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Renal protection is likely to be a class effect of SGLT-2 inhibitors and GLP-1RA. When used simultaneously, there may be a synergistic effect. Both agents are also safe to use in high renal risk patients (eGFR between 21 and 30 mL/min/1.73m2).
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OBJECTIVE: To evaluate a case of pembrolizumab-induced hypoparathyroidism leading to hypocalcemia. METHODS: The diagnostic tests performed included calcium and parathyroid hormone level detection and calcium-sensing receptor gene analysis. RESULTS: A 71-year-old Caucasian man was diagnosed with stage IIIB adenocarcinoma of the lung and received radiation therapy but had no other exposure to radiation. Pembrolizumab 200 mg intravenous every 3 weeks was started 5 years after the initial diagnosis. The patient's corrected calcium level was 9.2 mg/dL (normal, 8.5-10.5 mg/dL) at the start of pembrolizumab therapy. The calcium level after the 13th dose of pembrolizumab was 8.1 mg/dL (normal, 8.5-10.2 mg/dL), leading to endocrinology referral. The patient's parathyroid hormone and corrected calcium levels after the 22nd dose were 4.3 mg/dL (normal, 14-72 pg/mL) and 6.5 mg/dL (normal, 8.5-10.2 mg/dL), respectively. He denied symptoms of latent tetany on presentation while on pembrolizumab for 15 months but complained of fatigue and weakness. The patient had no history of autoimmune diseases or neck injuries. Calcium-sensing receptor gene analysis was negative for genetic mutations. Immunotherapy-mediated hypoparathyroidism was diagnosed. He was treated with daily oral calcium carbonate (2000 mg), calcitriol 0.5 µg, 1 dose of calcium gluconate 2 g intravenous, and 3 doses of calcium chloride 1 g intravenous. His fatigue, weakness, and calcium levels improved with therapy. CONCLUSION: Pembrolizumab treatment may have resulted in immune-mediated hypoparathyroidism, leading to hypocalcemia. It is important to report such cases to understand its presentation and timing in relation to pembrolizumab, which further facilitates its timely treatment.
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AIM: To investigate the effects of liraglutide treatment on glycaemic control and adipose tissue metabolism in overweight and obese people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS: A total of 84 adult overweight and obese patients with T1DM, with no detectable C-peptide, were randomized (1:1) to either placebo or 1.8 mg/d liraglutide for 6 months. Blood samples were collected at 0, 12 and 26 weeks. Subcutaneous adipose tissue biopsies, a high-calorie high-fat meal challenge test, continuous glucose monitoring, dual-energy X-ray absorptiometry and MRI were performed before and at the end of treatment. RESULTS: In all, 37 and 27 patients who received liraglutide and placebo, respectively, completed the study. Glycated haemoglobin fell by 0.41 ± 0.18% (4.5±1.4 mmol/mol) from baseline after liraglutide treatment (P = 0.001), and by 0.29 ± 0.19% (3.1±2.0 mmol/mol) compared to placebo (P = 0.1). There was no increase in hypoglycaemia, while the time spent in normal glycaemia increased (P = 0.015) and time spent in hyperglycaemia decreased (P = 0.019). Body weight fell significantly in the liraglutide group, mostly in the form of fat mass loss (including visceral fat), with no change in lean mass. Systolic blood pressure (SBP) also fell after liraglutide treatment. Liraglutide also caused a significant increase in the expression of adipose tissue triglyceride lipase, carnitine palmitoyl transferase-1, peroxisome proliferator-activated receptor (PPAR)α, PPARδ, uncoupling protein-2 and type 2 iodothyronine deiodinase in the adipose tissue. CONCLUSIONS: Liraglutide improves glycaemia, reduces adiposity and SBP. Liraglutide also stimulates mechanisms involved with an increase in lipid oxidation and thermogenesis, while conserving lean body mass.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Glucemia , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Método Doble Ciego , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Liraglutida/uso terapéutico , Obesidad/complicaciones , Sobrepeso/complicaciones , Sobrepeso/tratamiento farmacológico , Resultado del Tratamiento , Pérdida de PesoRESUMEN
