RESUMO
In view of the known vasodilatory effects of glucagon-like peptide-1 and exenatide, we investigated the effects of exenatide on vasoactive factors. We analysed blood samples and mononuclear cells (MNCs) from a previous study, collected after a single dose and 12 weeks of exenatide or placebo treatment in a series of 24 patients with type 2 diabetes mellitus. After exenatide treatment, plasma concentrations of atrial natriuretic peptide, cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate increased significantly at 12 weeks. Plasma cGMP and adenylate cyclase expression in MNCs increased significantly after a single dose. Angiotensinogen concentration fell significantly 2 hours after a single dose and at 12 weeks, while renin and angiotensin II levels fell significantly only after a single dose and not after 12 weeks of treatment. Exenatide also suppressed the plasma concentration of transforming growth factor-ß and the expression of P311 in MNCs at 12 weeks. Thus, exenatide induces an increase in a series of vasodilators, while suppressing the renin-angiotensin system. These changes may contribute to the overall vasodilatory effect of exenatide.
Assuntos
Anti-Hipertensivos/uso terapêutico , Fator Natriurético Atrial/agonistas , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Leucócitos Mononucleares/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas Oncogênicas/antagonistas & inibidores , Peptídeos/uso terapêutico , Peçonhas/uso terapêutico , Adenilil Ciclases/química , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Angiotensinogênio/antagonistas & inibidores , Angiotensinogênio/sangue , Fármacos Antiobesidade/uso terapêutico , Fator Natriurético Atrial/sangue , Pressão Sanguínea/efeitos dos fármacos , AMP Cíclico/agonistas , AMP Cíclico/sangue , GMP Cíclico/agonistas , GMP Cíclico/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Exenatida , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/imunologia , Obesidade/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Reprodutibilidade dos Testes , Método Simples-Cego , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/sangueRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Corpos Cetônicos/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Liraglutida/uso terapêutico , Adulto , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada , Ácidos Graxos não Esterificados/antagonistas & inibidores , Ácidos Graxos não Esterificados/sangue , Feminino , Grelina/antagonistas & inibidores , Grelina/sangue , Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Insulina/administração & dosagem , Insulina/uso terapêutico , Sistemas de Infusão de Insulina , Corpos Cetônicos/biossíntese , Corpos Cetônicos/sangue , Liraglutida/administração & dosagem , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ferritinas/efeitos dos fármacos , Hepcidinas/efeitos dos fármacos , Hipogonadismo/tratamento farmacológico , Ferro/metabolismo , Testosterona/farmacologia , Adulto , Idoso , Proteínas de Transporte de Cátions/biossíntese , Proteínas de Transporte de Cátions/sangue , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Eritropoetina/sangue , Ferritinas/sangue , Hematócrito , Hepcidinas/sangue , Humanos , Hipogonadismo/sangue , Ferro/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores da Transferrina/biossíntese , Receptores da Transferrina/sangueRESUMO
This study was conducted to investigate whether a high-fat/high-carbohydrate (HFHC) meal induces an increase in plasma concentrations of glucagon, dipeptidyl peptidase-IV (DPP-IV), and CD26 expression in mononuclear cells (MNC) while reducing insulin, C-peptide, proinsulin, GIP, and GLP-1 concentrations. Ten healthy normal subjects were given either a 910-calorie HFHC meal or an American Heart Association (AHA) meal rich in fruit and fiber during the first visit and the other meal during the second visit in crossover design. Blood samples were collected at baseline and at 15, 30, 45, 60, 75, 90, 120, 180, and 300 min following the meal. There was a significantly greater increase in glucose concentrations and lower increase in postprandial insulin, C-peptide, and proinsulin concentrations and lower insulin/glucose ratios following the HFHC meal. HFHC meal intake induced marked increases in plasma glucagon and DPP-IV concentrations and an increase in CD26 mRNA expression in MNC compared with the AHA meal. In addition, the HFHC meal induced a reduction in GIP and peak GLP-1 secretion compared with the AHA meal. This was associated with a significantly greater increase in oxidative stress and proinflammatory mediators including, ROS generation, TNFα, and IL-1ß mRNA expression and plasma concentrations of TBARS, FFA, and LPS. We conclude that the proinflammatory HFHC meals result in lower insulin, C-peptide, proinsulin, and GIP secretion in association with higher plasma glucagon and DPP-IV concentrations and CD26 expression in MNC compared with the AHA meal.
