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BACKGROUND & AIMS: Cotadutide, a peptide co-agonist at the glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors, has demonstrated robust improvements in body weight, glycemia, and hepatic fat fraction (HFF) in patients living with obesity and type 2 diabetes mellitus. METHODS: In PROXYMO, a 19-week randomized double-blind placebo-controlled trial, the safety and efficacy of cotadutide (600 µg, 300 µg) or placebo were evaluated in 74 participants with biopsy-proven noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Analyses were performed using intent-to-treat and modified intent-to-treat population data. RESULTS: Dose- and time-dependent improvements in HFF, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), markers of liver health, and metabolic parameters were observed with significant improvements after 19 weeks with 600 µg ([least squares] mean difference vs placebo, [95% confidence interval] for absolute HFF: -5.0% [-8.5 to -1.5]; ALT: -23.5 U/L [-47.1 to -1.8]; AST: -16.8 U/L [-33.0 to -0.8]). Incidences of any grade treatment-emergent adverse events (TEAEs) were 91.7%, 76.9%, and 37.5% with cotadutide 600 µg, 300 µg, and placebo, respectively. The majority were gastrointestinal, mild to moderate in severity, and generally consistent with other incretins at this stage of development. TEAEs leading to treatment discontinuation were 16.7%, 7.7%, and 4.2% with cotadutide 600 µg, 300 µg, and placebo, respectively. CONCLUSIONS: PROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven noncirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH. CLINICAL TRIAL REGISTRATION NUMBER: NCT04019561.
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Incretinas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Adulto , Resultado do Tratamento , Placebos/administração & dosagem , Idoso , Biópsia , Incretinas/uso terapêutico , Incretinas/efeitos adversos , Incretinas/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Fígado Gorduroso/tratamento farmacológico , Adulto JovemRESUMO
Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ2 distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.
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Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Biomarcadores , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Fibrose , Fígado/diagnóstico por imagem , Fígado/patologia , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos ProspectivosRESUMO
There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Fibrose , Biomarcadores , Biópsia/efeitos adversosRESUMO
OBJECTIVE: This study assessed the impact of diabetes mellitus (DM) on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) with advanced fibrosis prevalence in adults with overweight or obesity in the United States. METHODS: Participants (National Health and Nutrition Examination Survey [NHANES] 2015-2016 database) included 834 middle-aged patients with DM (21.7%) and 3,007 without DM (78.3%). NAFLD was defined by Fatty Liver Index (FLI) ≥ 60 or United States FLI (USFLI) ≥ 30. Moderate-to-high and high risk of advanced fibrosis was defined by fibrosis-4 index (FIB-4) ≥ 1.67 and ≥ 2.67, respectively, and NAFLD fibrosis scores > 0.676 also indicated a high risk. RESULTS: NAFLD prevalence increased with BMI. Steatosis was higher in individuals with overweight with DM versus without DM (USFLI ≥ 30: 48.3% vs. 17.4%; p < 0.01) and in individuals with obesity with DM versus without DM (USFLI ≥ 30: 79.9% vs. 57.6%; p < 0.01). DM significantly increased the proportion of individuals at moderate-to-high risk of fibrosis (FIB-4 ≥ 1.67: 31.8% vs. 20.1%; p < 0.05). In the high risk of advanced fibrosis group (FIB-4 ≥ 2.67), the risk almost doubled (3.8% vs. 7.1%). Among individuals with obesity, DM increased the proportion of adults with moderate and high risk of fibrosis by 1.8- and 2.5-fold, respectively (p < 0.01 and p = 0.39, respectively, vs. without DM). CONCLUSIONS: In this US cohort, DM modestly impacted steatosis, which was primarily obesity-driven. DM added a significant risk of fibrosis to individuals with overweight or obesity, suggesting that screening is imperative in adults with DM.