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1.
Artigo em Inglês | MEDLINE | ID: mdl-34728468

RESUMO

BACKGROUND: Worsening glycemic control indicates elevated risk of pancreatic ductal adenocarcinoma [PDAC]. We developed prediction models for PDAC among those with worsening glycemic control after diabetes diagnosis. METHODS: In 2000-2016 records within the VA Health System, we identified three cohorts with progression of diabetes: (a) insulin initiation (n=449,685), (b) initiation of combination oral hypoglycemic medication (n=414,460), and (c) hemoglobin A1c (HbA1c) >=8% with at least 1% change within 15 months (n=593,401). We computed 12-, 36- and 60-month incidence of PDAC and developed prediction models separately for males and females, with consideration of >30 demographic, behavioral, clinical and laboratory variables. Models were selected to optimize Akaike's Information Criterion, and performance for predicting 12-, 36-, 60-month incident PDAC was evaluated by bootstrap. RESULTS: Incidence of PDAC was highest for insulin-initiators and greater in males than in females. Optimism corrected c-indices of the models for predicting 36-month incidence of PDAC in the male population were: (a) 0.72, (b) 0.70, and (c) 0.71, respectively. Models performed better for predicting 12-month incident PDAC (c-index (a) 0.78, (b) 0.73, (c) 0.76 for males), and worse for predicting 60-month incident PDAC (c-index (a) 0.69, (b) 0.67, (c) 0.68 for males). Model performance was lower among females. For subjects whose model-predicted 36-months PDAC risks were >=1%, the observed incidences were (a) 1.9%, (b) 2.2%, and (c) 1.8%. CONCLUSIONS: Sex-specific models for PDAC can estimate risk of PDAC at the time of progression of diabetes. IMPACT: Our models can identify diabetes patients who would benefit from PDAC screening.

2.
Diabetes Care ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789503

RESUMO

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

3.
Front Nutr ; 8: 729510, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692745

RESUMO

Background: Nutrient imbalance can frequently occur in patients with indications for parenteral nutrition (PN) after gastrointestinal surgery. This study aimed to compare the recommendations of a surgeon to those of a dietitian in the field of parenteral nutrition. Methods: This study was performed on 256 patients undergoing gastrointestinal surgery who received PN, which included 120 patients who received PN based on recommendations of the surgeons and 136 patients who were referred to receive PN under the supervision of a dietitian in Razi Hospital in Rasht, Iran. Data on PN and clinical outcomes of the patients were collected. Results: Patients under the supervision of dietitians received higher vitamin B complex and lipids and lower vitamin A and vitamin E than the surgeon-supervised patients (all P < 0.001). In the group receiving PN under the supervision of a surgeon, the level of blood glucose (207 vs. 182, P < 0.01), sodium (138 vs. 136, P = 0.01), potassium (3.97 vs. 3.53, P < 0.01), and white blood cell count (9.83 vs. 9.28, P < 0.01) increased significantly at the end of the PN compared to baseline. In the group receiving PN under the supervision of a dietician, the level of serum Cr (1.23 vs. 1.32, P = 0.04), Mg (2.07 vs. 1.84, P < 0.01), and pH (7.45 vs. 7.5, P = 0.03) significantly improved after receiving parenteral nutrition compared to baseline. Conclusion: The amounts of nutrients recommended for PN by the surgeon and dietitian were different. Implementation of dietitian recommendations in critically ill patients under PN can improve patients' clinical parameters.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34669940