CONTEXT: Adenosine 5'-monophosphate-activated protein kinase-α (AMPKα) is a mediator of exercise-induced glucose uptake in skeletal muscle. OBJECTIVE: We evaluated whether AMPKα expression and phosphorylation are reduced in skeletal muscle and adipose tissue of patients with hypogonadotropic hypogonadism (HH), and whether testosterone replacement therapy results in restoration of the expression and phosphorylation of AMPKα. DESIGN: This is a secondary analysis of a previously completed trial that showed an insulin-sensitizing effect of testosterone therapy in men with type 2 diabetes and HH. SETTING: Clinical research center at university. PATIENTS: Thirty-two men with HH and 32 eugonadal men were compared at baseline. INTERVENTIONS: Men with HH were treated with intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Quadriceps muscle biopsies and subcutaneous abdominal fat biopsies were obtained before and after 4-hour euglycemic hyperinsulinemic clamp, prior to and after testosterone or placebo therapy. OUTCOME MEASURES AND RESULTS: mRNA expression of AMPKα in hypogonadal men was lower by 37% in adipose tissue and 29% in skeletal muscle, respectively, compared with levels in eugonadal men, while phosphorylated AMPKα was lower by 22% and 28%, respectively. Following testosterone replacement, the expression of AMPKα did not alter in the fasting state but increased markedly by 41% and 46% in adipose tissue and muscle, respectively, after the clamp. In contrast, phosphorylated AMPKα increased by 69% in muscle after testosterone therapy but did not change following the clamp. CONCLUSIONS: Testosterone modulates the expression of AMPKα and phosphorylated AMPKα. These effects may contribute to the improved insulin sensitivity following testosterone therapy.
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Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Terapia de Reemplazo de Hormonas/métodos , Hipogonadismo/tratamiento farmacológico , Testosterona/farmacología , Adulto , Anciano , Biomarcadores/análisis , Estudios de Seguimiento , Humanos , Hipogonadismo/enzimología , Hipogonadismo/epidemiología , Masculino , Persona de Mediana Edad , Fosforilación , Pronóstico , Estados Unidos/epidemiologíaRESUMEN
CONTEXT: Fibroblast growth factor (FGF)2 is an important stimulatory modulator of satellite cells in skeletal muscle. Satellite cells play a cardinal role in muscle growth and repair. OBJECTIVE: We evaluated whether skeletal muscle expression of FGF2 and muscle growth and differentiation factors are reduced in patients with hypogonadotropic hypogonadism (HH) and whether testosterone replacement therapy results in their restoration. DESIGN: This is a secondary analysis of a previously completed trial of testosterone replacement in men with type 2 diabetes and HH. SETTING: Clinical Research Center at a university. PATIENTS: Twenty-two men with HH and 20 eugonadal men were compared at baseline. INTERVENTIONS: Twelve men with HH were treated with intramuscular injections of 250 mg testosterone every 2 weeks for 22 weeks, and 10 men received placebo injections. Quadriceps muscle biopsies and blood samples were obtained before and after testosterone therapy. OUTCOME MEASURES AND RESULTS: The expression of FGF2 and FGF receptor (FGFR)2 in skeletal muscle of men with HH was significantly lower than that in eugonadal men by 57% and 39%, respectively (P < 0.05). After 22 weeks of testosterone, the expression of FGF2 increased, whereas that of myogenic regulatory factor (MRF)4 and myostatin decreased significantly. There was no change in expression of FGFR2, myogenin, or myogenic differentiation protein in the skeletal muscle. Plasma FGF2 and IGF-1 concentrations increased after testosterone therapy. CONCLUSIONS: These data show that testosterone is a major modulator of FGF2, MRF4, and myostatin expression in skeletal muscle. These effects may contribute to the increase in muscle mass after testosterone therapy.