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Cirrose Hepática/epidemiologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Inquéritos Nutricionais , Obesidade/complicações , Obesidade/epidemiologia , Prevalência , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Elevated postprandial lipemia is an independent risk factor for cardiovascular disease, yet methods to quantitate postmeal handling of dietary lipids in humans are limited. This study tested a new method to track dietary lipid appearance using a stable isotope tracer (2H11-oleate) in liquid meals containing three levels of fat [low fat (LF), 15 g; moderate fat (MF), 30 g; high fat (HF), 60 g]. Meals were fed to 12 healthy men [means ± SD, age 31.3 ± 9.2 yr, body mass index (BMI) 24.5 ± 1.9 kg/m2] during four randomized study visits; the HF meal was administered twice for reproducibility. Blood was collected over 8 h postprandially, triglyceride (TG)-rich lipoproteins (TRL), and particles with a Svedberg flotation rate >400 (Sf > 400, n = 8) were isolated by ultracentrifugation, and labeling of two TG species (54:3 and 52:2) was quantified by LC-MS. Total plasma TRL-TG concentrations were threefold greater than Sf > 400-TG. Both Sf > 400- and TRL-TG 54:3 were present at higher concentrations than 52:2, and singly labeled TG concentrations were higher than doubly labeled. Furthermore, TG 54:3 and the singly labeled molecules demonstrated higher plasma absolute entry rates differing significantly across fat levels within a single TG species (P < 0.01). Calculation of fractional entry showed no significant differences in label handling supporting the utility of either TG species for appearance rate calculations. These data demonstrate the utility of labeling research meals with stable isotopes to investigate human postprandial lipemia while simultaneously highlighting the importance of examining individual responses. Meal type and timing, control of prestudy activities, and effects of sex on outcomes should match the research goals. The method, optimized here, will be beneficial to conduct basic science research in precision nutrition and clinical drug development.NEW & NOTEWORTHY A novel method to test human intestinal lipid handling using stable isotope labeling is presented and, for the first time, plasma appearance and lipid turnover were quantified in 12 healthy men following meals with varying amounts of fat. The method can be applied to studies in precision nutrition characterizing individual response to support basic science research or drug development. This report discusses key questions for consideration in precision nutrition that were highlighted by the data.
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Ensaios de Triagem em Larga Escala/métodos , Hiperlipidemias/sangue , Lipídeos/sangue , Período Pós-Prandial , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Cromatografia Líquida/métodos , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Humanos , Hiperlipidemias/diagnóstico , Lipídeos/análise , Masculino , Refeições , Ciências da Nutrição/métodos , Ciências da Nutrição/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion. METHODS: Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and ß cell function were measured before and following each stimulus. RESULTS: Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of ß cell function. CONCLUSIONS/INTERPRETATION: Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/ß cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.
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Arginina/administração & dosagem , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Ingestão de Alimentos , Células Enteroendócrinas/efeitos dos fármacos , Hormônios Gastrointestinais/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Estado Pré-Diabético/sangue , Administração Intravenosa , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Células Enteroendócrinas/metabolismo , Polipeptídeo Inibidor Gástrico/sangue , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Peptídeo YY/sangue , Período Pós-Prandial , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/fisiopatologia , Fatores de Tempo , Estados UnidosRESUMO
Standard practice to minimize variability in beta cell function (BCF) measurement is to test in inpatient (IP) settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP) testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in two separate type 2 diabetes (T2DM) cohorts (OP, n = 20; IP n = 22) in test-retest design. MMTT variables included: insulin sensitivity (Si); beta cell responsivity (Φtot); and disposition index (DItot = Si* Φtot) following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg) and during hyperglycemia (AIRargMAX). RESULTS: Baseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility) across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort. [Table: see text] In conclusion, the variability (reproducibility) of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies.
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LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC-GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin-like growth factor 1 (IGF-1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561-570).
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Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of ß-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.
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Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Oxintomodulina/uso terapêutico , Adulto , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Índice de Massa Corporal , Estudos de Coortes , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Relação Dose-Resposta a Droga , Método Duplo-Cego , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/administração & dosagem , Glucose/efeitos adversos , Humanos , Hiperglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Infusões Intravenosas , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Obesidade/sangue , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações , Oxintomodulina/administração & dosagem , Oxintomodulina/efeitos adversos , Receptores de Glucagon/agonistas , Receptores de Glucagon/metabolismo , Adulto JovemRESUMO
AIMS: Patients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of cases of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycaemic control (HbA1c) in GADA-positive LADA vs GADA-negative T2D patients. METHODS: A post-hoc analysis was performed using data from 3 randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development programme in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12 months of treatment with dulaglutide or comparator were analysed using mixed-effect model repeated measures. RESULTS: Of 2466 adults tested for GADA (dulaglutide, 1710; glargine, 298; sitagliptin, 294; placebo, 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) were GADA-positive, including 58 GADA-high patients (> 200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups. Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LS mean change [95%CI], -1.09% [-1.15, -1.03]) and GADA-positive patients (-0.94% [-1.15, -0.72]) at 12 months. HbA1c reductions were numerically, but not statistically, significantly larger in GADA-low patients (-1.02% [-1.26, -0.78]) vs GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months. CONCLUSIONS: These data are the first to indicate that dulaglutide was effective in reducing HbA1c in LADA patients.
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Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobinas Glicadas/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Diabetes Autoimune Latente em Adultos/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Glicemia/metabolismo , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Diabetes Autoimune Latente em Adultos/sangue , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos , Resultado do TratamentoRESUMO
Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively ( P < 0.001 for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1. Robust reproducibility of the sitagliptin-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins.
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Técnica Clamp de Glucose/métodos , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Refeições/fisiologia , Fosfato de Sitagliptina/farmacologia , Adolescente , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Via Secretória/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Glucose homeostasis improves within days following Roux-en-Y gastric bypass (RYGB) surgery. The dynamic metabolic response to caloric intake following RYGB has been assessed using liquid mixed meal tolerance tests (MMTT). Few studies have evaluated the glycemic and hormonal response to a solid mixed meal in subjects with diabetes prior to, and within the first month following RYGB. METHODS: Seventeen women with type 2 diabetes of less than 5 years duration participated. Fasting measures of glucose homeostasis, lipids and gut hormones were obtained pre- and post-surgery. MMTT utilizing a solid 4 oz chocolate pudding performed pre-, 2 and 4 weeks post-surgery. Metabolic response to 4 and 2 oz MMTT assessed in five diabetic subjects not undergoing surgery. RESULTS: Significant reductions in fasting glucose and insulin at 3 days, and in fasting betatrophin, triglycerides and total cholesterol at 2 weeks post-surgery. Hepatic insulin clearance was greater at 3 days post-surgery. Subjects exhibited less hunger and greater feelings of fullness and satisfaction during the MMTT while consuming 52.9 ± 6.5% and 51.0 ± 6.5% of the meal at 2 and 4 weeks post-surgery respectively. At 2 weeks post-surgery, glucose and insulin response to MMTT were improved, with greater GLP-1 and PYY secretion. Improved response to solid MMTT not replicated by consumption of smaller pudding volume in diabetic non-surgical subjects. CONCLUSIONS: With a test meal of size and composition representative of the routine diet of post-RYGB subjects, improved glycemic and gut hormone responses occur which cannot be replicated by reducing the size of the MMTT in diabetic subjects not undergoing surgery. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00957957 August 11, 2009.
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BACKGROUND: Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM. METHODS AND RESULTS: In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (18F-fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean±SEM: 1.95±0.43 versus 1.67±0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Δtarget-to-background ratio [95% confidence interval]: -0.18 [-0.35 to -0.004] versus 0.09 [-0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (ß=-0.27; P=0.038). CONCLUSIONS: In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261.
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Anti-Inflamatórios/uso terapêutico , Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Vasos Coronários/efeitos dos fármacos , Fluordesoxiglucose F18/administração & dosagem , Placa Aterosclerótica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/administração & dosagem , Adulto , Idoso , Biomarcadores/sangue , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Método Duplo-Cego , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/tratamento farmacológicoRESUMO
OBJECTIVE: Standardized, reproducible, and feasible quantification of ß-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (â¼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from â¼0.3 to â¼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.
Assuntos
Arginina , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Refeições , Estado Pré-Diabético/metabolismo , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Glucose , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Estado Pré-Diabético/diagnóstico , Padrões de Referência , Reprodutibilidade dos Testes , Estados UnidosRESUMO
AIM: A traditional oral fatty acid challenge assesses absorption of triacylglycerol (TG) into the periphery through the intestines, but cannot distinguish the composition or source of fatty acid in the TG. Stable isotope-labeled tracers combined with LC-MRM can be used to identify and distinguish TG synthesized with dietary and stored fatty acids. RESULTS: Concentrations of three abundant TGs (52:2, 54:3 and 54:4) were monitored for incorporation of one or two (2)H11-oleate molecules per TG. This method was subjected to routine assay validation and meets typical requirements for an assay to be used to support clinical studies. CONCLUSION: Calculations for the fractional appearance rate of TG in plasma are presented along with the intracellular enterocyte precursor pool for 12 study participants.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Mucosa Intestinal/metabolismo , Triglicerídeos/análise , Adolescente , Adulto , Deutério/análise , Dieta , Humanos , Marcação por Isótopo/métodos , Masculino , Ácido Oleico/análise , Ácido Oleico/sangue , Ácido Oleico/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Adulto JovemRESUMO
The graded glucose infusion (GGI) examines insulin secretory response patterns to continuously escalating glycemia. The current study series sought to more fully appraise its performance characteristics. Key questions addressed were comparison of the GGI to the hyperglycemic clamp (HGC), comparison of insulin secretory response patterns across three volunteer populations known to differ in ß-cell function (healthy nonobese, obese nondiabetic, and type 2 diabetic), and characterization of effects of known insulin secretagogues in the context of a GGI. Insulin secretory response was measured as changes in insulin, C-peptide, insulin secretion rates (ISR), and ratio of ISR to prevailing glucose (ISR/G). The GGI correlated well with the HGC (r = 0.72 for ISR/G, P < 0.01). The insulin secretory response in type 2 diabetes (T2DM) was significantly blunted (P < 0.001), whereas it was significantly increased in obese nondiabetics compared with healthy nonobese (P < 0.001). Finally, robust (P < 0.001 over placebo) pharmacological effects were observed in T2DM and healthy nonobese volunteers. Collectively, the findings of this investigational series bolster confidence that the GGI has solid attributes for assessing insulin secretory response to glucose across populations and pharmacology. Notably, the coupling of insulin secretory response to glycemic changes was distinctly and uniformly linear across populations and in the context of insulin secretagogues. (Clinical Trial Registration Nos. NCT00782418, NCT01055340, NCT01373450).
Assuntos
Diabetes Mellitus/metabolismo , Teste de Tolerância a Glucose/métodos , Glucose/administração & dosagem , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Obesidade/sangue , Método Duplo-Cego , Glucose/farmacocinética , Humanos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Modelos Lineares , Modelos Biológicos , Dinâmica não Linear , Efeito Placebo , Taxa de SobrevidaRESUMO
BACKGROUND: Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. OBJECTIVE: The goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m(2)/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. RESULTS: Compared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43-2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17-0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. CONCLUSIONS: Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.
RESUMO
BACKGROUND: A direct comparison of radioimmunoassay (RIA) and LC-MS/MS for insulin glargine quantification in human plasma is provided. RESULTS: Compared with the RIA, the LC-MS/MS assay exhibited comparable/improved sensitivity (LLOQ at 0.1 ng/ml [Ë16.7 pM or 2.8 µU/ml] for glargine and its metabolites M1 and M2, respectively) and ruggedness. Most importantly, it demonstrated a superior specificity advantage against the interference from endogenous insulin, exogenous insulin analogs (e.g., Novolog(®), Humalog(®) or Levemir(®), routine treatment for diabetes mellitus) and potentially pre-existing anti-insulin antibodies in patient samples. The data obtained from diabetic patients suggested the LC-MS/MS assay substantially improved pharmacokinetic characterization of glargine. CONCLUSION: LC-MS/MS overcame common limitations of RIA, and provided critically needed specificity to support glargine clinical development, without sacrificing assay sensitivity and ruggedness.