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. We defined the risk protection haplotype of SLC16A11, T-C-G-T-T, as allele 2 of a diallelic genetic model with three genotypes, SLC16A11*11, *12, and *22, where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB1*16:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [*22] and 0.78 [*12]); an added interaction term was statistically significant (OR 0.49 [*12]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30-41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes.

The association of insulin responses and insulin sensitivity with cognition in adults with pre-diabetes: The Diabetes Prevention Program Outcomes Study.

OBJECTIVE: Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet ß-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. RESEARCH DESIGN AND METHODS: IResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. RESULTS: Higher IResp was associated with poorer performance on the DSST (-0.69 points per 100 unit increase in IGI, 95 % CI: -1.37, -0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. CONCLUSIONS: These results suggest that a greater ß-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.

Within and post-trial effects of an intensive lifestyle intervention on kidney disease in adults with overweight or obesity and type 2 diabetes mellitus: a secondary analysis of the Look AHEAD clinical trial.

INTRODUCTION: The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45-76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial's secondary outcome of kidney disease. RESEARCH DESIGN AND METHODS: We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to <45 mL/min/1.73 m2 or need for kidney replacement therapy (KRT: dialysis or kidney transplant) during intervention and post-intervention follow-up (median 15.6 years overall). RESULTS: Incidence of eGFR <45 mL/min/1.73 m2 was lower in ILI during the intervention (HR=0.80, 95% CI=0.66 to 0.98) but not post-intervention (HR=1.03, 0.86 to 1.23) or overall (HR=0.92, 0.80 to 1.04). There were no significant treatment group differences in KRT. In prespecified subgroup analyses, age×treatment interactions were significant over total follow-up: p=0.001 for eGFR <45 mL/min/1.73 m2 and p=0.01 for KRT. The 2205 participants aged >60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR <45 mL/min/1.73 m2; HR=0.62, 0.43 to 0.91 for KRT). The absolute treatment effects were greater post-intervention: ILI reduced the rate of eGFR <45 mL/min/1.73 m2 by 0.46 and 0.76 cases/100 person-years during and post-intervention, respectively; and reduced KRT by 0.15 and 0.21 cases/100 person-years. The younger participants experienced no such post-intervention benefits. CONCLUSIONS: ILI reduced kidney disease progression during and following the active intervention in persons aged ≥60 years. ILI should be considered for reducing kidney disease incidence in older persons with type 2 diabetes.

Prevalence of Distal Symmetrical Polyneuropathy by Diabetes Prevention Program Treatment Group, Diabetes Status, Duration of Diabetes, and Cumulative Glycemic Exposure.

OBJECTIVE: To assess associations between distal symmetric polyneuropathy (DSPN) and Diabetes Prevention Program (DPP) treatment groups, diabetes status or duration, and cumulative glycemic exposure approximately 21 years after DPP randomization. RESEARCH DESIGN AND METHODS: In the DPP, 3,234 adults ≥25 years old at high risk for diabetes were randomized to an intensive lifestyle (ILS), metformin, or placebo intervention to prevent diabetes. After the DPP ended, 2,779 joined the Diabetes Prevention Program Outcomes Study (DPPOS). Open-label metformin was continued, placebo was discontinued, ILS was provided in the form of semiannual group-based classes, and all participants were offered quarterly lifestyle classes. Symptoms and signs of DSPN were assessed in 1,792 participants at DPPOS year 17. Multivariable logistic regression models were used to evaluate DSPN associations with treatment group, diabetes status/duration, and cumulative glycemic exposure. RESULTS: At 21 years after DPP randomization, 66% of subjects had diabetes. DSPN prevalence did not differ by initial DPP treatment assignment (ILS 21.5%, metformin 21.5%, and placebo 21.9%). There was a significant interaction between treatment assignment to ILS and age (P < 0.05) on DSPN. At DPPOS year 17, the odds ratio for DSPN in comparison with ILS with placebo was 17.4% (95% CI 3.0, 29.3) lower with increasing 5-year age intervals. DSPN prevalence was slightly lower for those at risk for diabetes (19.6%) versus those with diabetes (22.7%) and was associated with longer diabetes duration and time-weighted HbA1c (P values <0.001). CONCLUSIONS: The likelihood of DSPN was similar across DPP treatment groups but higher for those with diabetes, longer diabetes duration, and higher cumulative glycemic exposure. ILS may have long-term benefits on DSPN for older adults.

Increased Genetic Risk for ß-Cell Failure Is Associated With ß-Cell Function Decline in People With Prediabetes.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (ß-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher ß-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD -0.04, P = 9.6 × 10-7, and -8.45 µU/mg, P = 5.6 × 10-6, respectively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD -4.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the ß-cell cluster pPS had worsening in measures of ß-cell function.

Effects of the ABCC8 R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy.

INTRODUCTION: The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. The effects of an ABCC8 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. We used hierarchical logistic regression models to study cross-sectional associations with diabetes complications including increased albuminuria (albumin-to-creatinine ratio (ACR) ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2), and retinopathy. This study included 7675 individuals (254 variant carriers) previously genotyped for the R1420H with available phenotypic data and with a median follow-up time of 13.5 years (IQR 4.5-26.8). RESULTS: Variant carriers had worse beta-cell function than non-carriers (p=0.0004; on average estimated secretion was 22% lower, in carriers), in children and adults, with no difference in insulin sensitivity (p=0.50). At any body mass index and age before 35 years, carriers had higher type 2 diabetes incidence. This variant did not associate with prevalence of increased albuminuria (OR 0.87, 95% CI 0.66 to 1.16), severe albuminuria (OR 0.96, 95% CI 0.55 to 1.68), or reduced eGFR (OR 0.44, 95% CI 0.18 to 1.06). By contrast, the variant significantly associated with higher retinopathy prevalence (OR 1.74, 95% CI 1.19 to 2.53) and this association was only partially mediated (<11%) by glycemia, duration of diabetes, risk factors of retinopathy, or insulin use. Retinopathy prevalence in carriers was higher regardless of diabetes presence. CONCLUSIONS: The ABCC8 R1420H variant is associated with increased risks of diabetes and of retinopathy, which may be partially explained by higher glycemia levels and worse beta-cell function.