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Factor 2 de Crecimiento de Fibroblastos/sangre , Hipogonadismo/tratamiento farmacológico , Músculo Esquelético/efectos de los fármacos , Factores Reguladores Miogénicos/genética , Miostatina/sangre , Testosterona/farmacología , Adulto , Anciano , Factor 2 de Crecimiento de Fibroblastos/genética , Humanos , Hipogonadismo/fisiopatología , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana Edad , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
We aimed to test the hypothesis that addition of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to insulin in C-peptide-positive patients with type 1 diabetes (T1D) will result in a reduction in glycated haemoglobin (HbA1c) with reduced insulin requirements and a rise in C-peptide concentrations. We conducted a retrospective analysis of 11 normal-weight patients with T1D consecutively treated with a GLP-1RA in addition to insulin. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, and C-peptide concentrations prior to and 12 ± 1 weeks after GLP-1RA therapy. At the end of 12 ± 1 weeks of GLP-1RA therapy, HbA1c fell from 10.74 ± 0.96% (95 ± 10.5 mmol/mol) to 7.4 ± 0.58% (58 ± 6.3mmol/mol) (P < 0.01), body weight fell from 71 ± 2.0 to 69 ± 2 kg (P = 0.06), and total insulin dose was reduced by 64% from 33 ± 6 to 11 ± 5 units (P < 0.01). Five out of 10 patients did not require any insulin. C-peptide concentrations increased significantly from 0.43 ± 0.09 ng/ml (0.14 ± 0.02 nmol/L) to 1.42 ± 0.42ng/ml (0.47 ± 0.13 nmol/L) (P = 0.01). Addition of GLP-1RA therapy to insulin in normal-weight patients with T1D led to a reduction in HbA1c with reduced insulin requirements, a 3.5-fold increase in C-peptide concentrations and freedom from insulin therapy in 50% of patients who tolerated the GLP-1RA therapy over a period of 12 ± 1 weeks.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Insulina/uso terapéutico , Liraglutida/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Autoanticuerpos/inmunología , Peso Corporal , Péptido C/metabolismo , Deprescripciones , Diabetes Mellitus Tipo 1/metabolismo , Quimioterapia Combinada , Femenino , Péptidos Similares al Glucagón/uso terapéutico , Glutamato Descarboxilasa/inmunología , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Pérdida de PesoAsunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inducido químicamente , Antitiroideos/efectos adversos , Enfermedad de Graves/tratamiento farmacológico , Propiltiouracilo/efectos adversos , Enfermedades de la Piel/inducido químicamente , Adulto , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Anticuerpos Antinucleares/inmunología , Femenino , Humanos , Mieloblastina/inmunología , Peroxidasa/inmunología , Piel/patología , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/patologíaRESUMEN
AIMS: One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression. MATERIALS AND METHODS: This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism. RESULTS: The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men. CONCLUSIONS: We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits.
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Andrógenos/uso terapéutico , Aromatasa/genética , Diabetes Mellitus Tipo 2/metabolismo , Receptor alfa de Estrógeno/genética , Hipogonadismo/tratamiento farmacológico , Leucocitos Mononucleares/metabolismo , Receptores Androgénicos/genética , Testosterona/uso terapéutico , Adulto , Anciano , Aromatasa/metabolismo , Western Blotting , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Receptor alfa de Estrógeno/metabolismo , Humanos , Hipogonadismo/complicaciones , Hipogonadismo/genética , Hipogonadismo/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Grasa Subcutánea/metabolismoRESUMEN
