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OBJECTIVES: Obesity-associated gonadal dysfunction is a common comorbidity in patients seeking weight loss interventions. We examined the incremental effect of weight loss on gonadal axes in men and women over 3 years. Changes in sex hormones were compared between dietary intervention (Diet) and bariatric procedures: Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and laparoscopic adjustable gastric banding (LAGB). Additional analysis assessed changes in corticotropic, somatotropic and thyroid axes after weight loss interventions. METHODS: This prospective, observational study included 61 adults with Body Mass Index >30 kg/m2, mean age 51 (SD = 11) years. Endocrine parameters were measured at baseline and at 6 timepoints over 36-months. RESULTS: For each 1 kg of weight lost, between baseline and 36 months, total testosterone increased by 0.6% (95% CI: 0.2%, 1.0%, p = 0.002) in males and decreased by 0.8% (95% CI: -1.4%, -0.3%, p = 0.003) in females. These changes remained statistically significant when controlled for age and for menopausal status in females. At 36 months, in comparison with Diet, RYGB women had lower total testosterone by 54% (95% CI: -90%, -17%, p = 0.004), reduced free androgen index (FAI) by 65% (95% CI; -114%, -17%, p = 0.009) while SG had reduced FAI by 39% (95% CI; -77%, 0%, p = 0.05). No such differences between groups were noted for male subjects. Adrenocorticotropic hormone declined by 0.3% (95% CI: 0.0, -0.5%, p = 0.05), insulin-like growth factor-1 increased by 0.4% (95% CI; 0.2%, 0.7%, p = 0.005), without such thyrotrophin change for each 1 kg of weight loss, for entire cohort, over 36 months. CONCLUSIONS: The testosterone changes observed in this study were proportional to the amount of weight loss. In females, reduction in androgens was independent of age and menopausal status and more pronounced after bariatric procedures. This study finding warrants further clinical research to explore an impact of androgen reduction on functional and cognitive status in postmenopausal women. The observed changes in pituitary hormones may contribute to the metabolic benefits of bariatric surgery.
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BACKGROUND: Premature cardiovascular disease is the leading cause of death in people living with type 1 diabetes. Therapies are urgently needed to address cardiovascular risk in this group. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, has been shown to reduce cardiovascular events and improve weight and glycaemia in type 2 diabetes. Semaglutide may offer cardioprotective and metabolic benefits in type 1 diabetes. METHODS: We will study 60 adults aged 25-70 years with type 1 diabetes of duration at least 2 years, body mass index ≥25 kg/m2, HbA1c ≥7% and at least one cardiovascular risk factor (microalbuminuria, hypertension or anti-hypertensive treatment, hyperlipidemia or lipid lowering therapy, current smoking). Participants will receive semaglutide up to 1.0 mg weekly or matched placebo for 26 weeks. The primary outcome is carotid femoral pulse wave velocity, a measure of arterial stiffness, as a surrogate marker of cardiovascular risk. Potential mechanisms for metabolic changes will be explored including change in insulin sensitivity determined by hyperinsulinaemic-euglycaemic clamp; and incretin and pancreatic hormone action measured during mixed meal tolerance test. CONCLUSION: The REducing cardiometabolic risk with SEmaglutide in Type 1 diabetes study will investigate whether semaglutide, a long acting glucagon-like peptide receptor agonist, can improve markers of cardiometabolic health in T1D. Underlying mechanisms predicting response, including insulin resistance and incretin hormone status, will also be explored.
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AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and cardio-renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio-economic variation in use is not well understood. METHODS: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose-lowering medicines among people with T2D and the prevalence of SGLT2i and GLP-1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose-lowering medicine). We measured the prevalence by small-level geography, stratified by age group, and characterized by remoteness and socio-economic status. RESULTS: The prevalence of SGLT2i (29.7%) and GLP-1RA (8.3%) use in people with T2D aged 40-64 increased with geographic remoteness and in areas of greater socio-economic disadvantage, similar to other glucose-lowering medicines. The prevalence of SGLT2i (55.4%) and GLP-1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP-1RA use (2.5 times the median). Compared with people aged 40-64 years, the prevalence of SGLT2i and GLP-1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. CONCLUSIONS: The prevalence of SGLT2i and GLP-1RA use varied by geography, probably reflecting a combination of system- and prescriber-level factors. Socio-economic variation in GLP-1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Masculino , Femenino , Nueva Gales del Sur/epidemiología , Adulto , Anciano , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéuticoRESUMEN
AIMS: Advanced chronic liver disease and advanced chronic liver disease-related ascites have a high mortality. The pharmacological treatment of ascites and fluid overload has changed little over time. Empagliflozin, a sodium-glucose cotransporter type 2 inhibitor is an untested potential novel treatment in cirrhosis, as it has survival benefits in heart failure, which has similar pathophysiological fluid overload mechanisms. Before investigating empagliflozin's potential benefit in cirrhosis, its safety must be addressed. METHODS: Ten participants (five each with compensated or decompensated advanced chronic liver disease, based on Child-Pugh class) received empagliflozin 10 mg orally daily for 4 weeks with 2 weeks follow-up. Empagliflozin safety, pharmacokinetics and pharmacodynamics were investigated. RESULTS: In total, eight patients (80%) reported an adverse event, and three patients (30%) experienced a serious adverse event, one of which was attributed to empagliflozin. Overall, the frequency of adverse events was similar to previous phase 3 trials of gliflozins. Higher plasma empagliflozin concentrations did not significantly increase the risk of adverse events. CONCLUSIONS: Four-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data support assessment of long-term treatment on disease-related and mortality outcomes in patients with cirrhosis through randomized control trials.