Assuntos
Dieta Hiperlipídica , Fibras na Dieta/administração & dosagem , Frutas , Glucagon/sangue , Incretinas/sangue , Insulina/metabolismo , Adulto , Gorduras na Dieta/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , Refeições , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Adulto JovemRESUMO
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.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Terapia de Reposição Hormonal/métodos , Hipogonadismo/tratamento farmacológico , Testosterona/farmacologia , Adulto , Idoso , Biomarcadores/análise , Seguimentos , Humanos , Hipogonadismo/enzimologia , Hipogonadismo/epidemiologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Estados Unidos/epidemiologiaRESUMO
CONTEXT: One-third of men with type 2 diabetes have subnormal free testosterone concentrations. We evaluated the following: (i) whether bone mineral density (BMD) and bone strength are affected by gonadal status in type 2 diabetes and (ii) the effect of testosterone replacement on markers of osteoblast and osteoclast activity. DESIGN: This is a secondary analysis of a previously completed, randomized, placebo-controlled trial. Ninety-four men with type 2 diabetes were recruited; 44 had subnormal free testosterone concentrations. Men with subnormal free testosterone concentrations were randomized to receive intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Dual energy X-ray absorptiometry scans were performed at baseline and at 23 weeks. RESULTS: Men with subnormal free testosterone had similar BMD compared with men with normal free testosterone. However, bone strength indices were lower in men with subnormal free testosterone. BMD was related to free estradiol concentrations (r = 0.37, P = 0.004 at hip), whereas bone strength was related to free testosterone concentrations (r = 0.41, P < 0.001). Testosterone replacement increased osteocalcin concentrations [mean change (95% CI), 3.52 (0.45, 6.59), P = 0.008]. C-Terminal telopeptide (CTx) concentrations also increased at 15 weeks but reverted to baseline following that. There were no changes in other bone turnover markers or BMD. CONCLUSION: We conclude that testosterone replacement resulted in an increase in osteocalcin and a transient increase in CTx, indicating an increase in osteoblastic activity and transient increase in bone breakdown. Therefore, a major action of testosterone is to increase bone turnover in men with type 2 diabetes.
RESUMO
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.
Assuntos
Fator 2 de Crescimento de Fibroblastos/sangue , Hipogonadismo/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Fatores de Regulação Miogênica/genética , Miostatina/sangue , Testosterona/farmacologia , Adulto , Idoso , Fator 2 de Crescimento de Fibroblastos/genética , Humanos , Hipogonadismo/fisiopatologia , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
AIMS: Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic-hyperinsulinemic clamp (EHC). DESIGN AND METHODS: This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 h of EHC. RESULTS: The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72 ± 20%) and myogenin differentiation protein (MyoD; by 81 ± 22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (MRF4) by 34 ± 14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change. CONCLUSIONS: Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Insulina/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Absorciometria de Fóton , Adulto , Idoso , Diferenciação Celular/efeitos dos fármacos , Técnica Clamp de Glucose , Humanos , Hipogonadismo/tratamento farmacológico , Hipogonadismo/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Regulação Miogênica/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We report the case of a 54-year-old Caucasian female who presented with a two-year history of persistent hypocalcemia requiring multiple hospitalizations. Her medical history was significant for HIV diagnosed four years ago. She denied any history of prior neck surgery or radiation. Her vital signs were stable with an unremarkable physical exam. Pertinent medications included calcium carbonate, vitamin D3, calcitriol, efavirenz, emtricitabine, tenofovir disoproxil, hydrochlorothiazide, and inhaled budesonide/formoterol. Laboratory testing showed total calcium of 5.7 mg/dL (normal range: 8.4-10.2 mg/dL), ionized calcium of 2.7 mg/dL (normal range: 4.5-5.5 mg/dL), serum phosphate of 6.3 mg/dL (normal range: 2.7-4.5 mg/dL), and intact PTH of 7.6 pg/mL (normal range: 15-65 pg/mL). She was diagnosed with primary hypoparathyroidism. Anti-calcium-sensing receptor antibodies and NALP5 antibodies were tested and found to be negative. During subsequent clinic visits, doses of calcium supplements and calcitriol were titrated. Last corrected serum calcium level was 9.18 mg/dL. She was subsequently lost to follow-up. This case gives insight into severe symptomatic hypocalcemia from primary hypoparathyroidism attributed to HIV infection. We suggest that calcium levels should be closely monitored in patients with HIV infection.
RESUMO
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.
Assuntos
Androgênios/uso terapêutico , Aromatase/genética , Diabetes Mellitus Tipo 2/metabolismo , Receptor alfa de Estrogênio/genética , Hipogonadismo/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Receptores Androgênicos/genética , Testosterona/uso terapêutico , Adulto , Idoso , Aromatase/metabolismo , Western Blotting , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Receptor alfa de Estrogênio/metabolismo , Humanos , Hipogonadismo/complicações , Hipogonadismo/genética , Hipogonadismo/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gordura Subcutânea/metabolismoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/sangue , Obesidade/tratamento farmacológico , Peptídeos/farmacologia , Peçonhas/farmacologia , Elementos de Resposta Antioxidante/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Quimioterapia Combinada , Indução Enzimática/efeitos dos fármacos , Exenatida , Feminino , Glutationa S-Transferase pi/biossíntese , Heme Oxigenase-1/biossíntese , Humanos , Insulina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/biossíntese , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Obesidade/sangue , Obesidade/complicaçõesRESUMO
OBJECTIVES: To estimate the prevalence of the association between thyroid disease and idiopathic thrombocytopenia (ITP), and to examine the effect of treatment of the thyroid condition on platelet count. DESIGN: Retrospective cohort study performed in a tertiary care center setting. All patients who were diagnosed with ITP by a single provider at the Cleveland Clinic Hematology/Oncology Department between 1988 and 2005 were included. MAIN OUTCOME: Among the 98 patients, thyroid function tests were available in 80 patients. Of these, 16 (20%) had abnormal thyroid function: 6 had hyperthyroidism and 10 had hypothyroidism. The median interval from the onset of the thyroid or hematological condition (whichever came first) was 84 months (range: 25-612). The autoimmune nature of the thyroid disease was proven in 12 cases (75%). Three patients showed a transient increase in the platelet count after restoring the euthyroid state; however, durable improvement of thrombocytopenia was not encountered. CONCLUSIONS: The prevalence of hypothyroidism in patients with ITP is higher than in the general population. Based on this observation, routine assessment of thyroid function should be done in patients with ITP. The long-term course of ITP was not influenced by the treatment of the thyroid condition.
Assuntos
Trombocitopenia/etiologia , Doenças da Glândula Tireoide/complicações , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombocitopenia/sangue , Doenças da Glândula Tireoide/terapiaRESUMO
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.
Assuntos
Glicemia/efeitos dos fármacos , Dieta Hiperlipídica , Fibras na Dieta/farmacologia , Ingestão de Energia , Leucócitos Mononucleares/efeitos dos fármacos , Refeições , Período Pós-Prandial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Adulto , Glicemia/metabolismo , Peptídeo C/efeitos dos fármacos , Peptídeo C/metabolismo , Feminino , Humanos , Insulina/metabolismo , Resistência à Insulina , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Leucócitos Mononucleares/imunologia , Receptores de Lipopolissacarídeos/efeitos dos fármacos , Receptores de Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/imunologia , Período Pós-Prandial/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas/genética , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemRESUMO
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.