Purpose: We previously demonstrated the anti-inflammatory and antioxidant effects of exenatide. We now hypothesized that exenatide also increases the plasma concentration of interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein, and modulates the nuclear factor erythroid 2ârelated factorâKelchlike ECH-associated protein 1âantioxidant response element (Nrf-2âKeap-1âARE) system to induce key antioxidant enzymes to suppress inflammatory and oxidative stress. Methods: Twenty-four patients with obesity and type 2 diabetes receiving combined oral and insulin therapy were randomly assigned to receive either exenatide 10 µg or placebo twice a day for 12 weeks. Results: Exenatide increased IL-1RA concentration by 61% (from 318 ± 53 to 456 ± 88 pg/mL; P < 0.05). Exenatide treatment also suppressed Keap-1 protein (P < 0.05) and increased messenger RNA expression of NQO-1, glutathione S-transferase PI, heme oxygenase-1, and p21 and increased NAD(P)H dehydrogenase [quinone] 1 protein (P < 0.05) in mononuclear cells. Conclusions: Because IL-1RA protects, maintains, and stimulates ß-cell function in humans and Nrf-2âKeap-1âARE protects ß cells in animals with experimental diabetes, these actions of exenatide may contribute to a potential protective effect on ß cells in diabetes.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Proteína Antagonista del Receptor de Interleucina 1/sangre , Obesidad/tratamiento farmacológico , Péptidos/farmacología , Ponzoñas/farmacología , Elementos de Respuesta Antioxidante/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Quimioterapia Combinada , Inducción Enzimática/efectos de los fármacos , Exenatida , Femenino , Gutatión-S-Transferasa pi/biosíntesis , Hemo-Oxigenasa 1/biosíntesis , Humanos , Insulina/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/efectos de los fármacos , Masculino , Persona de Mediana Edad , NAD(P)H Deshidrogenasa (Quinona)/biosíntesis , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Obesidad/sangre , Obesidad/complicacionesRESUMEN
BACKGROUND AND AIMS: Inflammation and postprandial lipemia are associated with increased cardiovascular disease. We investigated whether ezetimibe and simvastatin combination, a lipid lowering combination of simvastatin and ezetimibe, exerts an anti-inflammatory effect in the fasting state and after dairy cream intake. METHODS: Twenty obese patients were randomized to either ezetimibe and simvastatin combination or placebo treatment for 6 weeks. All patients were asked to ingest 33 ml of dairy cream (300 Calories) at the beginning and at the end of intervention. Fasting and post-cream blood samples were obtained. RESULTS: At 0 week, ingestion of cream induced significant increases in MNC expression of IL-1ß (105 ± 18%), TNFα (97 ± 12%), CD68 (48 ± 8%), CD16 (141 ± 39%), MMP-9 (122 ± 31%), PECAM (66 ± 10%), TLR-4 (84 ± 11%) and TLR-2 (67 ± 9%) and in endotoxin (LPS) concentrations (49 ± 7%) (p < 0.05). Ezetimibe and simvastatin combination treatment lowered fasting total cholesterol, LDLc and Lp(a) concentrations and Apo B/A1 ratio and suppressed the MNC expression of IL-1ß and CD68 (by 21 ± 7 and 24 ± 10, p < 0.05) and the concentrations of LPS, CRP, FFA and IL-18 by 24 ± 7%, 32 ± 11%, 19 ± 8% 15 ± 4%, respectively, (p < 0.05). Cream-induced increases in the expression of IL-1ß, CD68, CD16, MMP-9, TNFα and PECAM were reduced in the ezetimibe and simvastatin combination group by 74 ± 15%, 68 ± 13%, 57 ± 13%, 64 ± 16%, 67 ± 14% and 45 ± 9%, respectively, while those of LPS and MMP-9 concentrations were reduced by 53 ± 9% and 38 ± 8%, respectively, compared to the increases at week 0 (p < 0.05). There was a suppression of TLR-2 and TLR-4 expression by 21 ± 8% and 18 ± 7%, respectively, compared to 0-h baseline, after cream intake following ezetimibe and simvastatin combination treatment. CONCLUSIONS: Ezetimibe and simvastatin combination exerts a profound anti-inflammatory effect both in the fasting state and acutely after the ingestion of saturated fat.
