RESUMEN
AIMS: The metabolic syndrome is a frequent phenomenon in people with Type 1 diabetes and is associated with diabetic nephropathy. The aim of this study was to investigate if the INPPL1 (inositol polyphosphate phosphatase-like 1) gene encoding lipid phosphatase SHIP2 is associated with the metabolic syndrome and diabetic nephropathy in Finnish people with Type 1 diabetes. METHODS: Participants were selected from the FinnDiane study for this cross-sectional study. The individuals were divided into controls without the metabolic syndrome (n = 1074) and cases with the metabolic syndrome (n = 1328), or into groups based upon their albumin excretion rate. Nine single-nucleotide polymorphisms covering the INPPL1 gene +/- 20 kb were genotyped. The associations between the single-nucleotide polymorphisms and outcome variables were analysed with the χ(2) test and logistic regression. RESULTS: Two INPPL1 single-nucleotide polymorphisms, rs2276048 (silent mutation) and rs2276047 (intronic), were associated with the metabolic syndrome in men with odds ratios of 0.23 (95% CI 0.11-0.45, P = 2.1 × 10(-5) ), and 0.37 (0.21-0.65, P = 0.001), adjusted for age, duration of diabetes and history of smoking. When both sexes were included, these associations were less significant. No association between the genotyped single-nucleotide polymorphisms and diabetic nephropathy was observed. CONCLUSIONS: INPPL1 gene variants may contribute to susceptibility to the metabolic syndrome in men with Type 1 diabetes, but not to diabetic nephropathy.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Síndrome Metabólico/genética , Monoéster Fosfórico Hidrolasas/genética , Adulto , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 1/epidemiología , Nefropatías Diabéticas/epidemiología , Femenino , Finlandia/epidemiología , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Síndrome Metabólico/epidemiología , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Polimorfismo de Nucleótido Simple/genética , Factores Sexuales , Fumar/epidemiologíaRESUMEN
The molecular control of self-renewal and differentiation of stem cells has remained enigmatic. Transgenic loss-of-function and overexpression models now show that the dosage of glial cell line-derived neurotrophic factor (GDNF), produced by Sertoli cells, regulates cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis. Gene-targeted mice with one GDNF-null allele show depletion of stem cell reserves, whereas mice overexpressing GDNF show accumulation of undifferentiated spermatogonia. They are unable to respond properly to differentiation signals and undergo apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors are regularly formed in older GDNF-overexpressing mice. Thus, GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.
Asunto(s)
Proteínas de Drosophila , Factores de Crecimiento Nervioso , Proteínas del Tejido Nervioso/fisiología , Espermatogénesis , Espermatogonias/citología , Células Madre/citología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular , Diferenciación Celular/efectos de los fármacos , Cobalto/metabolismo , Femenino , Expresión Génica , Marcación de Gen , Factor Neurotrófico Derivado de la Línea Celular Glial , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Masculino , Ratones , Ratones Transgénicos , Mitosis , Proteínas del Tejido Nervioso/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Células de Sertoli/citología , Células de Sertoli/fisiología , Espermatogonias/efectos de los fármacos , Neoplasias Testiculares/patología , Testículo/anatomía & histología , Vitamina A/farmacologíaRESUMEN
High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.