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BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
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Alopurinol/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Adulto , Idoso , Alopurinol/efeitos adversos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina , Falha de TratamentoRESUMO
BACKGROUND: Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits. METHODS: Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013-2018) and were 1:1 propensity score-matched, adjusting for >95 baseline covariates. The primary outcomes were a composite cardiovascular end point (comprising myocardial infarction, stroke, and all-cause mortality) and heart failure hospitalization. Adjusted hazard ratios (HRs) and 95% CIs were estimated in each dataset and pooled through fixed-effects meta-analysis. RESULTS: Among 12 584 propensity score-matched pairs (mean [SD] age, 58.3 [10.9] years; 48.2% male) across the 3 datasets, there were 107 composite cardiovascular end point events (incidence rate per 1000 person-years, 9.9 [95% CI, 8.1-11.9]) among SGLT2i initiators compared with 129 events (incidence rate, 13.0 [95% CI, 10.9-15.3]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.76 (95% CI, 0.59-0.98); this decrease in composite cardiovascular end point was driven by numeric decreases in the risk of myocardial infarction (HR, 0.71 [95% CI, 0.51-1.003]) and all-cause mortality (HR, 0.68 [95% CI, 0.40-1.14]) but not stroke (HR, 1.05 [95% CI, 0.62-1.79]). For the outcome of heart failure hospitalization, there were 141 events (incidence rate, 13.0 [95% CI, 11.0-15.2]) among SGLT2i initiators versus 206 events (incidence rate, 20.8 [95% CI, 18.1-23.8]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.65 (95% CI, 0.50-0.82). CONCLUSIONS: Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of patients with diabetes already on GLP-1RA, addition of SGLT2i conferred greater cardiovascular benefit compared with addition of sulfonylurea. The magnitude of the cardiovascular risk reduction was comparable with the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo, where baseline GLP-1RA use was minimal.
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Doenças Cardiovasculares/diagnóstico , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Hospitalização/estatística & dados numéricos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/uso terapêuticoRESUMO
Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting.
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Aterosclerose/complicações , Diabetes Mellitus Tipo 2/complicações , Insuficiência Cardíaca/complicações , Aterosclerose/tratamento farmacológico , Gerenciamento Clínico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de RiscoRESUMO
OBJECTIVE: To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease. METHODS: Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial. RESULTS: Participants were mostly Caucasian males, age 60±7 years, BMI 31.4±3.0 kg/m2 , fasting glucose 92.8±11.0 mg/dL, and HbA1c 5.8±0.3%. Reductions in mean fasting glucose -5.70 mg/dL (95%CI: -7.44 to -3.97 mg/dL, P<0.001), HbA1c -0.11% (95%CI: -0.210 to -0.002%, P=0.046) and glycated serum protein -81.8 µg/mL (95%CI: -93.7 to -69.9 µg/mL, P<0.001) were demonstrated in salsalate compared to placebo-assigned groups over 30 months. Reductions in fasting glucose and glycated serum protein were greater with salsalate compared to placebo in participants with prediabetes compared to a normoglycemic sub-group (Pinteraction =0.018). Salsalate lowered total white blood cell counts (mean difference -0.7x103 /µL, 95%CI: -1.0 to -0.4 x103 /µL, P<0.001) and increased adiponectin (mean difference 1.8 µg/mL, 95%CI: 0.9 to 2.6 µg/mL, P<0.001) and albuminurea (16.7 µg/mg, 95%CI: 6.4 to 27.1 µg/mg, P<0.001) compared to placebo, consistent with previous results for patients with type 2 diabetes taking salsalate for shorter times. CONCLUSIONS: Salsalate improves glycemia in obese persons at increased risk for diabetes, and hence may decrease risk of incident type 2 diabetes. Salsalate may inform new therapeutic approaches for diabetes prevention, but renal safety may limit clinical utility.
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Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Sobrepeso/sangue , Sobrepeso/tratamento farmacológico , Estado Pré-Diabético/sangue , Estado Pré-Diabético/tratamento farmacológico , Salicilatos/uso terapêutico , Adulto , Idoso , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Placebos , Estado Pré-Diabético/complicações , Fatores de Risco , Resultado do TratamentoRESUMO
Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of ß-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying ß-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in ß cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulin-resistant states.