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BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now indicated for heart failure and chronic kidney disease (CKD), irrespective of the presence of diabetes. Hence, cardiologists and nephrologists have an important role in initiating these drugs. AIMS: To explore cardiologists' and nephrologists' perspectives regarding initiating SGLT2i and their safety monitoring practices when initiating SGLT2i. METHODS: Purposive and snowball approaches were used to recruit participants working in diverse areas in New South Wales, Australia. Semi-structured interviews were conducted with 12 cardiologists and 12 nephrologists. Interviews were conducted until thematic saturation was reached. Emergent themes were identified from transcripts. An iterative general inductive approach was used for data analysis. RESULTS: There was a reluctance amongst most non-heart-failure subspecialist cardiologists to initiate SGLT2i. Reasons included the perception of SGLT2i as diabetes drugs, concern about side effects, lack of experience and issues with follow-up. In contrast, nephrologists reported feeling confident to initiate SGLT2i. Nephrologists varied in their opinions about the severity of CKD at which SGLT2i initiation was reasonable and monitoring of renal function following initiation. Government subsidisation was an important factor in the decision to prescribe SGLT2i to people without diabetes. CONCLUSIONS: Our findings highlight the complex transition from the perception of SGLT2i as diabetes drugs to cardiometabolic and reno-protective agents. Interdisciplinary collaboration may enable greater confidence amongst specialists to initiate SGLT2i, including in patients with CKD. Additionally, there is a need for clear and detailed guidance about SGLT2i prescription in patients with renal dysfunction and renal function monitoring following SGLT2i initiation.
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AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Metformina , Humanos , Masculino , Metformina/efectos adversos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios Transversales , Hipoglucemiantes/efectos adversos , Estudios Longitudinales , Estudios Prospectivos , Ácido Láctico , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/inducido químicamenteRESUMEN
PURPOSE: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. METHODS: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. RESULTS: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. CONCLUSION: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Simportadores , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Australia , Hipoglucemiantes/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Glucosa , SodioRESUMEN
BACKGROUND: Many people living with type 1 diabetes (type 1 diabetes mellitus (T1DM)) do not meet glycaemic targets. Adjunctive therapies have both risks and metabolic benefits and may have a role in selected patients. AIM: To review the prescribing patterns of adjunctive therapy for the treatment of T1DM diabetes in Australia. METHODS: We conducted an online survey of Australian endocrinologists and endocrinology registrars. We surveyed the frequency of, motivations and concerns regarding the prescription of metformin, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose transport protein 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonist (GLP1RA) in T1DM. RESULTS: Fifty-two practitioners participated. Most respondents (94%) had prescribed adjuncts for the treatment of T1DM in some form. Weight (89%), large insulin doses (73%), glycaemic variability (52%), high HbA1c (48%) and the presence of cardiovascular disease (48%) were the most common factors determining the use of adjuncts. The most commonly prescribed adjuncts were metformin (94%) and SGLT-2 inhibitors (65%). Respondents who had never prescribed an SGLT-2 inhibitor (n = 18) reported risk of diabetic ketoacidosis (DKA) (100%), off-label status (39%), lack of evidence (39%), withdrawal of support from the European Medicines Agency (17%) and cost (17%) as factors contributing to their decision. Thirty-one respondents (60%) had prescribed a GLP1RA. Among those who had never prescribed a GLP1RA (n = 21), off-label status (57%), lack of evidence (48%), cost (38%) and expected lack of efficacy (14%) were factors affecting their decision. Only five respondents (10%) had prescribed a DPP-IV inhibitor. CONCLUSION: Australian endocrinologists commonly prescribe adjuncts to address cardiometabolic concerns in T1DM. DKA risk and off-label status are significant factors contributing to reluctance to prescribe.