RESUMO

CONTEXT: Though polycystic ovarian syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age, risk factors that may cause the syndrome are poorly understood. Based on epidemiologic studies, PCOS is thought to cause several adverse outcomes such as cardiovascular disease; however, the common presence of co-morbidities such as obesity may be responsible for such associations, rather than PCOS in and of itself. To overcome the limitations of observational studies, investigators have employed Mendelian randomization (MR), which uses genetic variants to interrogate causality between exposures and outcomes. EVIDENCE ACQUISITION: To clarify causes and consequences of PCOS, this review will describe MR studies involving PCOS, both as an exposure and as an outcome. The literature was searched using the terms Mendelian randomization, Mendelian randomization, polycystic ovary syndrome, polycystic ovarian syndrome, and PCOS (to May 2021). EVIDENCE SYNTHESIS: MR studies have suggested that obesity, testosterone levels, fasting insulin, serum SHBG concentrations, menopause timing, male-pattern balding and depression may play a causal role in PCOS. In turn, PCOS may increase the risk of estrogen receptor positive breast cancer, decrease the risk of endometrioid ovarian cancer, and have no direct causal effect on type 2 diabetes, coronary heart disease, or stroke. CONCLUSIONS: The accumulation of genome-wide association studies in PCOS has enabled multiple MR analyses identifying factors that may cause PCOS or be caused by PCOS. This knowledge will be critical to future development of measures to prevent PCOS in girls at risk as well as prevent complications in those who have PCOS.

5.
Metabolites ; 11(7)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206745

RESUMO

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.

6.
Curr Opin Gastroenterol ; 37(5): 520-525, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265796

RESUMO

PURPOSE OF REVIEW: Diabetes secondary to pancreatic diseases (i.e., acute pancreatitis, chronic pancreatitis, and pancreatic cancer) is increasingly studied, but remains challenging to distinguish from type 2 diabetes (T2DM). We review the clinical significance and potential biomarkers that may help differentiate these types of diabetes. RECENT FINDINGS: Recent studies have identified several complications (including nonvascular) that occur more frequently in patients with diabetes secondary to acute and chronic pancreatitis than T2DM, and biomarkers to differentiate these types of diabetes. There have been advances that may enable the enrichment of a population of adults with new onset diabetes to potentially screen for occult pancreatic cancer, but efforts are needed to identify and validate promising diagnostic biomarkers. SUMMARY: High-quality studies are needed to more precisely understand the risk factors and natural course of diabetes secondary to pancreatic diseases. Mechanistic and interventional studies are awaited to provide insights that will distinguish diabetes secondary to pancreatic diseases and refine the management of hyperglycemia in this patient population.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Pancreatopatias , Neoplasias Pancreáticas , Pancreatite , Doença Aguda , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Pancreatopatias/diagnóstico , Pancreatopatias/etiologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico
7.
Curr Opin Gastroenterol ; 37(5): 526-531, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074860

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to delineate risk factors for the development of diabetes in patients with chronic pancreatitis. The natural history including progression to diabetes and complications that develop once diabetes occurs in chronic pancreatitis is also reviewed. RECENT FINDINGS: Studies have found that predictors of diabetes in chronic pancreatitis include both risk factors for type 2 diabetes (e.g., obesity, genetic variants) as well as pancreas-specific factors (e.g., pancreatic calcification, exocrine insufficiency). Rates of diabetes in chronic pancreatitis are strongly related to the duration of chronic pancreatitis, reflecting progressive dysfunction and damage to the insulin-secreting beta cells. Patients with diabetes and chronic pancreatitis experience an excess burden of complications, including higher all-cause and cancer-related mortality. SUMMARY: The high incidence and significant impact of diabetes on the morbidity and mortality of patients with chronic pancreatitis highlights the urgent need for clinically applicable models to predict diabetes in those with chronic pancreatitis, allowing efforts for targeted interventions to prevent diabetes. Research being carried out in the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer holds promise to fulfill these goals.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias Pancreáticas , Pancreatite Crônica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Pâncreas , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/etiologia , Pancreatite Crônica/epidemiologia , Pancreatite Crônica/etiologia , Fatores de Risco
8.
Hum Mol Genet ; 30(22): 2190-2204, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34165540

RESUMO

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.