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Carboxipeptidase H/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fator de Iniciação Eucariótico 4G/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Animais , Carboxipeptidase H/genética , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Estresse do Retículo Endoplasmático/fisiologia , Fator de Iniciação Eucariótico 4G/genética , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biossíntese de Proteínas/fisiologia , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Transativadores/metabolismoRESUMO
Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione peroxidase mimetic. A single-site, randomized, double-masked, placebo-controlled, crossover trial was carried out in 26 patients with type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg po twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 wk duration, with a 4-wk washout between treatments. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced to oxidized glutathione. Vascular ultrasound of the brachial artery and plethysmographic measurement of blood flow were used to assess flow-mediated and methacholine-induced endothelium-dependent vasodilation of conduit and resistance vessels, respectively. Ebselen administration did not affect parameters of oxidative stress or conduit artery or forearm arteriolar vascular function compared with placebo treatment. There was no difference in outcome by diabetes type. Ebselen, at the dose and duration evaluated, does not improve the oxidative stress profile, nor does it affect endothelium-dependent vasodilation in patients with diabetes mellitus.
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Antioxidantes/farmacologia , Azóis/farmacologia , Artéria Braquial/efeitos dos fármacos , Diabetes Mellitus/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiopatologia , Estudos de Casos e Controles , Estudos Cross-Over , Diabetes Mellitus/metabolismo , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Método Duplo-Cego , Endotélio Vascular/fisiopatologia , Feminino , Antebraço/irrigação sanguínea , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Isoindóis , Masculino , Cloreto de Metacolina/farmacologia , Pessoa de Meia-Idade , Parassimpatomiméticos/farmacologia , Pletismografia , Tirosina/análogos & derivados , Tirosina/efeitos dos fármacos , Tirosina/metabolismo , UltrassonografiaRESUMO
OBJECTIVE: We aimed to compare metabolic control in adults with diabetes in the general population to those newly referred to a diabetes center and after 1 year of specialty care. METHODS: We performed a retrospective comparison of adults with diabetes aged ≥20 years data from the National Health and Nutrition Examination Survey (NHANES, n = 1,674) and a diabetes center (n = 3,128) from 2005-2010. NHANES participants represented the civilian, non-institutionalized U.S. POPULATION: Diabetes center referrals lived primarily around eastern Massachusetts. The proportion attaining targets for glycated hemoglobin A1c (A1c), blood pressure (BP), low-density lipoprotein (LDL) cholesterol, or all 3 (ABC control) and the proportion prescribed medications to lower A1c, BP, or cholesterol were evaluated. RESULTS: Compared to the general sample, a smaller proportion of new diabetes center referrals had A1c <7% (<53 mmol/mol, 24% vs. 53%, P<.001), BP <130/80 mm Hg (38% vs. 50%, P<.001), and ABC control (5.6% vs. 17%, P<.001) but not LDL<100 mg/dL (<2.6 mmol/L, 54% vs. 53%, P = .65). After 1 year, more diabetes center referrals attained targets for A1c (40%), BP (38%), LDL (67%), and ABC control (15%) (P<.001 for all versus baseline). ABC control was not different between the general sample and diabetes center referrals at 1 year (P = .16). After 1 year, a greater percentage of diabetes center referrals compared to the general sample were prescribed medications to lower glucose (95% vs. 72%), BP (79% vs. 64%), and cholesterol (77% vs. 54%)(all P<.001). CONCLUSION: Compared to the general population, glycemic control was significantly worse for adults newly referred to the diabetes center. Within 1 year of specialty care, ABC control increased 270% in the setting of significant therapy escalation. ABBREVIATIONS: A1c = glycated hemoglobin A1c ABC = composite of A1c, blood pressure, and cholesterol ACEi = angiotensin-converting enzyme inhibitor ARB = angiotensin receptor blocker BMI = body mass index BP = blood pressure EHR = electronic health record LDL = low-density lipoprotein NCHS = National Center for Health Statistics NHANES = National Health and Nutrition Examination Survey PCP = primary care provider.
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OBJECTIVE: Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein that has a costimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis and inflammatory bowel disease, associated with DPP4i in patients with T2DM. METHODS: Using US insurance claims data (2005-2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators versus non-DPP4i, controlling for potential confounders. RESULTS: After asymmetric trimming on the PS, 73â 928 patients with T2DM starting DPP4i combination therapy and 163â 062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group versus non-DPP4i with the PS-stratified HR of 0.66 (95% CI 0.44 to 0.99) for RA, 0.73 (0.51 to 1.03) for other AD and 0.68 (95% CI 0.52 to 0.89) for composite AD. CONCLUSIONS: In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared with those initiating non-DPP4i combination therapy. These results may suggest possible pharmacological pathways for prevention or treatment of AD.
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Doenças Autoimunes/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Artrite Reumatoide/epidemiologia , Estudos de Coortes , Feminino , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Modelos de Riscos Proporcionais , Fatores de Proteção , Psoríase/epidemiologia , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Dietary supplement use is widespread in the United States. Although it has been suggested in both in vitro and small in vivo human studies that chromium has potentially beneficial effects in type 2 diabetes (T2D), chromium supplementation in diabetes has not been investigated at the population level. OBJECTIVE: The objective of this study was to examine the use and potential benefits of chromium supplementation in T2D by examining NHANES data. METHODS: An individual was defined as having diabetes if he or she had a glycated hemoglobin (HbA1c) value of ≥6.5%, or reported having been diagnosed with diabetes. Data on all consumed dietary supplements from the NHANES database were analyzed, with the OR of having diabetes as the main outcome of interest based on chromium supplement use. RESULTS: The NHANES for the years 1999-2010 included information on 62,160 individuals. After filtering the database for the required covariates (gender, ethnicity, socioeconomic status, body mass index, diabetes diagnosis, supplement usage, and laboratory HbA1c values), and when restricted to adults, the study cohort included 28,539 people. A total of 58.3% of people reported consuming a dietary supplement in the previous 30 d, 28.8% reported consuming a dietary supplement that contained chromium, and 0.7% consumed supplements that had "chromium" in the title. Compared with nonusers, the odds of having T2D (HbA1c ≥6.5%) were lower in persons who consumed chromium-containing supplements within the previous 30 d than in those who did not (OR: 0.73; 95% CI: 0.62, 0.86; P = 0.001). Supplement use alone (without chromium) did not influence the odds of having T2D (OR: 0.89; 95% CI: 0.77, 1.03; P = 0.11). CONCLUSIONS: Over one-half the adult US population consumes nutritional supplements, and over one-quarter consumes supplemental chromium. The odds of having T2D were lower in those who, in the previous 30 d, had consumed supplements containing chromium. Given the magnitude of exposure, studies on safety and efficacy are warranted.
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Cromo/administração & dosagem , Diabetes Mellitus Tipo 2/epidemiologia , Suplementos Nutricionais , Adolescente , Adulto , Idoso , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , Fatores de Risco , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). OBJECTIVE: To assess 1-year efficacy and safety of salsalate in T2DM. DESIGN: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643). SETTING: 3 private practices and 18 academic centers in the United States. PATIENTS: Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes. INTERVENTION: 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). MEASUREMENTS: Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures. RESULTS: The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. LIMITATION: Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. CONCLUSION: Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.
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Anti-Inflamatórios não Esteroides/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Salicilatos/administração & dosagem , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Salicilatos/efeitos adversos , Método Simples-Cego , Adulto JovemRESUMO
BACKGROUND: Growth Differentiation Factor 15 (GDF15), a divergent member of the TGF-ß superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer. METHODS: MBL949 was evaluated in multiple nonclinical species and then in humans in two randomized and placebo-controlled clinical trials. In the Phase 1 first-in-human, single ascending dose trial MBL949 or placebo was injected subcutaneously to overweight and obese healthy volunteers (n=65) at doses ranging from 0.03 to 20 mg. In Phase 2, MBL949 or placebo was administered subcutaneously every other week for a total of 8 doses to obese participants (n=126) in five different dose regimens predicted to be efficacious based on data from the Phase 1 trial. RESULTS: In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight in mice, rats, dogs, and monkeys. Weight loss was primarily from reduced fat, and metabolic endpoints improved. A single ascending dose study in overweight or obese healthy adults demonstrated mean terminal half-life of 18-22 days, and evidence of weight loss at the higher doses. In the Phase 2, weight loss was minimal following biweekly dosing of MBL949 for 14 weeks. MBL949 was safe and generally tolerated in humans over the dose range tested, adverse events of the gastrointestinal system were the most frequent observed. CONCLUSION: The prolonged half-life of MBL949 supports biweekly dosing in patients. MBL949 had an acceptable safety profile. The robust weight loss observed in nonclinical species did not translate to weight loss efficacy in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT05199090.
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Islet beta-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates beta-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28-Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of beta-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by approximately 40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperinsulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of beta-cell secretory response when using these methods during prolonged dynamic testing.
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Glucose/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/farmacologia , Adulto , Glicemia/metabolismo , Peptídeo C/metabolismo , Peptídeo C/farmacocinética , Ensaio de Imunoadsorção Enzimática , Feminino , Hormônios/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Insulina/farmacocinética , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Taxa de Depuração Metabólica , Método Simples-Cego , Adulto JovemRESUMO
Introduction: Continuous glucose monitoring (CGM) devices capture longitudinal data on interstitial glucose levels and are increasingly used to show the dynamics of diabetes metabolism. Given the complexity of CGM data, it is crucial to extract important patterns hidden in these data through efficient visualization and statistical analysis techniques. Methods: In this paper, we adopted the concept of glucodensity, and using a subset of data from an ongoing clinical trial in pediatric individuals and young adults with new-onset type 1 diabetes, we performed a cluster analysis of glucodensities. We assessed the differences among the identified clusters using analysis of variance (ANOVA) with respect to residual pancreatic beta-cell function and some standard CGM-derived parameters such as time in range, time above range, and time below range. Results: Distinct CGM data patterns were identified using cluster analysis based on glucodensities. Statistically significant differences were shown among the clusters with respect to baseline levels of pancreatic beta-cell function surrogate (C-peptide) and with respect to time in range and time above range. Discussion: Our findings provide supportive evidence for the value of glucodensity in the analysis of CGM data. Some challenges in the modeling of CGM data include unbalanced data structure, missing observations, and many known and unknown confounders, which speaks to the importance of--and provides opportunities for--taking an approach integrating clinical, statistical, and data science expertise in the analysis of these data.
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BACKGROUND: Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. METHODS: We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. RESULTS: Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). CONCLUSIONS: Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.
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Tecido Adiposo Marrom , Índice de Massa Corporal , Metabolismo Energético , Adipócitos Marrons , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Adiposidade , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Fatores Etários , Idoso , Glicemia/análise , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pescoço , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Caracteres Sexuais , Estatísticas não Paramétricas , Temperatura , Adulto JovemRESUMO
AIMS: Insulin potentiates glucose-stimulated insulin secretion. These effects are attenuated in beta cell-specific insulin receptor knockout mice and insulin resistant humans. This investigation examines whether short duration insulin exposure regulates beta cell responsiveness to arginine, a non-glucose secretagogue, in healthy humans. MATERIALS AND METHODS: Arginine-stimulated insulin secretion was studied in 10 healthy humans. In each subject arginine was administered as a bolus followed by continuous infusion on two occasions one month apart, after sham/saline or hyperinsulinemic-isoglycemic clamp, respectively providing low and high insulin pre-exposure conditions. Arginine-stimulated insulin secretion was measured by C-peptide deconvolution, and by a selective immunogenic (DAKO) assay for direct measurement of endogenous but not exogenous insulin. RESULTS: Pre-exposure to exogenous insulin augmented arginine-stimulated insulin secretion. The effect was seen acutely following arginine bolus (endogenous DAKO insulin incremental AUC240-255min 311.6⯱â¯208.1 (post-insulin exposure) versus 120.6⯱â¯42.2 µU/mlâ¢min (sham/saline) (t-test Pâ¯=â¯0.021)), as well as in response to continuous arginine infusion (DAKO insulin incremental AUC260-290min 1095.3⯱â¯592.1 (sham/saline) versus 564.8⯱â¯207.1 µU/mlâ¢min (high insulin)(Pâ¯=â¯0.009)). Findings were similar when beta cell response was assessed using C-peptide, insulin secretion rates by deconvolution, and the C-peptide to glucose ratio. CONCLUSIONS: We demonstrate a physiologic role of insulin in regulation of the beta cell secretory response to arginine.
Assuntos
Arginina/farmacologia , Secreção de Insulina/efeitos dos fármacos , Insulina/farmacologia , Adulto , Glicemia/análise , Peptídeo C/sangue , Feminino , Humanos , Células Secretoras de Insulina/fisiologia , Masculino , Adulto JovemRESUMO
BACKGROUND AND AIMS: The regulation of cell-cholesterol efflux is not completely understood. Our aim was to assess the role of HDL- and non-HDL-related parameters in ATP-binding cassette transporter-A1 (ABCA1) and scavenger receptor class B-type-I (SRBI) cell-cholesterol efflux capacity (CEC) in coronary heart disease (CHD) cases and controls. METHODS: Lipids and apoA-I-containing HDL particles (by 2D gel-electrophoresis and immunodetection) were measured in 534 statin-treated CHD patients and in 1076 age-, gender-, and BMI-matched controls. ABCA1-CEC and SRBI-CEC were measured in apoB-depleted serum of 100 cases and 100 controls. RESULTS: Cases had significantly higher concentrations of preß-1 particles (88%) and ABCA1-CEC (34%) compared to controls. ABCA1-CEC was positively correlated with the concentrations of preß-1 particles, triglycerides, small-dense (sd) LDL-C, and LDL-C in both cases and controls. Moreover, both the concentration and the functionality of preß-1 particles (ABCA1-CEC/mg preß-1) were positively associated with the concentrations of sdLDL-C and triglycerides. Cases had 27% lower levels of large HDL particles but similar SRBI-CEC compared to controls. SRBI-CEC was correlated positively with HDL-C, apoA-I, and large-HDL particle levels. However, the functionality of large-HDL particles (SRBI-CEC/mg large particles) was significantly and positively correlated with the preß-1/α-1 ratio, sdLDL-C, and triglycerides. CONCLUSIONS: CHD patients have significantly higher concentration, but less functional preß-1 particles in term of cholesterol efflux capacity compared to controls. Triglyceride-rich lipoproteins have significant influence on either the concentration or the functionality or both of HDL particles and consequently HDL-CEC.
Assuntos
Doença das Coronárias , Inibidores de Hidroximetilglutaril-CoA Redutases , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I , Transporte Biológico , Colesterol , HDL-Colesterol , Humanos , LipoproteínasRESUMO
PURPOSE: To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS: Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS: In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT03466203.
Assuntos
Biomarcadores/sangue , Índice de Massa Corporal , Fígado Gorduroso/prevenção & controle , Fatores de Crescimento de Fibroblastos/administração & dosagem , Hipertrigliceridemia/terapia , Obesidade/fisiopatologia , Triglicerídeos/sangue , Adulto , Método Duplo-Cego , Feminino , Fatores de Crescimento de Fibroblastos/genética , Seguimentos , Humanos , Hipertrigliceridemia/genética , Hipertrigliceridemia/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
OBJECTIVE: The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS: A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N = 195) or medical/lifestyle therapy (N = 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c [HbA1c] ≤6.5% for 3 months without usual glucose-lowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS: Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m2, and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA1c (Δ = -1.9 ± 2.0 vs. -0.1 ± 2.0%; P < 0.001), fasting plasma glucose (Δ = -52 [-105, -5] vs. -12 [-48, 26] mg/dL; P < 0.001), and BMI (Δ = -8.0 ± 3.6 vs. -1.8 ± 2.9 kg/m2; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). CONCLUSIONS: Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used.
Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/cirurgia , Hemoglobinas Glicadas/metabolismo , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND: Chronic inflammation may participate in the pathogenesis of insulin resistance, type 2 diabetes, and cardiovascular disease and may be a common denominator that links obesity to these disease states. CONTENT: Epidemiologic studies have linked inflammatory biomarkers to incident diabetes and cardiovascular disease risk. Cellular and animal studies have provided support to the idea that inflammation mediates these disease processes, providing impetus to pharmacologically target these pathways for disease treatment and prevention. We review clinical strategies to target inflammation, with a focus on the antiinflammatory and antihyperglycemic effects of salicylates. SUMMARY: The evolving concept of diet-induced obesity driving insulin resistance, type 2 diabetes, and cardiovascular disease through immunologic processes provides new opportunities for the use of antiinflammatory strategies to correct the metabolic consequences of excess adiposity.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Tecido Adiposo/fisiopatologia , Animais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Resistência à Insulina , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/imunologia , Salicilatos/uso terapêuticoRESUMO
BACKGROUND: Biomarkers for estimating reduced glucose tolerance, insulin sensitivity, or impaired insulin secretion would be clinically useful, since these physiologic measures are important in the pathogenesis of type 2 diabetes mellitus. METHODS: We conducted a cross-sectional study in which 94 individuals, of whom 84 had 1 or more risk factors and 10 had no known risk factors for diabetes, underwent oral glucose tolerance testing. We measured 34 protein biomarkers associated with diabetes risk in 250-µL fasting serum samples. We applied multiple regression selection techniques to identify the most informative biomarkers and develop multivariate models to estimate glucose tolerance, insulin sensitivity, and insulin secretion. The ability of the glucose tolerance model to discriminate between diabetic individuals and those with impaired or normal glucose tolerance was evaluated by area under the ROC curve (AUC) analysis. RESULTS: Of the at-risk participants, 25 (30%) were found to have impaired glucose tolerance, and 11 (13%) diabetes. Using molecular counting technology, we assessed multiple biomarkers with high accuracy in small volume samples. Multivariate biomarker models derived from fasting samples correlated strongly with 2-h postload glucose tolerance (R(2) = 0.45, P < 0.0001), composite insulin sensitivity index (R(2) = 0.91, P < 0.0001), and insulin secretion (R(2) = 0.45, P < 0.0001). Additionally, the glucose tolerance model provided strong discrimination between diabetes vs impaired or normal glucose tolerance (AUC 0.89) and between diabetes and impaired glucose tolerance vs normal tolerance (AUC 0.78). CONCLUSIONS: Biomarkers in fasting blood samples may be useful in estimating glucose tolerance, insulin sensitivity, and insulin secretion.