RESUMO
AIM: To investigate the mechanisms underlying improvements in blood pressure (BP) and congestive heart failure outcomes following treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor. RESEARCH DESIGN AND METHODS: A total of 52 patients with type 2 diabetes (T2D) with an HbA1c of less than 8% participated in this prospective, double-blind and placebo-controlled study. Patients were randomized (1:1) to either dapagliflozin 10 mg daily or placebo for 12 weeks. Half the patients were also monitored for 6 h following their first dose for acute effects on BP. Blood and urine samples were collected and levels of angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide, cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and neprilysin were measured. The expression of angiotensin-converting enzyme, guanylate cyclase and phosphodiesterase 5 (PDE5) was measured in circulating mononuclear cells (MNC). RESULTS: A total of 24 and 23 patients receiving dapagliflozin and placebo, respectively, completed the 12-week study. Systolic BP decreased significantly, compared with placebo, both after single-dose (by 7 ± 3 mmHg) and 12-week (by 7 ± 2 mmHg) treatment with dapagliflozin. Dapagliflozin suppressed angiotensin II and angiotensinogen (by 10.5 ± 2.1 and 1.45 ± 0.42 µg/mL, respectively) and increased ANP and cGMP (by 34 ± 11 and 29 ± 11 pmol/mL, respectively) compared with the placebo group. cGMP levels also increased acutely following a single dose of dapagliflozin. Dapagliflozin also suppressed PDE5 expression by 26% ± 11% in MNC. There were no changes observed in the other vasoactive mediators investigated. CONCLUSIONS: Dapagliflozin administration in T2D resulted in both acute and chronic reduction in systolic BP, a reduction in vasoconstrictors and an increase in vasodilators. These changes may potentially contribute to its antihypertensive effects and its benefits in congestive cardiac failure.
Assuntos
Diabetes Mellitus Tipo 2 , Compostos Benzidrílicos , Glicemia , Pressão Sanguínea , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Glucosídeos/uso terapêutico , Humanos , Estudos ProspectivosRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Método Duplo-Cego , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Obesidade/complicações , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Resultado do Tratamento , Redução de PesoRESUMO
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
The purpose of this study was to determine whether an insulin infusion exerts an anti-inflammatory effect and whether the infusion of small amounts of glucose results in oxidative and inflammatory stress in patients with type 1 diabetes. Ten patients with type 1 diabetes were infused with either 2 U/h of insulin with 100 ml 5% dextrose/h to or just dextrose (100 ml/h) or physiological saline (100 ml/h) for 4 h after an overnight fast on three separate days. Blood samples were collected at 0, 2, 4, and 6 h. Insulin with glucose infusion led to the maintenance of euglycemia and a significant suppression of reactive oxygen species (ROS) generation, p47(phox) expression, Toll-like receptor (TLR)-4, TLR-2, TLR-1, CD14, high-mobility group-B1 (HMGB1), p38 mitogen-activated protein (MAP) kinase, c-Jun NH2-terminal kinase (JNK)-1, and platelet/endothelial cell adhesion molecule expression and a fall in serum concentrations of C-reactive protein, HMGB1, and rapid upon activation T cell expressed and secreted. Glucose infusion led to an increase in plasma glucose concentration from 115 (fasting) to 215 (at 4 and 6 h) mg/dl and to an increase in ROS generation, the expression of TLR-4, TLR-2, TLR-1, HMGB1, p38 MAP kinase, and JNK-1, and plasma concentrations of HMGB1. While insulin reduces indexes of oxidative and inflammatory stress in patients with type 1 diabetes, even small amounts of glucose (20 g over 4 h) induce oxidative and inflammatory stress. These effects are reflected in TLR, p38 MAP kinase, and HMGB1 expression. The induction of significant oxidative and inflammatory stress by small amounts of glucose in patients with type 1 diabetes may have important pathophysiological and therapeutic implications.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose/administração & dosagem , Proteína HMGB1/metabolismo , Inflamação/tratamento farmacológico , Insulina/administração & dosagem , Receptores Toll-Like/metabolismo , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Ácidos Graxos não Esterificados/sangue , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Proteína HMGB1/genética , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Inflamação/sangue , Inflamação/imunologia , Infusões Intravenosas , Insulina/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Receptor 1 Toll-Like/genética , Receptor 1 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
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: Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration. OBJECTIVE: Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. DESIGN: Prospective, randomized, and placebo-controlled study. SETTING: Single endocrinology center. PATIENTS: Fifty-two obese type 2 diabetes patients. INTERVENTION: Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared. MAIN OUTCOME MEASURE: Hepcidin and other hematopoietic factors. RESULTS: Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. CONCLUSIONS: We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eritropoese/efeitos dos fármacos , Glucosídeos/uso terapêutico , Hepcidinas/uso terapêutico , Obesidade/fisiopatologia , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Método Duplo-Cego , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Hepcidinas/antagonistas & inibidores , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
CONTEXT: The intake of macronutrients as components of a Western dietary pattern leads to oxidative stress and inflammation. EVIDENCE ACQUISITION: Data were largely retrieved from our previous and most recent work. PubMed and Google Scholar were searched for recent articles on the effect of macronutrients/dietary intake on inflammation, insulin resistance, obesity, and atherogenesis. The most relevant, high-quality articles were included in our review. EVIDENCE SYNTHESIS: Our previous work has demonstrated the molecular mechanisms of macronutrient-mediated oxidative stress and inflammation. With the induction of inflammation, proinflammatory molecules potentially interfere with insulin signal transduction, thus causing insulin resistance. In addition, other molecules promote atherogenic inflammation. More recently, our work has also shown that certain foods are noninflammatory or anti-inflammatory and thus, do not interfere with insulin signaling. Finally, as obesity is induced by chronic excessive caloric intake, it is characterized by an increase in the expression of proinflammatory molecules, which are induced acutely by a Western diet. Caloric restriction, including fasting, is associated with a reduction in oxidative and inflammatory stress. CONCLUSIONS: This review summarizes and attempts to provide an up-to-date profile of the molecular mechanisms involved in macronutrient-mediated oxidative/inflammatory stress and its potential consequences. An understanding of these underlying mechanisms is crucial for making appropriate dietary choices.
Assuntos
Aterosclerose/etiologia , Mediadores da Inflamação/efeitos adversos , Inflamação/etiologia , Resistência à Insulina/fisiologia , Nutrientes/efeitos adversos , Obesidade/etiologia , Estresse Oxidativo/fisiologia , Animais , Aterosclerose/metabolismo , Dieta , Humanos , Inflamação/metabolismo , Obesidade/metabolismo , Fatores de RiscoRESUMO
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
One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA1c in men with diabetes. The effect of testosterone replacement on cardiovascular events or mortality in men with diabesity is not known and remains to be studied in prospective trials.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Hipogonadismo/complicações , Obesidade/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipogonadismo/sangue , Hipogonadismo/epidemiologia , Insulina/sangue , Resistência à Insulina/fisiologia , Leptina/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Obesidade/sangue , Obesidade/epidemiologia , Prevalência , Testosterona/sangueRESUMO
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
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.