10.
J Transl Med ; 19(1): 128, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781275

RESUMO

BACKGROUND: Omega-3 polyunsaturated fatty acids (n3-PUFAs) may exert beneficial effects on the immune system of patients with viral infections. This paper aimed to examine the effect of n3-PUFA supplementation on inflammatory and biochemical markers in critically ill patients with COVID-19. METHODS: A double-blind, randomized clinical trial study was conducted on 128 critically ill patients infected with COVID-19 who were randomly assigned to the intervention (fortified formula with n3-PUFA) (n = 42) and control (n = 86) groups. Data on 1 month survival rate, blood glucose, sodium (Na), potassium (K), blood urea nitrogen (BUN), creatinine (Cr), albumin, hematocrit (HCT), calcium (Ca), phosphorus (P), mean arterial pressure (MAP), O2 saturation (O2sat), arterial pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), bicarbonate (HCO3), base excess (Be), white blood cells (WBCs), Glasgow Coma Scale (GCS), hemoglobin (Hb), platelet (Plt), and the partial thromboplastin time (PTT) were collected at baseline and after 14 days of the intervention. RESULTS: The intervention group had significantly higher 1-month survival rate and higher levels of arterial pH, HCO3, and Be and lower levels of BUN, Cr, and K compared with the control group after intervention (all P < 0.05). There were no significant differences between blood glucose, Na, HCT, Ca, P, MAP, O2sat, PO2, PCO2, WBCs, GCS, Hb, Plt, PTT, and albumin between two groups. CONCLUSION: Omega-3 supplementation improved the levels of several parameters of respiratory and renal function in critically ill patients with COVID-19. Further clinical studies are warranted. Trial registry Name of the registry: This study was registered in the Iranian Registry of Clinical Trials (IRCT); Trial registration number: IRCT20151226025699N3; Date of registration: 2020.5.20; URL of trial registry record: https://en.irct.ir/trial/48213.


Assuntos
COVID-19/dietoterapia , COVID-19/diagnóstico , Estado Terminal/terapia , Ácidos Graxos Ômega-3/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biomarcadores/sangue , Gasometria , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , COVID-19/mortalidade , COVID-19/fisiopatologia , Estado Terminal/mortalidade , Suplementos Nutricionais , Método Duplo-Cego , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Hematócrito , Humanos , Mediadores da Inflamação/análise , Mediadores da Inflamação/sangue , Irã (Geográfico)/epidemiologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Rim/virologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/fisiopatologia , Sistema Respiratório/virologia , SARS-CoV-2/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento
11.
Diabetes ; 70(2): 627-637, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33158931

RESUMO

Polycystic ovary syndrome (PCOS) has been associated with diabetes and cardiovascular disease; however, whether the relationship is causal is uncertain. We conducted a two-sample Mendelian randomization study to investigate the associations of PCOS with type 2 diabetes, coronary heart disease (CHD), and stroke. Association between PCOS and diabetes risk was examined in European and Asian cohorts, both sex specific and sex combined. Causal effects of PCOS on risks of CHD and stroke were evaluated in European cohorts. Stroke was analyzed as any stroke as well as four subtypes of stroke (ischemic, large artery, cardioembolic, small vessel). We found no association of genetically predicted PCOS with risk of diabetes, CHD, or stroke. This suggests that PCOS in and of itself does not increase the risk of these outcomes. Other features of PCOS (obesity, elevated testosterone, low sex hormone binding globulin) may explain the association between PCOS and cardiometabolic diseases. In light of these results, efforts to prevent cardiometabolic complications in PCOS should focus on women with high-risk features rather than all women with PCOS.


