Hepatic Insulin Resistance Increases Risk of Gallstone Disease in Indigenous Americans in the Southwestern United States.

Introduction: Animal models indicate that hepatic insulin resistance (IR) promotes cholesterol gallstone disease (GSD). We sought to determine whether hepatic and whole-body IR is associated with incident GSD.

Methods: At baseline, 450 Southwestern Indigenous American adults without GSD were included.

Prostate cancer detection through unbiased capture of methylated cell-free DNA.

Prostate cancer screening using prostate-specific antigen (PSA) has been shown to reduce mortality but with substantial overdiagnosis, leading to unnecessary biopsies. The identification of a highly specific biomarker using liquid biopsies, represents an unmet need in the diagnostic pathway for prostate cancer. In this study, we employed a method that enriches for methylated cell-free DNA fragments coupled with a machine learning algorithm which enabled the detection of metastatic and localized cancers with AUCs of 0.

Pleiotropic effects of an eQTL in the CELSR2/PSRC1/SORT1 cluster that associates with LDL-C and resting metabolic rate.

Context: The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism.

Objective: To determine biological mechanisms that govern diverse functions of this locus.

An E115A Missense Variant in CERS2 Is Associated With Increased Sleeping Energy Expenditure and Hepatic Insulin Resistance in American Indians.

Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp.

Epistasis Between HLA-DRB1*16:02:01 and SLC16A11 T-C-G-T-T Reduces Odds for Type 2 Diabetes in Southwest American Indians.

We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) in an indigenous American community by genotyping all study participants for both high-resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test.

Novel signals and polygenic score for height are associated with pubertal growth traits in Southwestern American Indians.

Most genetic variants associated with adult height have been identified through large genome-wide association studies (GWASs) in European-ancestry cohorts. However, it is unclear how these variants influence linear growth during adolescence. This study uses anthropometric and genotypic data from a longitudinal study conducted in an American Indian community in Arizona between 1965-2007.

Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

Aim: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset.

Materials And Methods: Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes.

Effects of the R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy.

Introduction: The gene regulates insulin secretion and plays a critical role in glucose homeostasis. The effects of an R1420H loss-of-function variant on beta-cell function, incidence of type 2 diabetes, and age-at-onset, prevalence, and progression of diabetes complications were assessed in a longitudinal study in American Indians.

Research Design And Methods: We analyzed beta-cell function through the relationship between insulin secretion and insulin sensitivity in members of this population without diabetes aged ≥5 years using standard major axis regression.

Diagnostic criteria and etiopathogenesis of type 2 diabetes and its complications: Lessons from the Pima Indians.

The Phoenix Epidemiology and Clinical Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases has conducted prospective studies of diabetes and its complications in the Pima Indians living in Arizona, USA for over 50 years. In this review we highlight areas in which these studies provided vital insights into the criteria used to diagnose type 2 diabetes, the pathophysiologic changes that accompany the development of type 2 diabetes, and the course and determinants of diabetes complications-focusing specifically on diabetic kidney disease. We include data from our longitudinal population-based study of diabetes and its complications, studies on the role of insulin resistance and insulin secretion in the pathophysiology of type 2 diabetes, and in-depth studies of diabetic kidney disease that include measures of glomerular function and research kidney biopsies.

Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS).

Background: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes.

Methods: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study.

Glycemic Measures in Childhood as Predictors of Future Diabetes-Related Microvascular Complications in an Indigenous American Population.

Objective: To examine the role of glycemic measures performed during childhood in predicting future diabetes-related nephropathy and retinopathy in a high-risk indigenous American cohort.

Research Design And Methods: We studied associations between glycated hemoglobin (HbA1c) and 2-h plasma glucose (PG), measured during childhood (age 5 to <20 years) in a longitudinal observational study of diabetes and its complications (1965-2007), and future albuminuria (albumin creatinine ratio [ACR] ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), and retinopathy (at least one microaneurysm or hemorrhage or proliferative retinopathy on direct ophthalmoscopy). Areas under the receiver operating characteristic curve (AUCs) for childhood glycemic measures when predicting nephropathy and retinopathy were compared.

Adolescent Growth Spurt and Type 2 Diabetes Risk in Southwestern American Indians.

Early puberty onset is associated with higher risk of diabetes, but most studies have not accounted for childhood factors that may confound the association. Using data from a study conducted in an Indigenous community in Arizona (1965-2007), we examined associations of timing and velocity of the adolescent growth spurt with type 2 diabetes, and whether these associations are mediated by childhood body mass index and insulinemia. Adolescent growth parameters were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, for 861 participants with height measurements spanning the whole period of growth.

The utility of a type 2 diabetes polygenic score in addition to clinical variables for prediction of type 2 diabetes incidence in birth, youth and adult cohorts in an Indigenous study population.

Aims/hypothesis: There is limited information on how polygenic scores (PSs), based on variants from genome-wide association studies (GWASs) of type 2 diabetes, add to clinical variables in predicting type 2 diabetes incidence, particularly in non-European-ancestry populations.

Methods: For participants in a longitudinal study in an Indigenous population from the Southwestern USA with high type 2 diabetes prevalence, we analysed ten constructions of PS using publicly available GWAS summary statistics. Type 2 diabetes incidence was examined in three cohorts of individuals without diabetes at baseline.

Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians.

Background: Genome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians.

Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP).

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms.

Short-Term Efficacy of Using a Novel Low-Volume Bone Marrow Aspiration Technique to Treat Knee Osteoarthritis: A Retrospective Cohort Study.

Background: Intra-articular bone marrow concentrate (BMC) and aspirate (BMA) injections have been used with mixed results to treat osteoarthritis (OA). Given the various aspiration and concentration methods available for preparing bone marrow, more data are needed to identify the optimal bone marrow harvesting techniques to treat OA.

Methods: This retrospective cohort study examined the effect of using low-volume BMAs harvested using the Marrow Cellution™ (MC) device on 160 patients (262 knees) suffering from pain due to knee OA, KL grades 2-4, that did not respond to conservative treatment.