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Anticolesterolemiantes/uso terapéutico , Productos Lácteos/efectos adversos , Combinación Ezetimiba y Simvastatina/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/prevención & control , Inflamación/prevención & control , Obesidad/tratamiento farmacológico , Adulto , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Método Doble Ciego , Combinación Ezetimiba y Simvastatina/efectos adversos , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hiperlipidemias/sangre , Hiperlipidemias/diagnóstico , Hiperlipidemias/etiología , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/etiología , Mediadores de Inflamación/sangre , Lípidos/sangre , Masculino , Persona de Mediana Edad , New York , Obesidad/sangre , Obesidad/diagnóstico , Periodo Posprandial , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
In view of the occurrence of diabetic ketoacidosis associated with the use of sodium-glucose transport protein-2 inhibitors in patients with type 1 diabetes (T1DM) and the relative absence of this complication in patients treated with liraglutide in spite of reductions in insulin doses, we investigated the effect of liraglutide on ketogenesis. Twenty-six patients with inadequately controlled T1DM were randomly divided into 2 groups of 13 patients each. After an overnight fast, patients were injected, subcutaneously, with either liraglutide 1.8 mg or with placebo. They were maintained on their basal insulin infusion and were followed up in our clinical research unit for 5 hours. The patients injected with placebo maintained their glucose and glucagon concentrations without an increase, but there was a significant increase in free fatty acids (FFA), acetoacetate and ß-hydoxybutyrate concentrations. In contrast, liraglutide significantly reduced the increase in FFA, and totally prevented the increase in acetoacetate and ß-hydroxybutyrate concentrations while suppressing glucagon and ghrelin concentrations. Thus, a single dose of liraglutide is acutely inhibitory to ketogenesis.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Glucagón/antagonistas & inhibidores , Hipoglucemiantes/uso terapéutico , Cuerpos Cetónicos/antagonistas & inhibidores , Lipólisis/efectos de los fármacos , Liraglutida/uso terapéutico , Adulto , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Método Doble Ciego , Resistencia a Medicamentos , Quimioterapia Combinada , Ácidos Grasos no Esterificados/antagonistas & inhibidores , Ácidos Grasos no Esterificados/sangre , Femenino , Ghrelina/antagonistas & inhibidores , Ghrelina/sangre , Glucagón/sangre , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Inyecciones Subcutáneas , Insulina/administración & dosificación , Insulina/uso terapéutico , Sistemas de Infusión de Insulina , Cuerpos Cetónicos/biosíntesis , Cuerpos Cetónicos/sangre , Liraglutida/administración & dosificación , Masculino , Persona de Mediana EdadRESUMEN
Background: Fiber intake is associated with a reduction in the occurrence of cardiovascular events and diabetes. Objective: To investigate whether the addition of fiber to a high-fat, high-calorie (HFHC) meal prevents proinflammatory changes induced by the HFHC meal. Design: Ten normal fasting subjects consumed an HFHC meal with or without an additional 30 g of insoluble dietary fiber on 2 separate visits. Blood samples were collected over 5 hours, and mononuclear cells (MNCs) were isolated. Results: Fiber addition to the HFHC meal significantly lowered glucose excursion in the first 90 minutes and increased insulin and C-peptide secretion throughout the 5-hour follow-up period compared with the meal alone. The HFHC meal induced increases in lipopolysaccharide (LPS) concentrations, MNC reactive oxygen species generation, and the expression of interleukin (IL)-1ß, tumor necrosis factor α (TNF-α), Toll-like receptor (TLR)-4, and CD14. The addition of fiber prevented an increase in LPS and significantly reduced the increases in ROS generation and the expression of IL-1ß, TNF-α, TLR-4, and CD14. In addition, the meal increased Suppressor of cytokine signaling (SOCS)-3 and protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and protein levels, which were inhibited when fiber was added. Conclusions: The addition of fiber to a proinflammatory HFHC meal had beneficial anti-inflammatory and metabolic effects. Thus, the fiber content of the American Heart Association meal may contribute to its noninflammatory nature. If these actions of dietary fiber are sustained following long-term intake, they may contribute to fiber's known benefits in the prevention of insulin resistance, type 2 diabetes, and atherosclerosis.
