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OBJECTIVE: To evaluate changes in the prevalence of depressive symptoms, loneliness, and insomnia among older adults with type 2 diabetes from 2016 to 2020 and to assess risk factors for these conditions including demographics, multimorbidity, BMI, treatment group, and pre-coronavirus 2019 (COVID-19) measure scores. RESEARCH DESIGN AND METHODS: This was a prospective, observational study of participants from the Look AHEAD (Action for Health in Diabetes) cohort study. Data were from two assessments before COVID-19 (visit 1: April 2016-June 2018 and visit 2: February 2018-February 2020) and one assessment during COVID-19 (visit 3: July-December 2020). Surveys were administered to assess depressive symptoms, loneliness, and insomnia. RESULTS: The study included 2829 adults (63.2% female, 60.6% White, mean [SD] age 75.6 [6.0] years). The prevalence of mild or greater depressive symptoms did not change significantly between the two pre-pandemic visits (P = 0.88) but increased significantly from pre- to during COVID-19 (19.3% at V2 to 30.4% at V3; P < 0.001). Higher odds of mild or greater depressive symptoms at V3 were associated with being female (adjusted odds ratio [OR] 1.4 [95% CI 1.1-1.7]), identifying as non-Hispanic White (OR 1.4 [95% CI 1.1-1.7]), having obesity (OR 1.3 [95% CI 1.0-1.5]), and reporting mild or greater depressive symptoms at V1 (OR 4.0 [95% CI 2.9-5.4]), V2 (OR 4.4 [95% CI 3.2-5.9]), or both visits (OR 13.4 [95% CI 9.7-18.4]). The prevalence of loneliness increased from 12.3% at V1 to 22.1% at V3 (P < 0.001), while the prevalence of insomnia remained stable across visits at 31.5-33.3%. CONCLUSIONS: The prevalence of mild or greater depressive symptoms in older adults with diabetes was more than 1.6 times higher during COVID-19 than before the pandemic.

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PURPOSE: Obesity and type 2 diabetes are associated with an increased risk of cardiovascular disease (CVD) and the combination of weight loss and increased physical exercise are commonly recommended to reduce CVD. This study examined whether people with obesity and type 2 diabetes with an abnormal graded exercise tolerance test (GXT) or a history of CVD would have less success in achieving weight loss and improved fitness, compared to adults without these conditions. METHODS: The Look AHEAD Study examined whether an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) reduced cardiovascular events in adults with overweight/obesity and type 2 diabetes. Participants underwent a baseline maximal GXT and provided medical history data. Weight loss and fitness change were examined in 5011 participants over four years in those with or without an abnormal baseline GXT and/or history of CVD. RESULTS: After four years, weight loss in both ILI and DSE were significantly greater in those without a prior history of CVD than in those with a CVD history (6.69% vs 5.98%, p=0.02, in ILI and 0.73 vs -.07% (weight gain), p=0.01, in DSE). Likewise, those without a prior history of CVD experienced greater improvements in fitness in both ILI and DSE relative to those with a history of CVD. Having an abnormal GXT at baseline did not affect weight loss or fitness. CONCLUSIONS: A history of CVD at baseline modestly lessened weight loss and fitness changes at 4 years, whereas having any abnormality on the baseline GXT did not affect these outcomes. Thus, weight loss and improved fitness are achievable in adults with a history of CVD or ECG abnormalities.

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OBJECTIVE: Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry. METHODS: Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis. RESULTS: In the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. CONCLUSIONS: PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.

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OBJECTIVE: This study aimed to explore the genetic mechanisms of regional fat deposition, which is a strong risk factor for metabolic diseases beyond total adiposity. METHODS: A genome-wide association study of 7,757,139 single-nucleotide polymorphisms (SNPs) in 983 Mexican Americans (nmale = 403; nfemale = 580) from the Insulin Resistance Atherosclerosis Family Study was performed. Association analyses were performed with and without sex stratification for subcutaneous adipose tissue, visceral adipose tissue (VAT), and visceral-subcutaneous ratio (VSR) obtained from computed tomography. RESULTS: The strongest signal identified was SNP rs2185405 (minor allele frequencies [MAF] = 40%; PVAT = 1.98 × 10-8 ) with VAT. It is an intronic variant of the GLIS family zinc finger 3 gene (GLIS3). In addition, SNP rs12657394 (MAF = 19%) was associated with VAT in males (Pmale = 2.39×10-8 ; Pfemale = 2.5 × 10-3 ). It is located intronically in the serum response factor binding protein 1 gene (SRFBP1). On average, male carriers of the variant had 24.6 cm2 increased VAT compared with noncarriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF = 14%; Pint = 3.07 × 10-8 ) in PAPPA2 and rs10923724 (MAF = 38%; Pint = 2.89 × 10-8 ) upstream of TBX15 were strongly associated with the interaction effect for VSR. CONCLUSIONS: Six loci were identified with genome-wide significant associations with fat deposition and interactive effects. These results provided genetic evidence for a differential basis of fat deposition between genders.