Assuntos
Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Síndrome do Ovário Policístico/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Adulto , Estudos de Casos e Controles , Comorbidade , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Análise da Randomização Mendeliana , Síndrome do Ovário Policístico/genética , Risco , Acidente Vascular Cerebral/genética
12.
Front Physiol ; 11: 570276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250773

RESUMO

The clinical significance of diabetes arising in the setting of pancreatic disease (also known as diabetes of the exocrine pancreas, DEP) has drawn more attention in recent years. However, significant improvements still need to be made in the recognition, diagnosis and treatment of the disorder, and in the knowledge of the pathological mechanisms. The clinical course of DEP is different from type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). DEP develops in patients with previous existing exocrine pancreatic disorders which damage both exocrine and endocrine parts of pancreas, and lead to pancreas exocrine insufficiency (PEI) and malnutrition. Therefore, damage in various exocrine and endocrine cell types participating in glucose metabolism regulation likely contribute to the development of DEP. Due to the limited amount of clinical and experimental studies, the pathological mechanism of DEP is poorly defined. In fact, it still not entirely clear whether DEP represents a distinct pathologic entity or is a form of T2DM arising when ß cell failure is accelerated by pancreatic disease. In this review, we include findings from related studies in T1DM and T2DM to highlight potential pathological mechanisms involved in initiation and progression of DEP, and to provide directions for future research studies.

13.
Front Genet ; 11: 615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754192

RESUMO

Aims: Causal transcripts at genomic loci associated with type 2 diabetes (T2D) are mostly unknown. The chr8p23.1 variant rs4841132, associated with an insulin-resistant diabetes risk phenotype, lies in the second exon of a long non-coding RNA (lncRNA) gene, LOC157273, located 175 kilobases from PPP1R3B, which encodes a key protein regulating insulin-mediated hepatic glycogen storage in humans. We hypothesized that LOC157273 regulates expression of PPP1R3B in human hepatocytes. Methods: We tested our hypothesis using Stellaris fluorescent in situ hybridization to assess subcellular localization of LOC157273; small interfering RNA (siRNA) knockdown of LOC157273, followed by RT-PCR to quantify LOC157273 and PPP1R3B expression; RNA-seq to quantify the whole-transcriptome gene expression response to LOC157273 knockdown; and an insulin-stimulated assay to measure hepatocyte glycogen deposition before and after knockdown. Results: We found that siRNA knockdown decreased LOC157273 transcript levels by approximately 80%, increased PPP1R3B mRNA levels by 1.7-fold, and increased glycogen deposition by >50% in primary human hepatocytes. An A/G heterozygous carrier (vs. three G/G carriers) had reduced LOC157273 abundance due to reduced transcription of the A allele and increased PPP1R3B expression and glycogen deposition. Conclusion: We show that the lncRNA LOC157273 is a negative regulator of PPP1R3B expression and glycogen deposition in human hepatocytes and a causal transcript at an insulin-resistant T2D risk locus.

14.
J Endocr Soc ; 4(8): bvaa092, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32803094

RESUMO

Objective: To assess the relationship of physical activity with bone mineral density (BMD) at various sites and examine potential modifying metabolic factors. Methods: Responses from physical activity questionnaires were used to determine total physical activity (PA), moderate physical activity (mod-PA), and sedentary time. Regression analyses were performed to evaluate association of activity traits with insulin sensitivity by euglycemic clamp, adiponectin, C-reactive protein (CRP), and plasminogen activator inhibitor-1 (PAI-1) in 741 healthy subjects. Results: The cohort was relatively sedentary. Activity level was associated with arm, pelvis, and leg BMD in univariate analyses. In multivariate association analyses of arm BMD, only female sex (ß = -0.73, P < 0.0001) and adiponectin (ß = -0.076, P = 0.0091) were significant. Multivariate analyses of pelvis BMD found independent associations with body mass index (BMI) (ß = 0.33, P < 0.0001), adiponectin (ß = -0.10, P = 0.013), female sex (ß = -0.18, P < 0.0001), sedentary time (ß = -0.088, P = 0.034), PA (ß = 0.11, P = 0.01), and mod-PA (ß = 0.11, P = 0.014). Age (ß = -0.10, P = 0.0087), female sex (ß = -0.63, P < 0.0001), BMI (ß = 0.24, P < 0.0001), and mod-PA (ß = 0.10, P = 0.0024) were independently associated with leg BMD. Conclusions: These results suggest that BMD increases with physical activity in the arms, legs, and pelvis and is inversely related to sedentary time in the pelvis and legs; these associations may be modified by age, sex, BMI, and adiponectin, depending on the site, with physical activity being more important to pelvis and leg BMD than arm BMD and sedentary time being important for pelvis BMD. Moreover, we demonstrated that CRP, PAI-1, and insulin sensitivity play a minor role in BMD.