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Glucemia/efectos de los fármacos , Dieta Alta en Grasa , Fibras de la Dieta/farmacología , Ingestión de Energía , Leucocitos Mononucleares/efectos de los fármacos , Comidas , Periodo Posprandial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Adulto , Glucemia/metabolismo , Péptido C/efectos de los fármacos , Péptido C/metabolismo , Femenino , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/inmunología , Leucocitos Mononucleares/inmunología , Receptores de Lipopolisacáridos/efectos de los fármacos , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Periodo Posprandial/inmunología , Periodo Posprandial/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/efectos de los fármacos , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/efectos de los fármacos , Proteína 3 Supresora de la Señalización de Citocinas/genética , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/inmunología , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/inmunología , Adulto JovenRESUMEN
CONTEXT: It is imperative that novel approaches to treatment of type 1 diabetes (T1D) are devised. OBJECTIVE: The objective of the study was to investigate whether addition of dapagliflozin to insulin and liraglutide results in a significant reduction in glycemia and body weight. DESIGN: This was a randomized clinical trial. SETTING: The study was conducted at a single academic medical center. PARTICIPANTS: Participants included T1D patients on liraglutide therapy for at least last 6 months. INTERVENTION: Thirty T1D patients were randomized (in 2:1 ratio) to receive either dapagliflozin 10 mg or placebo daily for 12 weeks. MAIN OUTCOME MEASURE: Change in mean glycated hemoglobin after 12 weeks of dapagliflozin when compared with placebo was measured. RESULTS: In the dapagliflozin group, glycated hemoglobin fell by 0.66% ± 0.08% from 7.8% ± 0.21% (P < .01 vs placebo), whereas it did not change significantly in the placebo group from 7.40% ± 0.20% to 7.30% ± 0.20%. The body weight fell by1.9 ± 0.54kg (P < .05 vs placebo). There was no additional hypoglycemia (blood glucose < 3.88 mmol/L; P = .52 vs placebo). In the dapagliflozin group, there were significant increases in the plasma concentrations of glucagon by 35% ± 13% (P < .05), hormone-sensitive lipase by 29% ± 11% (P < .05), free fatty acids by 74% ± 32% (P < .05), acetoacetate by 67% ± 34% (P < .05), and ß-hydroxybutyrate by 254% ± 81% (P < .05). Urinary ketone levels also increased significantly (P < .05). None of these changes was observed in the placebo group. Two patients in the dapagliflozin group developed diabetic ketoacidosis. CONCLUSIONS: Addition of dapagliflozin to insulin and liraglutide in patients with T1D results in a significant improvement in glycemia and weight loss while increasing ketosis. If it is decided to use this approach, then it must be used only by a knowledgeable patient along with an endocrinologist who is well versed with it.
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Compuestos de Bencidrilo/uso terapéutico , Biomarcadores/análisis , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Liraglutida/uso terapéutico , Adolescente , Adulto , Anciano , Glucemia/análisis , Diabetes Mellitus Tipo 1/metabolismo , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
CONTEXT: As the syndrome of hypogonadotropic hypogonadism (HH) is associated with anaemia and the administration of testosterone restores haematocrit to normal, we investigated the potential underlying mechanisms. DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: We measured basal serum concentrations of erythropoietin, iron, iron binding capacity, transferrin (saturated and unsaturated), ferritin and hepcidin and the expression of ferroportin and transferrin receptor (TR) in peripheral blood mononuclear cells (MNC) of 94 men with type 2 diabetes. Forty-four men had HH (defined as subnormal free testosterone along with low or normal LH concentrations) while 50 were eugonadal. Men with HH were randomized to testosterone or placebo treatment every 2 weeks for 15 weeks. Blood samples were collected at baseline, 3 and 15 weeks after starting treatment. Twenty men in testosterone group and 14 men in placebo group