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BACKGROUND: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. METHODS: Post-hoc analysis to compare PTDM and other metabolic outcomes in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients (RADTAC1 study). RESULTS: There were 39 participants in the trial; mean follow-up was 6.4±1.5 years. There was a high rate of pre-existing diabetes (26%) and newly diagnosed PTDM (36%) during follow-up. Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). In the first 12 months there was a higher use of non-insulin treatment for diabetes in the everolimus-tacrolimus group compared to the standard tacrolimus group. CONCLUSIONS: This study suggests that treatment with everolimus may be associated with improved glycaemic control of PTDM relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials.
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Diabetes Mellitus , Trasplante de Corazón , Humanos , Everolimus , Tacrolimus/uso terapéutico , Inhibidores de la Calcineurina/efectos adversos , Estudios Prospectivos , Progresión de la Enfermedad , Rechazo de InjertoRESUMEN
The global burden of chronic kidney disease (CKD) has increased significantly over the past few decades. This reflects the rising prevalence of type 2 diabetes mellitus (T2DM) and hypertension, two leading causes of CKD. Hypertension, which can also be a complication of CKD, accelerates renal disease progression and augments cardiovascular risk, especially in individuals with diabetic kidney disease. Hence, blood pressure (BP) reduction is a vital component of CKD management. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively novel class of medications developed to treat T2DM by inducing glycosuria and hence, lowering glycaemia. Additionally, SGLT2 inhibitors are antihypertensive, renoprotective and cardioprotective, even in individuals without T2DM, making them effective therapeutic agents for CKD. Another therapy that has proven to be antihypertensive, renoprotective and cardioprotective is dietary sodium restriction. This review evaluates the potential combined benefits of SGLT2 inhibition and dietary sodium restriction on the BP and renal parameters of individuals with CKD.
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Diabetes Mellitus Tipo 2 , Hipertensión , Insuficiencia Renal Crónica , Sodio en la Dieta , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Antihipertensivos/uso terapéutico , Glucemia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Hipoglucemiantes/uso terapéutico , Riñón , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Sodio , Sodio en la Dieta/farmacología , Sodio en la Dieta/uso terapéutico , Transportador 2 de Sodio-Glucosa/farmacología , Transportador 2 de Sodio-Glucosa/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
BACKGROUND: Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. METHODS: We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c ≤ 80 mmol/mol [9.5%], fasting C-peptide <0.3 nmol/L) and 20 age-, gender- and body mass index (BMI)-matched controls. Insulin sensitivity will be determined by the two-step hyperinsulinaemic-euglycaemic clamp method with deuterated glucose to document liver, muscle and adipose insulin sensitivity. Subjects with Type 1 diabetes will be randomised to metformin extended-release 1500 mg daily or matched placebo for 26 weeks. The primary outcome is change in hepatic insulin sensitivity, assessed by change in basal rate of appearance (Ra) of glucose and suppression of endogenous glucose production (EGP) during the low-dose stage of the clamp. CONCLUSION: The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an individual's response to metformin in Type 1 diabetes. TRIAL REGISTRATION: ACTRN12619001440112.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Ayuno/sangre , Hemoglobina Glucada/metabolismo , Resistencia a la Insulina/fisiología , Metformina/uso terapéutico , Adulto , Diabetes Mellitus Tipo 1/sangre , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Patients with Addison's disease (AD) and comorbid type 1 diabetes mellitus (T1DM) are at increased risk of certain acute metabolic disorders relative to patients with one of these conditions only. The reasons for this are unknown. METHODS: All attendances for acute illness by AD patients at the emergency department of a Sydney hospital between 2000 and 2017 were reviewed. Physiological parameters and illness management strategies were compared between AD patients, those with T1DM and AD combined, and a control group of patients with T1DM. RESULTS: There were 39 presentations for an acute medical illness by 20 nondiabetic AD (28 attendances) and 5 diabetic AD patients (11 presentations) and 40 attendances by 10 T1DM controls. In AD patients, 17 (43.6%) attendances were medically diagnosed adrenal crises (AC) (63.6% [n = 7] in diabetic AD and 35.7% [n = 10] in nondiabetic AD). This corresponded to an estimated incidence of 12.5 AC/100 patient-years (PY) for diabetic AD patients compared to 4.7 AC/100PY for nondiabetic AD patients (P < .05). Glucocorticoid stress doses preceded 61.5% (n = 24) of all attendances. Patients who used stress doses had more presentations than those who did not (2.0 ± 1.3 vs 1.2 ± 0.5, P = .01). Diabetic AD patients had a lower mean blood glucose level on presentation (5.6 ± 3.9 mmol/L) than the T1DM control sample (11.6 ± 6.2 mmol/L) P < .001. No T1DM patients had hypoglycaemia in the 3.0-3.9 mmol/L range but 2 (18.2%) of the diabetic AD patients had presenting blood glucose levels in this category (P < .05). Hyperglycaemia was more common among T1DM control patients (62.5%, n = 26) than diabetic AD patients (18.2%, n = 2), P < .01. CONCLUSION: Addison's disease patients with T1DM have a higher incidence of adrenal crisis (AC) and hypoglycaemia than nondiabetic AD patients and a lower incidence of hyperglycaemia than those with T1DM alone. This information may be of value in counselling patients with T1DM and AD about AC and hypoglycaemia prevention.
