Insulin Longitudinal Evaluation Study Research Articles

Metabolites Link Intake of a Healthy Diet to Better Insulin and Glucose Homeostasis in the Microbiome and Insulin Longitudinal Evaluation Study

BackgroundDietary quality has been linked to better glycemic control, but the precise molecular mechanisms giving rise to these associations are not fully understood. ObjectivesTo examine the association of metabolites associated with the intake of a healthy diet with measures of insulin/glucose homeostasis. MethodsUsing cross-sectional data from 295 United States adults, the associations between 3 diet pattern scores and metabolome-wide metabolites were estimated via linear regression models, which controlled for demographic factors and health behaviors. Subsequently, the associations between the diet-related metabolites with 6 measures of glucose/insulin homeostasis were examined in similar models. A Bonferroni correction was applied to control the familywise error rate at 5%. ResultsFifty-five metabolites were significantly associated with ≥1 diet score (all P < 1.7∗10–5). When these were summed into each of the 3 diet-specific metabolite summary scores, all 3 aggregate measures showed strong associations with 5 out of 6 measures of glucose/insulin homeostasis (P = 9.7∗10–5–4.1∗10–13). ConclusionsAdherence to a priori-defined “healthy diet” is associated with the plasma metabolites that, in turn, are associated with better glycemia. If the associations between replicated in future studies and examined using large-scale longitudinal data, the identified molecules could yield insights into mechanisms by which diet may support glucose and insulin homeostasis.

Increased Plasma Branched Short-Chain Fatty Acids and Improved Glucose Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Short chain fatty acids (SCFA) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched short chain fatty acids (BSCFA), isobutyrate, isovalerate, and methylbutyrate, is largely unknown. In a cohort of 219 non-Hispanic Whites and 126 African Americans, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, lipid traits, and other SCFA. We observed a bimodal distribution of BSCFA, with 25 individuals having high levels (HBSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared to the L-BSCFA group (16% versus 49%, P=0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFA. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose were lower and disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial Cpeptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.

The Roles of Gut Microbiome and Plasma Metabolites in the Associations between ABO Blood Groups and Insulin Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Non-O blood groups are associated with decreased insulin sensitivity and risk of type 2 diabetes. A recent study pinpointed the associations between ABO blood groups and gut microbiome, which may serve as potential mediators for the observed increased disease risks. We aimed to characterize associations between ABO haplotypes and insulin-related traits as well as potential mediating pathways. We assessed insulin homeostasis in African Americans (AAs; n = 109) and non-Hispanic whites (n = 210) from the Microbiome and Insulin Longitudinal Evaluation Study. The ABO haplotype was determined by six SNPs located in the ABO gene. Based on prior knowledge, we included 21 gut bacteria and 13 plasma metabolites for mediation analysis. In the white study cohort (60 ± 9 years, 42% male), compared to the O1 haplotype, A1 was associated with a higher Matsuda insulin sensitivity index, while a lower relative abundance of Bacteroides massiliensis and lactate levels. Lactate was a likely mediator of this association but not Bacteroides massiliensis. In the AAs group (57 ± 8 years, 33% male), we found no association between any haplotype and insulin-related traits. In conclusion, the A1 haplotype may promote healthy insulin sensitivity in non-Hispanic whites and lactate likely play a role in this process but not selected gut bacteria.

Metabolomic Scores Mediate Associations between Dietary Patterns and Insulin Homeostasis in The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

ObjectivesTo examine whether the metabolomic correlates of three diet patterns mediate the observed associations between diet and insulin homeostasis.MethodsData were included from 295 adults without diabetes (mean age 59.3 y ± 9.00; 63.46% non-Hispanic White and 36.54% African American) participating in MILES. An oral glucose tolerance test was used to measure fasting glucose, insulin, and C-peptide, as well as insulin secretion, insulin sensitivity, and disposition index. Self-reported dietary intake was used to create three diet scores: a Mediterranean-style diet, the Dietary Approaches to Stop Hypertension, and the USDA's Healthy Eating Index-2015. A global metabolomics panel of 1525 metabolites was measured using LC/MS global metabolomic profiling using validated reference standards in fasting plasma.. Main effects models that controlled for age, sex, ethnicity, socioeconomic status, smoking status, physical activity, and daily energy intake examined associations between the three diet scores, metabolite information and insulin homeostasis. 115 individual diet-metabolite associations across 76 metabolites reached significance after correcting for the effective number of independent tests (P < 3.4 * 10−05), informing the creation of diet-specific unweighted metabolite sum scores (MSS). Where warranted, mediation was assessed using the ‘mediate’ package in R.ResultsInsulin secretion did not show a significant association with any diet nor any MSS (all P > 0.01). All other insulin homeostasis traits were strongly associated with all diet-specific MSSs (P < 0.001-P < 2.5 * 10−09). MSSs significantly mediated any associations between insulin homeostasis and diet scores (P < 0.04-P < 2.0 * 10−16) with no evidence of direct effects of diet on insulin homeostasis in mediation models (all P > 0.05).ConclusionsThese data suggest that the metabolomic correlates of three diet patterns, when aggregated, mark insulin homeostasis and mediate the associations of diet with insulin traits. Such metabolomic diet scores may hold promise for revealing the underlying pathways between a healthy diet and glycemic control.Funding SourcesMILES was supported by NIDDK (R01-DK109588, P30-DK063491) and the National Center for Advancing Translational Sciences (UL1TR001420, UL1TR001881).