15.
Diabetes Obes Metab ; 22(11): 1976-1984, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32687239

RESUMO

AIM: To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). MATERIALS AND METHODS: The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. RESULTS: After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. CONCLUSIONS: The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Resistência à Insulina , Glicemia , Diabetes Mellitus Tipo 2/epidemiologia , Teste de Tolerância a Glucose , Humanos , Insulina
16.
Circ Res ; 126(11): 1526-1548, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32437307

RESUMO

Diabetes mellitus is a major risk factor for coronary heart disease (CHD). The major form of diabetes mellitus is type 2 diabetes mellitus (T2D), which is thus largely responsible for the CHD association in the general population. Recent years have seen major advances in the genetics of T2D, principally through ever-increasing large-scale genome-wide association studies. This article addresses the question of whether this expanding knowledge of the genomics of T2D provides insight into the etiologic relationship between T2D and CHD. We will investigate this relationship by reviewing the evidence for shared genetic loci between T2D and CHD; by examining the formal testing of this interaction (Mendelian randomization studies assessing whether T2D is causal for CHD); and then turn to the implications of this genetic relationship for therapies for CHD, for therapies for T2D, and for therapies that affect both. In conclusion, the growing knowledge of the genetic relationship between T2D and CHD is beginning to provide the promise for improved prevention and treatment of both disorders.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/genética , Animais , Doença das Coronárias/etiologia , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos
18.
Curr Nutr Rep ; 9(2): 83-93, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32157661

RESUMO

PURPOSE OF REVIEW: An increasing body of evidence suggests that the gut microbiome influences the pathogenesis of insulin resistance and type 2 diabetes (T2D). In this review, we will discuss the latest findings regarding the mechanisms linking the gut microbiome and microbial metabolites with T2D and therapeutic approaches based on the gut microbiota for the prevention and treatment of T2D. RECENT FINDINGS: Alterations in the gut microbial composition are associated with the risk of T2D. The gut microbiota can metabolize dietary- and host-derived factors to produce numerous microbial metabolites, which are involved in metabolic processes modulating nutrition and energy harvest, gut barrier function, systemic inflammation, and glucose metabolism. Microbial metabolites are important mediators of microbial-host crosstalk impacting host glucose metabolism. Furthermore, microbiome-based interventions may have beneficial effects on glycemic control. Future research is required to develop personalized T2D therapy based on microbial composition and/or metabolites.


Assuntos
Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal , Interações entre Hospedeiro e Microrganismos , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dietoterapia , Ácidos Graxos Voláteis/metabolismo , Transplante de Microbiota Fecal , Humanos , Imidazóis/metabolismo , Indóis/metabolismo , Resistência à Insulina/fisiologia , Metilaminas/metabolismo , Camundongos , Probióticos/uso terapêutico , Ratos
19.
J Clin Endocrinol Metab ; 105(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31714576

RESUMO

CONTEXT: Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D). OBJECTIVE: To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans. DESIGN, SETTING, AND PARTICIPANTS: A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L-GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans. RESULTS: Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L-GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method. CONCLUSIONS: Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L-GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Secreção de Insulina/genética , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores/análise , Índice de Massa Corporal , Grupos Étnicos/genética , Feminino , Seguimentos , Genótipo , Humanos , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Fatores de Risco , Estados Unidos/epidemiologia
20.
Pharmacogenomics J ; 20(3): 462-470, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31801993

RESUMO

It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.


Assuntos
LDL-Colesterol/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Análise da Randomização Mendeliana/métodos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/induzido quimicamente , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino
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