10-year trajectory of beta-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study

Abstract

BACKGROUND: The relative contributions of beta-cell function and insulin sensitivity in the pathogenesis of type 2 diabetes are not fully understood. We investigated the longitudinal change in beta-cell function and insulin sensitivity in the development of diabetes and the role of genetic variants in deterioration of glucose tolerance. METHODS: We followed up 4106 participants with normal glucose tolerance (NGT) from the Korean Genome and Epidemiology Study with oral glucose tolerance tests every 2 years for 10 years. We estimated pancreatic beta-cell function with the 60 min insulinogenic index (IGI60) and insulin sensitivity with the composite (Matsuda) insulin sensitivity index (ISI). We investigated the association of 66 known type 2 diabetes genetic variants with risk of prediabetes or diabetes and impaired beta-cell function and insulin sensitivity. FINDINGS: During 10 years of follow-up, 1093 (27%) of 4106 participants developed prediabetes and 498 (12%) participants developed diabetes. Compared with participants who remained NGT, those who progressed to diabetes had a lower IGI60 (unadjusted data 5.1 muU/mmol [95% CI 0.5-56.1] vs 7.9 muU/mmol [0.5-113.8]: p<0.0001) and lower ISI (unadjusted data 8.2 [2.6-26.0] vs 10.0 [3.2-31.6]: p<0.0001) at baseline. