RESUMO
CONTEXT: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood. OBJECTIVE: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D. METHODS: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D. RESULTS: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes. CONCLUSION: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Dieta , Peptídeo 1 Semelhante ao Glucagon , Estilo de Vida , Estado Pré-Diabético , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Estudos Transversais , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Idoso , Adulto , Resistência à Insulina , Jejum/sangue , Obesidade/sangue , Obesidade/metabolismo , Estudos de Coortes , Glicemia/metabolismo , Glicemia/análise , Adiposidade/fisiologiaRESUMO
BACKGROUND: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. METHODS: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 nâ¯=â¯403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 nâ¯=â¯458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariable regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. FINDINGS: A higher Tpred score was associated with healthier diets high in wholegrain (ß=3.36â¯g, 95% CI 0.31, 6.40 and ß=2.82â¯g, 95% CI 0.06, 5.57) and lower energy intake (ß=-75.53â¯kcal, 95% CI -144.71, -2.35 and ß=-122.51â¯kcal, 95% CI -186.56, -38.46), and saturated fat (ß=-0.92â¯g, 95% CI -1.56, -0.28 and ß=-0.98â¯g, 95% CI -1.53, -0.42â¯g), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and favourable lipid profiles HDL-cholesterol (ß=0.07â¯mmol/L, 95% CI 0.03, 0.1), (ß=0.08â¯mmol/L, 95% CI 0.04, 0.1), and triglycerides (ß=-0.1â¯mmol/L, 95% CI -0.2, -0.03), (ß=-0.2â¯mmol/L, 95% CI -0.3, -0.09), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat (ß=-0.74%, 95% CI -0.67, -0.81), and lower fasting concentrations of HbA1c (ß=-0.9â¯mmol/mol, 95% CI -1.5, -0.1), glucose (ß=-0.2â¯mmol/L, 95% CI -0.4, -0.05) and insulin (ß=-11.0â¯pmol/mol, 95% CI -19.5, -2.6). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (ß=-0.2â¯mmol/L, 95% CI -0.3, -0.01) and insulin (ß=-9.2â¯pmol/mol, 95% CI -17.9, -0.4) concentrations in cohort 2. INTERPRETATION: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health. FUNDING: This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies.
Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Metabolômica/métodos , Estado Pré-Diabético/dietoterapia , Idoso , Estudos de Casos e Controles , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Dieta Saudável , Ingestão de Energia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Triglicerídeos/sangueRESUMO
AIMS/HYPOTHESIS: There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on 'time to failure' methods, yet determining a 'coefficient of failure' has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration. METHODS: An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual's observed HbA1c measures from the first eligible HbA1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution. RESULTS: The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA1c per year. CONCLUSIONS/INTERPRETATION: We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/uso terapêutico , Idoso , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/metabolismo , Registros Eletrônicos de Saúde , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/uso terapêutico , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To identify the clinical and genetic factors that explain why the rate of diabetes progression is highly variable between individuals following diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 5,250 patients with type 2 diabetes using comprehensive electronic medical records in Tayside, Scotland, from 1992 onward. We investigated the association of clinical, biochemical, and genetic factors with the risk of progression of type 2 diabetes from diagnosis to the requirement of insulin treatment (defined as insulin treatment or HbA1c ≥8.5% [69 mmol/mol] treated with two or more noninsulin therapies). RESULTS: Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log triacylglyceride (TG) concentrations (hazard ratio [HR] 1.28 per mmol/L [95% CI 1.15-1.42]) and lower HDL concentrations (HR 0.70 per mmol/L [95% CI 0.55-0.87]). A high Genetic Risk Score derived from 61 diabetes risk variants was associated with a younger age at diagnosis and a younger age when starting insulin but was not associated with the progression rate from diabetes to the requirement of insulin treatment. CONCLUSIONS: Increased TG and low HDL levels are independently associated with increased rate of progression of diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid progression of diabetes, suggesting a difference in biological process that needs further investigation.