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Enfermedad de Addison , Diabetes Mellitus Tipo 1 , Hipoglucemia , Enfermedad Aguda , Enfermedad de Addison/complicaciones , Enfermedad de Addison/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Humanos , Hipoglucemia/epidemiología , Hipoglucemia/etiología , IncidenciaRESUMEN
BACKGROUND: Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. OBJECTIVES: The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. METHODS: Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, ß-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). RESULTS: We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. CONCLUSIONS: Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.
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Tejido Adiposo/metabolismo , Carotenoides/sangre , Carotenoides/metabolismo , Resistencia a la Insulina , Obesidad/sangre , Adulto , Citocinas/genética , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Glucosa , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVE: Graves' disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRAbs) are clearly pathogenic, but the role of thyroidperoxidase antibodies (TPOAbs) in Graves disease is unknown. METHODS: We retrospectively studied whether TPOAb positivity reduced risk of relapse following antithyroid drug (ATD) treatment in newly diagnosed Graves disease. RESULTS: During follow-up of 204 patients with TRAb-positive Graves disease, 107 (52%) relapsed following withdrawal of ATD. Mean age was 40.0 years, and 82% were female. The average duration of ATD treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAbs significantly increased risk of Graves relapse (odds ratio, 2.21). Male sex and younger age were other factors significantly associated with increased risk of relapse. CONCLUSION: TPOAb positivity significantly improves the odds of remission following ATD treatment in newly diagnosed Graves' disease.
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Antitiroideos , Enfermedad de Graves , Adulto , Antitiroideos/uso terapéutico , Autoanticuerpos , Femenino , Enfermedad de Graves/tratamiento farmacológico , Humanos , Yoduro Peroxidasa , Masculino , Receptores de Tirotropina , Recurrencia , Estudios RetrospectivosRESUMEN
AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS-1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long-term follow-up data. In 2 long-term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long-term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low-quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Enfermedades Renales/sangre , Riñón/metabolismo , Metformina/efectos adversos , Diálisis Renal , Acidosis/sangre , Acidosis/inducido químicamente , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Monitoreo de Drogas , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Enfermedades Renales/complicaciones , Enfermedades Renales/terapia , Ácido Láctico/sangre , Metformina/administración & dosificación , Metformina/farmacocinética , Metformina/uso terapéuticoRESUMEN
PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have important cardiovascular and renal benefits in adults with type 2 diabetes who have or are at high risk of cardiovascular and renal disease. These benefits are seen in patients with impaired renal function where the glucose-lowering effects are not observed. Here, we review the pharmacokinetics and pharmacology of SGLT2 inhibitors in relation to cardiovascular and renal outcomes in patients with chronic kidney disease (CKD). METHODS: We searched PubMed and EMBASE for original research, meta-analyses and review articles relevant to the pharmacokinetics, and cardiac and renal outcomes of SGLT2 inhibitors published up until June 2019. Specialist society guidelines and publications were also consulted. RESULTS: Renal impairment is currently a contraindication to SGLT2 inhibitor use largely due to limited anti-hyperglycaemic efficacy. However, in cardiovascular outcome trials, and a dedicated renal outcome trial, cardiovascular and renal benefits were seen in participants with CKD suggesting that mechanisms underlying the cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of the glucose-lowering action of these agents. CONCLUSIONS: Despite minimal glycaemic benefits in patients with type 2 diabetes and stage 3 CKD, the cardiovascular and renal benefits of these agents are preserved in this group of patients. Whether these agents have cardiovascular and renal benefits in patients with stage 4 CKD and patients with non-diabetic CKD needs further research.