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INTRODUCTION: Complications of Type 1 diabetes (T1DM) remain prevalent due to suboptimal glycaemic control despite advances in analogue insulin, its delivery and technological advances in glucose monitoring. Intensive insulin therapy is associated with hypoglycaemia and weight gain. Non-insulin-dependent glucose lowering strategies may provide a strategy in improving glycaemic control without hypoglycaemia and weight gain. SOURCES OF DATA: Research papers and reviews about adjunctive treatment with insulin in T1DM in the published literature. AREAS OF AGREEMENT: Non-insulin-dependent strategies may be beneficial inT1DM particularly when there is insulin resistance, but the evidence for benefit at the current time is limited. Although there have been trials with various drugs as adjunctive therapy to insulin in T1DM currently in the UK, there is only one sodium glucose transport protein 2 (SGLT2) inhibitor with a marketing authorization for use in this indication. AREAS OF CONTROVERSY: Potential for harm with SGLT2 inhibitors in T1DM is a potential issue, particularly euglycaemic diabetic ketoacidosis. Clinical trials confirm that there is a risk albeit small, but emerging safety data have led to questions as to whether the risk of euglycaemic diabetic ketoacidosis is higher with the use of SGLT2 inhibitors in clinical practice. GROWING POINTS: Patient education is paramount-the work being done in T1DM to ensure safe use of SGLT2 inhibitors may help improve safety in the prescribing of SGLT2 inhibitors in Type 2 diabetes. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need for larger clinical trials with SGLT2 inhibitors in T1DM and real world studies to clarify safety.
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Diabetes Mellitus Tipo 1 , Insulina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Quimioterapia Adyuvante , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina/administración & dosificación , Insulina/efectos adversos , Evaluación de Necesidades , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na+-K+-2Cl- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m2), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mmâ Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mmâ Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mmâ Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897.
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Glucocorticoids, also known as steroids, are a class of anti-inflammatory drugs utilised widely in clinical practice for a variety of conditions. They are associated with a range of side effects including abnormalities of glucose metabolism. Multiple guidelines have been published to illustrate best management of glucocorticoid-induced hyperglycaemia and diabetes in a variety of settings. This article discusses current best clinical practice including diagnosis, investigations and ongoing management of glucocorticoid-induced dysglycaemia in both in- and outpatient settings.
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1. This study explored the role of the potassium ion in endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine coronary artery. 2. Bradykinin-induced, EDHF-mediated vasodilatation was blocked by the Na(+)-K(+) ATPase inhibitor, ouabain (1 micro M), in a time-dependent manner, with maximal blockade seen after 90 min. In contrast, the K(IR) channel inhibitor, Ba(2+) (30 micro M), had no effect. 3. When the potassium content of the bathing solution was increased in a single step from 5.9 to 7-19 mM, powerful vasodilatation (max. 75.9+/-3.6%) was observed. Vasodilatation was transient and, consequently, cumulative addition of potassium produced little vasodilatation, with vasoconstriction predominating at the higher concentrations. 4. The magnitude of potassium-induced vasodilatation was similar in endothelium-containing and endothelium-denuded rings, and was unaffected by Ba(2+) (30 micro M), but abolished by ouabain (1 micro M). 5. Ouabain (1 micro M, 90 min) powerfully blocked bradykinin-induced, nitric oxide-mediated vasodilatation as well as that induced by the nitrovasodilator, glyceryl trinitrate, but that induced by the K(ATP) channel opener, levcromakalim, was hardly affected. 6. Thus, activation of Na(+)-K(+) ATPase is likely to be involved in the vasodilator responses of the bovine coronary artery to both nitric oxide and EDHF. These findings, together with the ability of potassium to induce powerful, ouabain- but not Ba(2+)-sensitive, endothelium-independent vasodilatation, are consistent with this ion contributing to the EDHF response in this tissue.
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Factores Biológicos/fisiología , Vasos Coronarios/fisiología , Potasio/fisiología , Vasodilatación/fisiología , Animales , Bradiquinina/farmacología , Cationes Monovalentes/farmacología , Bovinos , Vasos Coronarios/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Técnicas In Vitro , Ouabaína/farmacología , Potasio/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.
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Intolerancia a la Glucosa/genética , Glucógeno Sintasa Quinasa 3/biosíntesis , Glucógeno Sintasa Quinasa 3/genética , Músculo Esquelético/fisiología , Regiones Promotoras Genéticas/fisiología , Animales , Western Blotting , Composición Corporal/fisiología , Peso Corporal/fisiología , Cartilla de ADN , ADN Complementario/biosíntesis , ADN Complementario/genética , Femenino , Prueba de Tolerancia a la Glucosa , Glucógeno/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Proteínas Sustrato del Receptor de Insulina , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Lípidos/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Fenotipo , Fosfoproteínas/biosíntesis , Fosfoproteínas/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Se identificó la visión de las IPS que ejecutan labores odontológicas y se determinaron los parámetros que manejan las diferentes IPS de la ciudad de Medellín para elegir sus odontólogos y se analizaron las ventajas y desventajas en el campo laboral que tiene el odontólogo egresado del CES, al compararlo con los egresados de otras universidades. La recolección de datos se hizo por medios de encuestas a las personas encargadas de la contratación del personal para elaborar en el área odontológica de las IPS seleccionas. Se encontró que a nivel general el odontólogo del CES goza de una buena aceptación en las diferentes IPS, a su vez, se identificó que dicho odontólogo posee fortalezas como la disciplina, la preparación académica y ser un profesional integral. Estas características hacen que el odontólogo egresado del CES sea un Profesional competitivo, ubicándose en los primeros lugares de selección en una IPS. También se analizaron las debilidades de los odontólogos y las áreas en que este debe enfatizar; entre ellas se encontró el diagnóstico clínico, la aspiración salarial, la humildad y la dificultad para relacionarse en los equipos e trabajo. Se puede concluir que el odontólogo egresado del CES se encuentra posicionado en los primeros lugares en el momento de la selección de personal para laborar en las IPS de la ciudad de Medellín, convirtiéndolo en un profesional idóneo aunque con falencias que de cierto modo influyen en el momento de su contratación...