Cesarean delivery and insulin sensitivity in the older adult: The Microbiome and Insulin Longitudinal Evaluation Study

Cesarean delivery and insulin sensitivity in the older adult: The Microbiome and Insulin Longitudinal Evaluation Study

Cesarean Delivery and Insulin Sensitivity in the Older Adult: The Microbiome and Insulin Longitudinal Evaluation Study.

The present study was designed to evaluate if mode of delivery at birth is associated with body mass index (BMI) and glucose homeostasis traits in later life, controlling for possible confounders, including maternal history of diabetes. Data were obtained through a racially diverse, prospective cohort study of nondiabetic, older adults, the Microbiome and Insulin Longitudinal Evaluation Study (MILES). We used generalized linear models to estimate the association between mode of delivery and glycemic status, BMI (kg/m2), waist circumference (cm), fasting glucose, fasting insulin, insulin secretion, insulin sensitivity, and insulin clearance. Further, we estimated the direct and indirect effects of cesarean delivery on glucose and insulin-related traits, as mediated by BMI status. Relative to vaginal delivery, cesarean delivery was associated with a significantly higher BMI (adjusted beta [aβ] 3.53 kg/m2; 95% CI 0.15, 6.91) and fasting glucose (aβ 5.12; 95% CI 0.01, 10.23), a 14% decrease in insulin sensitivity (aβ –0.14; 95% CI –0.28, –0.01), and a 58% increased risk (adjusted relative risk [aRR] 1.58; 95% CI 1.08, 2.31) for prediabetes/diabetes. Associations were mediated in part by BMI, with the strongest evidence observed for glycemic status (proportion mediated 22.6%; P = .03), fasting insulin (proportion mediated 58.0%; P = .05), and insulin sensitivity index (proportion mediated 45.9%; P = .05). Independent of mediation, a significant direct effect of cesarean delivery on glycemic status was observed (aRR 1.88; 95% CI 1.16, 2.60). Cesarean delivery may lead to reduced insulin sensitivity and, ultimately, increased risk for developing prediabetes and diabetes.

Associations between adherence to the dietary approaches to stop hypertension (DASH) diet and six glucose homeostasis traits in the Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Background and aimsThe DASH diet conveys protection against type 2 diabetes mellitus (T2D) Via plant-based and non-plant-based recommendations. Research has not identified which glucose homeostasis pathways are improved. We examined associations between adherence to a DASH diet and six glucose homeostasis traits, probing whether associations could be attributed to the plant-based (DASH-P) and/or non-plant based (DASH-NP) components. Methods and resultsWe included data from 295 adults without T2D (age 59.3 ± 9.00 years; 63.46% non-Hispanic White and 36.54% African American, self-reported race ancestry) participating in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). An oral glucose tolerance test (OGTT) yielded fasting plasma glucose, insulin, C-peptide, and insulin secretion, sensitivity, and disposition index. Habitual dietary intake was assessed by food frequency questionnaire (FFQ). Associations between DASH components and glucose homeostasis traits were examined, controlling for demographics, body mass index (BMI), physical activity, and energy intake. For significant associations, the models were repeated with scores for DASH-P and DASH-NP as predictors in the same model.DASH and DASH-P scores were inversely associated with fasting plasma glucose (DASH:β = −0.036 ± 0.012,P = 0.005; DASH-P: β = −0.04 ± 0.017,P = 0.002), and positively associated with insulin sensitivity (DASH:β = 0.022 ± 0.012,P = 0.042; DASH-P: = 0.036 ± 0.015,P = 0.014). The DASH score was also associated with disposition index (β = 0.026 ± 0.013,P = 0.038), but this association did not reach significance with DASH-P (β = 0.035 ± 0.018,P = 0.051). No associations were observed with DASH-NP score (all P > 0.05). ConclusionsDASH diet is associated with improvement in specific glucose homeostasis traits, likely arising from increased plant-based foods. Such research may help tailor future dietary advice to specific metabolic risk, and to food groups most effective at improving these.

Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

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.

Rationale, design and baseline characteristics of the Microbiome and Insulin Longitudinal Evaluation Study (MILES).

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). 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. 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. 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.