completed the study. RESULTS: Haematocrit levels were lower in men with HH (41·1 ± 3·9% vs 43·8 ± 3·4%, P = 0·001). There were no differences in plasma concentrations of hepcidin, ferritin, erythropoietin, transferrin or iron, or in the expression of ferroportin or TR in MNC among HH and eugonadal men. Haematocrit increased to 45·3 ± 4·5%, hepcidin decreased by 28 ± 7% and erythropoietin increased by 21 ± 7% after testosterone therapy (P < 0·05). There was no significant change in ferritin concentrations, but transferrin concentration increased while transferrin saturation and iron concentrations decreased (P < 0·05). Ferroportin and TR mRNA expression in MNC increased by 70 ± 13% and 43 ± 10%, respectively (P < 0·01), after testosterone therapy. CONCLUSIONS: The increase in haematocrit following testosterone therapy is associated with an increase in erythropoietin, the suppression of hepcidin, and an increase in the expression of ferroportin and TR.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ferritinas/efectos de los fármacos , Hepcidinas/efectos de los fármacos , Hipogonadismo/tratamiento farmacológico , Hierro/metabolismo , Testosterona/farmacología , Adulto , Anciano , Proteínas de Transporte de Catión/biosíntesis , Proteínas de Transporte de Catión/sangre , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Eritropoyetina/sangre , Ferritinas/sangre , Hematócrito , Hepcidinas/sangre , Humanos , Hipogonadismo/sangre , Hierro/sangre , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Transferrina/biosíntesis , Receptores de Transferrina/sangreRESUMEN
OBJECTIVE: To investigate whether addition of three different doses of liraglutide to insulin in patients with type 1 diabetes (T1D) results in significant reduction in glycemia, body weight, and insulin dose. RESEARCH DESIGN AND METHODS: We randomized 72 patients (placebo = 18, liraglutide = 54) with T1D to receive placebo and 0.6, 1.2, and 1.8 mg liraglutide daily for 12 weeks. RESULTS: In the 1.2-mg and 1.8-mg groups, the mean weekly reduction in average blood glucose was -0.55 ± 0.11 mmol/L (10 ± 2 mg/dL) and -0.55 ± 0.05 mmol/L (10 ± 1 mg/dL), respectively (P < 0.0001), while it remained unchanged in the 0.6-mg and placebo groups. In the 1.2-mg group, HbA1c fell significantly (-0.78 ± 15%, -8.5 ± 1.6 mmol/mol, P < 0.01), while it did not in the 1.8-mg group (-0.42 ± 0.15%, -4.6 ± 1.6 mmol/mol, P = 0.39) and 0.6-mg group (-0.26 ± 0.17%, -2.8 ± 1.9 mmol/mol, P = 0.81) vs. the placebo group (-0.3 ± 0.15%, -3.3 ± 1.6 mmol/mol). Glycemic variability was reduced by 5 ± 1% (P < 0.01) in the 1.2-mg group only. Total daily insulin dose fell significantly only in the 1.2-mg and 1.8-mg groups (P < 0.05). There was a 5 ± 1 kg weight loss in the two higher-dose groups (P < 0.05) and by 2.7 ± 0.6 kg (P < 0.01) in the 0.6-mg group vs. none in the placebo group. In the 1.2- and 1.8-mg groups, postprandial plasma glucagon concentration fell by 72 ± 12% and 47 ± 12%, respectively (P < 0.05). Liraglutide led to higher gastrointestinal adverse events (P < 0.05) and ≤1% increases (not significant) in percent time spent in hypoglycemia (<55 mg/dL, 3.05 mmol/L). CONCLUSIONS: Addition of 1.2 mg and 1.8 mg liraglutide to insulin over a 12-week period in overweight and obese patients with T1D results in modest reductions of weekly mean glucose levels with significant weight loss, small insulin dose reductions, and frequent gastrointestinal side effects. These findings do not justify the use of liraglutide in all patients with T1D.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Liraglutida/uso terapéutico , Adulto , Glucemia/metabolismo , Peso Corporal , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Método Doble Ciego , Quimioterapia Combinada , Femenino , Glucagón/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Sobrepeso/complicaciones , Periodo Posprandial , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. RESEARCH DESIGN AND METHODS: A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. RESULTS: Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-ß, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1ß, tumor necrosis factor-α, and leptin (P < 0.05 for all). CONCLUSIONS: Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.
