RESUMEN
The recently CE-marked continuous real-time glucose monitoring (rtCGM) solution Accu-Chek® (AC) SmartGuide Solution was developed to enable people with diabetes mellitus (DM) to proactively control their glucose levels using predictive technologies. The comprehensive solution consists of three components that harmonize well with each other. The CGM device is composed of a sensor applicator and a glucose sensor patch whose data are transferred to the connected smartphone by Bluetooth® Low Energy. The user interface of the CGM solution is powered by the AC SmartGuide app delivering current and past glucose metrics, and the AC SmartGuide Predict app providing a glucose prediction suite enabled by artificial intelligence (AI). This article describes the innovative CGM solution.
RESUMEN
sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.
Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Modificación Traduccional de las Proteínas/fisiología , Secuencias de Aminoácidos/genética , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Animales , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Datos de Secuencia Molecular , Células PC12 , Unión Proteica/genética , Dominios y Motivos de Interacción de Proteínas/genética , Modificación Traduccional de las Proteínas/genética , Transporte de Proteínas/genética , RatasRESUMEN
AIMS: Certain systems for self-monitoring of blood glucose (SMBG) demonstrate inaccuracy at low and high hematocrit (HCT). Manufacturers define HCT ranges for accurate performance. Our objective was to assess the frequency of HCT values that can lead to clinically relevant errors. METHODS: In this cross-sectional study, we collected real-world data representing over 360,000 outpatients from the Netherlands (NL), the Czech Republic (CZ), and South Africa (ZA). These were subsequently stratified by sex and age and compared to commonly specified HCT range limits, reference intervals, and data from 1780 healthy Czech subjects. RESULTS: HCT values were comparably distributed in NL and CZ. Outpatients had a higher dispersion of values than healthy subjects. Low HCT values in Europe were common in age groups with a high prevalence of diabetes. All ZA age groups showed a higher prevalence of low HCT than in Europe. CONCLUSIONS: Real-world data indicate that SMBG systems specified to perform only within the frequently used 30-55% HCT range would leave 3% of outpatients in Europe and 18% in South Africa at risk of false SMBG results, with individual age strata being substantially higher. This could affect their diabetes management. Adequate SMBG systems should thus be chosen.
Asunto(s)
Automonitorización de la Glucosa Sanguínea , Glucemia , Estudios Transversales , Europa (Continente)/epidemiología , Hematócrito , Humanos , SudáfricaRESUMEN
Proper control of NaCl excretion in the kidney is central to bodily functions, yet many mechanisms that regulate reabsorption of sodium and chloride in the kidney remain incompletely understood. Here, we identify an important role played by the intracellular sorting receptor SORLA (sorting protein-related receptor with A-type repeats) in functional activation of renal ion transporters. We demonstrate that SORLA is expressed in epithelial cells of the thick ascending limb (TAL) of Henle's loop and that lack of receptor expression in this cell type in SORLA-deficient mice results in an inability to properly reabsorb sodium and chloride during osmotic stress. The underlying cellular defect was correlated with an inability of the TAL to phosphorylate Na(+)-K(+)-Cl(-) cotransporter 2 (NKCC2), the major sodium transporter in the distal nephron. SORLA functionally interacts with Ste-20-related proline-alanine-rich kinase (SPAK), an activator of NKCC2, and receptor deficiency is associated with missorting of SPAK. Our data suggest a novel regulatory pathway whereby intracellular trafficking of SPAK by the sorting receptor SORLA is crucial for proper NKCC2 activation and for maintenance of renal ion balance.
Asunto(s)
Riñón/enzimología , Proteínas de Transporte de Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de LDL/metabolismo , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Animales , Sistema Endocrino/metabolismo , Canales Epiteliales de Sodio/metabolismo , Homeostasis , Inmunohistoquímica , Iones/metabolismo , Riñón/citología , Riñón/metabolismo , Riñón/ultraestructura , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/deficiencia , Ratones , Modelos Biológicos , Canales de Potasio de Rectificación Interna/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Transporte de Proteínas , Receptores de LDL/química , Receptores de LDL/deficiencia , Sales (Química)/metabolismo , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , Miembro 1 de la Familia de Transportadores de Soluto 12 , Fracciones Subcelulares/metabolismo , Extractos de TejidosRESUMEN
Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid beta-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with pro-found stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.
Asunto(s)
Envejecimiento/fisiología , Precursor de Proteína beta-Amiloide/metabolismo , Diferenciación Celular , Sistema de Señalización de MAP Quinasas , Proteínas de Transporte de Membrana/metabolismo , Neuronas/citología , Neuronas/metabolismo , Receptores de LDL/metabolismo , Animales , Electrofisiología , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Noqueados , Técnicas de Placa-Clamp , Receptores de LDL/deficiencia , Receptores de LDL/genéticaRESUMEN
Megalin is a member of the LDL receptor gene family that plays an important role in forebrain development and in cellular vitamin D metabolism through endocytic uptake of vitamin D metabolites. Similar to other receptors in this gene family, megalin is believed to functionally interact with intracellular proteins through adaptors that bind to the receptor tail and regulate its endocytic and signal transducing activities. Using yeast two-hybrid screens, we identified a novel scaffold protein with tetratrico peptide repeats, the megalin-binding protein (MegBP) that associates with the receptor. The binding site of MegBP was mapped to an N-terminal region on the receptor tail harboring a proline-rich peptide element. MegBP binding did not block the endocytic activity of the receptor; however, overexpression resulted in cellular lethality. In further screens, we identified proteins that bound to MegBP and thus might be recruited to the megalin tail. MegBP-interacting partners included several transcriptional regulators such as the SKI-interacting protein (SKIP), a co-activator of the vitamin D receptor. These finding suggest a model whereby megalin directly participates in transcriptional regulation through controlled sequestration or release of transcription factors via MegBP.