RESUMEN
Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.
Asunto(s)
Resistencia a la Insulina/genética , Fosfoproteínas Fosfatasas/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Adulto , Anciano , Animales , Células CHO , Cricetinae , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Tipo 2/genética , Femenino , Mutación del Sistema de Lectura , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fosfoproteínas Fosfatasas/metabolismo , Proteína Fosfatasa 1 , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores de Transcripción/metabolismoRESUMEN
There is evidence that all hospital-based care needs to improve across 7 days. Inpatients with diabetes require better specialist attention and improved clinical outcomes. The East and North Herts inpatient diabetes service has responded to this challenge with care now delivered by consultants and diabetes nurses, 365 days per year. We set out to provide a prospectively measurable improvement in ascertainment of appropriate patients alongside a 'care bundle' to ensure they receive a better quality experience. We also set out to document quantifiable changes in clinical data. A seven-day service is now in place and provides a variety of benefits to both professionals and patients alike.
RESUMEN
Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.