OBJECTIVE Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters labeled: β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.
OBJECTIVE The temporal pattern of cognitive and functional change before and after incident diabetes remains unknown. RESEARCH DESIGN AND METHODS Data from wave 2 to wave 9 (2004–2018) of the English Longitudinal Study of Ageing were used. Global cognition (assessed by orientation, memory, and executive function) and daily functioning (calculated as the sum of impaired basic and instrumental activities of daily living) were measured in each wave. Incident diabetes was defined as glycated hemoglobin A1c ≥6.5% (47.5 mmol/mol), self-reported doctor diagnosis of diabetes, or glucose-lowering medication use during follow-up. RESULTS Among the 6,342 participants (mean age 65.0 years, 57.8% women) included, 576 participants (9.1%) with incident diabetes were identified during a median follow-up of 13.3 years. The annual rates of change in global cognition (β = −0.035 SD/year; 95% CI −0.054 to −0.015), orientation (−0.031 SD/year; −0.060 to −0.002), memory (−0.016 SD/year; −0.029 to −0.003), and executive function (−0.027 SD/year; −0.042 to −0.013) were accelerated after diabetes diagnosis compared with before the event. The postdiabetes annual changes in daily functioning (0.093 points/year; 95% CI 0.056–0.131) were also accelerated compared with the prediabetes diagnosis. However, the rate of cognitive and functional decline before the diabetes diagnosis in participants with future incident diabetes was similar to the rate in participants without diabetes. Also, no significant acute change was observed during its onset. CONCLUSIONS Incident diabetes is associated with accelerated cognitive and functional decline after, but not before, the event. We suggest careful monitoring for cognitive and physical dysfunction after a diabetes diagnosis.
Objective Hyperglycemia and autonomic dysfunction are bidirectionally related. We investigated the association of longitudinal evolution of heart rate variability (HRV) with incident type 2 diabetes (T2D) among the general population. Methods We included 7630 participants (mean age 63.7 years, 58% women) from the population-based Rotterdam Study who had no history of T2D and atrial fibrillation at baseline and had repeated HRV assessments at baseline and during follow-up. We used joint models to assess the association between longitudinal evolution of heart rate and different HRV metrics (including the heart-rate corrected standard deviation of the normal-to-normal RR intervals (SDNNc), and root mean square of successive RR-interval differences (RMSSDc)) with incident T2D. Models were adjusted for cardiovascular risk factors. Bidirectional Mendelian randomization (MR) using summary-level data was also performed. Results During a median follow-up of 8.6 years, 871 individuals developed incident T2D. One standard deviation (SD) increase in heart rate (hazard ratio [HR], 1.20, 95% confidence interval (CI), 1.09-1.33), and log(RMSSDc) (1.16, 95% CI 1.01-1.33) were independently associated with incident T2D. The HRs were 1.54 (95% CI 1.08-2.06) for participants younger than 62 years and 1.15 (95% CI 1.01-1.31) for those older than 62 years for heart rate (p for interaction <0.001). Results from bidirectional MR analyses suggested that HRV and T2D were not significantly related to each other. Conclusions Autonomic dysfunction preceeds development of T2D, especially among younger individuals, while MR analysis suggests no causal relationship. More studies are needed to further validate our findings.
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