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The Systolic Blood Pressure Intervention Trial (SPRINT) tested whether a systolic blood pressure (SBP) value <120 mm Hg reduces adverse clinical outcomes compared with the goal of <140 mm Hg. Here the authors describe the baseline characteristics of Hispanic participants in SPRINT. Nondiabetic hypertensive patients 50 years and older with SBP 130-180 mm Hg taking zero to four blood pressure (BP) medications were enrolled from the mainland United States and Puerto Rico. Cross-sectional, bivariate analysis was employed comparing sociodemographic and clinical factors in Hispanics vs non-Hispanics. Multivariable logistic regression models restricted to Hispanics were used to identify factors associated with achieved BP control (SBP <140 mm Hg and diastolic BP <90 mm Hg) at baseline. Eleven percent (n=984) of SPRINT participants were Hispanic; 56% (n=549) of Hispanics were living in Puerto Rico and the remainder were living on the US mainland. Hispanics overall were younger, more often female, less likely to live alone, and more likely to have lower education and be uninsured, although just as likely to be employed compared with non-Hispanics. BP control was not different between Hispanics vs non-Hispanics at baseline. However, a significantly higher percentage of Hispanics on the US mainland (compared with Hispanics in Puerto Rico) had controlled BP. BP control was independently associated with cardiovascular disease history and functional status among Hispanics, specifically those living in Puerto Rico, whereas functional status was the only independent predictor of BP control identified among mainland Hispanics. These findings highlight the diversity of the SPRINT population. It remains to be seen whether factors identified among Hispanics impact intervention goals and subsequent clinical outcomes.

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Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

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OBJECTIVE: The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI). METHODS: GUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican-American individuals in 1,346 pedigrees. Insulin sensitivity (SI ), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3,925 individuals) using variance components. RESULTS: Across studies, age, and gender-adjusted heritability of insulin sensitivity (SI , M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and -0.57 to -0.59 for AIRg and MCRI (all P < 0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P < 0.0001); and -0.16 to -0.36 for AIRg and MCRI (P < 0.0001-0.06). CONCLUSIONS: These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.

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OBJECTIVE: The census classification of Hispanic origin is used in epidemiological studies to group individuals, even though there is geographical, cultural, and genetic diversity within Hispanic Americans of purportedly similar backgrounds. We observed differences in our measures of adiposity between our two Mexican American populations, and examined whether these differences were attributed to social, behavioral, physiologic or genetic differences between the two populations. RESEARCH DESIGN AND METHODS: In the IRAS Family Study, we examined 478 Hispanics from San Antonio, Texas and 447 Hispanics from the San Luis Valley, Colorado. Associations with body mass index (BMI), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) using social, behavioral, physiologic and genetic variables were examined. RESULTS: Hispanics of Mexican origin in our clinic population in San Antonio had significantly higher mean BMI (31.09 vs. 28.35 kg/m2), VAT (126.3 vs. 105.5 cm2), and SAT (391.6 vs. 336.9 cm2), than Hispanics of Mexican origin in the San Luis Valley. The amount of variation in adiposity explained by clinic population was 4.5% for BMI, 2.8% for VAT, and 2.7% for SAT. After adjustment, clinic population was no longer associated with VAT and SAT, but remained associated with BMI, although the amount of variation explained by population was substantially less (1.0% for BMI). CONCLUSION: Adiposity differences within this population of Mexican origin can be largely explained by social, behavioral, physiologic and genetic differences.

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To determine and formally compare the ability of simple indexes of insulin resistance (IR) to predict type 2 diabetes, we used combined prospective data from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study, which include well-characterized cohorts of non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5-8 years of follow-up. Poisson regression was used to assess the ability of each candidate index to predict incident diabetes at the follow-up examination (343 of 3,574 subjects developed diabetes). The areas under the receiver operator characteristic (AROC) curves for each index were calculated and statistically compared. In pooled analysis, Gutt et al.'s insulin sensitivity index at 0 and 120 min (ISI(0,120)) displayed the largest AROC (78.5%). This index was significantly more predictive (P < 0.0001) than a large group of indexes (including those by Belfiore, Avignon, Katz, and Stumvoll) that had AROC curves between 66 and 74%. These findings were essentially similar both after adjustment for covariates and when analyses were conducted separately by glucose tolerance status and ethnicity/study subgroups. In conclusion, we found substantial differences between published IR indexes in the prediction of diabetes, with ISI(0,120) consistently showing the strongest prediction. This index may reflect other aspects of diabetes pathogenesis in addition to IR, which might explain its strong predictive abilities despite its moderate correlation with direct measures of IR.

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