Assuntos
Anticolesterolemiantes/uso terapêutico , Laticínios/efeitos adversos , Combinação Ezetimiba e Simvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/prevenção & controle , Inflamação/prevenção & controle , Obesidade/tratamento farmacológico , Adulto , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Método Duplo-Cego , Combinação Ezetimiba e Simvastatina/efeitos adversos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipidemias/sangue , Hiperlipidemias/diagnóstico , Hiperlipidemias/etiologia , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/etiologia , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , New York , Obesidade/sangue , Obesidade/diagnóstico , Período Pós-Prandial , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Liraglutida/uso terapêutico , Adulto , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucagon/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Período Pós-Prandial , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Terapia de Reposição Hormonal , Hipogonadismo/tratamento farmacológico , Inflamação/sangue , Resistência à Insulina , Testosterona/uso terapêutico , Adulto , Composição Corporal , Proteína C-Reativa/metabolismo , Ácidos Graxos não Esterificados/sangue , Humanos , Hipogonadismo/complicações , Insulina/uso terapêutico , Interleucina-1beta/sangue , Gordura Intra-Abdominal/metabolismo , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Gordura Subcutânea/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
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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Compostos Benzidrílicos/uso terapêutico , Biomarcadores/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Liraglutida/uso terapêutico , Adolescente , Adulto , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
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.
Assuntos
Asma/sangue , Diabetes Mellitus Tipo 2/sangue , Regulação da Expressão Gênica , Inflamação/sangue , Insulina/metabolismo , Obesidade/metabolismo , Adulto , Glicemia/análise , Índice de Massa Corporal , Estudos Cross-Over , Diabetes Mellitus Tipo 2/complicações , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Hemoglobinas Glicadas/metabolismo , Humanos , Infusões Intravenosas , Insulina/administração & dosagem , Resistência à Insulina , Luminescência , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Espécies Reativas de Oxigênio , Redução de PesoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Obesidade/tratamento farmacológico , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 1/complicações , Quimioterapia Combinada , Feminino , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Liraglutida , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Retrospectivos , Redução de Peso/efeitos dos fármacosRESUMO
OBJECTIVE: To assess whether liraglutide, a glucagon-like peptide-1 receptor agonist, has cardioprotective properties in addition to its glycemic effects. METHODS: We performed a retrospective analysis of medical records of 110 obese patients with type 2 diabetes mellitus treated with liraglutide for at least 6 months between March 2010 and April 2011 at our tertiary care referral center. The variables analyzed were body mass index, hemoglobin A(1c) (A1C), systolic blood pressure (SBP), plasma C-reactive protein (CRP) concentrations, and serum lipids. RESULTS: In our overall study cohort, we noted a reduction in mean weight from 120 ± 5 kg to 115 ± 3 kg and a decrease in mean A1C from 7.8% ± 0.6% to 7.2% ± 0.2%. The mean triglyceride concentration decreased from 173 ± 19 mg/dL to 151 ± 15 mg/dL, the mean SBP was reduced from 132 ± 6 mm Hg to 125 ± 4 mm Hg, and the mean CRP concentration declined from 4.7 ± 0.8 mg/L to 3.2 ± 0.4 mg/L after treatment with liraglutide for a minimal duration of 6 months and a mean duration of 7.5 months (for all the foregoing changes, P<.05). These variables decreased whether these patients were previously treated with orally administered hypoglycemic agents alone or in combination with insulin or exenatide. CONCLUSION: Our findings in a clinical practice show that liraglutide is a potent antidiabetes drug, whether given in combination with orally administered agents or insulin or as a substitution for exenatide. It lowers body weight, A1C levels, SBP, and CRP and triglyceride concentrations.