structural composition and dynamics of cells, tissues, and organisms. Datasets range in size from megabytes to terabytes and usually contain a combination of binary pixel data and metadata that describe the acquisition process and any derived results. The OMERO image data management platform allows users to securely share image datasets according to specific permissions levels: data can be held privately, shared with a set of colleagues, or made available via a public URL. Users control access by assigning data to specific Groups with defined membership and access rights. OMERO’s Permission system supports simple data sharing in a lab, collaborative data analysis, and even teaching environments. OMERO software is open source and released by the OME Consortium at www.openmicroscopy.org

Early changes in cardiovascular structure and function in adolescents with type 1 diabetes.

BACKGROUND: Children with type 1 diabetes (T1D) are at higher risk of early adult-onset cardiovascular disease. We assessed cardiovascular structure and function in adolescents with T1D compared with healthy controls and the relationships between peripheral vascular function and myocardial parameters. METHODS AND RESULTS: 199 T1D [14.4 ± 1.6 years, diabetes duration 6.2 (2.0-12.8) years] and 178 controls (14.4 ± 2.1 years) completed endothelial function by flow mediated vasodilatation (FMD), arterial stiffness using pulse wave velocity (PWV) along with M-mode, pulse wave and tissue Doppler, and myocardial deformation echocardiographic imaging. Systolic (113 ± 10 vs. 110 ± 9 mmHg; p = 0.0005) and diastolic (62 ± 7 vs. 58 ± 7 mmHg; p < 0.0001) blood pressures, carotid femoral PWV and endothelial dysfunction measurements were increased in T1D compared with controls. Systolic and diastolic left ventricular dimensions and function by M-mode and pulse wave Doppler assessment were not significantly different. Mitral valve lateral e' (17.6 ± 2.6 vs. 18.6 ± 2.6 cm/s; p < 0.001) and a' (5.4 ± 1.1 vs. 5.9 ± 1.1 cm/s; p < 0.001) myocardial velocities were decreased and E/e' (7.3 ± 1.2 vs. 6.7 ± 1.3; p = 0.0003) increased in T1D. Left ventricular mid circumferential strain (-20.4 ± 2.3 vs. -19.5 ± 1.7 %; p < 0.001) was higher, whereas global longitudinal strain was lower (-19.0 ± 1.9 vs. -19.8 ± 1.5 % p < 0.001) in T1D. CONCLUSIONS: Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening. Longitudinal follow-up of these changes in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension that could preferentially benefit from early therapeutic interventions.Funding was provided by the Juvenile Diabetes Research Foundation- Canadian Clinical Trial Network (JDRF-CCTN), the Canadian Diabetes Association, the Heart and Stroke Foundation of Canada and the Sick Kids Labatt Family Heart Center Innovation fund. Funding was also provided by the British Heart Foundation, Diabetes UK and the Juvenile Diabetes Research Foundation