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Diabetes Mellitus Tipo 2/complicaciones , Terapia de Reemplazo de Hormonas , Hipogonadismo/tratamiento farmacológico , Inflamación/sangre , Resistencia a la Insulina , Testosterona/uso terapéutico , Adulto , Composición Corporal , Proteína C-Reactiva/metabolismo , Ácidos Grasos no Esterificados/sangre , Humanos , Hipogonadismo/complicaciones , Insulina/uso terapéutico , Interleucina-1beta/sangre , Grasa Intraabdominal/metabolismo , Leptina/sangre , Masculino , Persona de Mediana Edad , Grasa Subcutánea/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND HYPOTHESIS: Following our recent demonstration that the chronic inflammatory and insulin resistant state of obesity is associated with an increase in the expression of mediators known to contribute to the pathogenesis of asthma and that weight loss after gastric bypass surgery results in the reduction of these genes, we have now hypothesized that insulin suppresses the cellular expression and plasma concentrations of these mediators. METHODS: The expression of IL-4, LIGHT, LTBR, ADAM-33, and TSLP in MNC and plasma concentrations of LIGHT, TGF-ß1, MMP-9, MCP-1, TSLP, and NOM in obese patients with T2DM were measured before, during, and after the infusion of a low dose (2 U/h) infusion of insulin for 4 hours. The patients were also infused with dextrose or saline for 4 hours on two separate visits and served as controls. Results. Following insulin infusion, the mRNA expression of IL-4, ADAM-33, LIGHT, and LTBR mRNA expression fell significantly (P < 0.05 for all). There was also a concomitant reduction in plasma NOM, LIGHT, TGF-ß1, MCP-1, and MMP-9 concentrations. CONCLUSIONS: Insulin suppresses the expression of these genes and mediators related to asthma and may, therefore, have a potential role in the treatment of asthma.
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Asma/sangre , Diabetes Mellitus Tipo 2/sangre , Regulación de la Expresión Génica , Inflamación/sangre , Insulina/metabolismo , Obesidad/metabolismo , Adulto , Glucemia/análisis , Índice de Masa Corporal , Estudios Cruzados , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Hemoglobina Glucada/metabolismo , Humanos , Infusiones Intravenosas , Insulina/administración & dosificación , Resistencia a la Insulina , Luminiscencia , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Especies Reactivas de Oxígeno , Pérdida de PesoRESUMEN
OBJECTIVE: Because approximately 40% of patients with type 1 diabetes have the metabolic syndrome, we tested the hypothesis that addition of liraglutide to insulin in obese patients with type 1 diabetes will result in an improvement in plasma glucose concentrations, a reduction in hemoglobin A1c (HbA1c), a fall in systolic blood pressure, and weight loss. METHODS: This is a retrospective analysis of data obtained from 27 obese patients with type 1 diabetes treated with liraglutide in addition to insulin. Patients were also treated for hypertension. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, 4-week mean blood glucose concentrations (28-day insulin pump mean blood glucose), blood pressure, and lipid parameters prior to and 180 ± 14 days after liraglutide therapy. RESULTS: Mean glucose concentrations fell from 191 ± 6 to 170 ± 6 mg/dL (P = .002). HbA1c fell from 7.89 ± 0.13% to 7.46 ± 0.13% (P = .001), without an increase in frequency of hypoglycemia. Mean body weight fell from 96.20 ± 3.68 kg to 91.56 ± 3.78 kg (P<.0001). Daily total and bolus doses of insulin fell from 73 ± 6 to 60 ± 4 (P = .008) units and from 40 ± 5 to 29 ± 3 units (P = .011), respectively. Mean systolic blood pressure fell from 130 ± 3 to 120 ± 4 mm Hg (P = .020). CONCLUSION: Addition of liraglutide to insulin in obese patients with type 1 diabetes mellitus leads to improvements in glycemic control and HbA1c and to reductions in insulin dose, systolic blood pressure, and body weight.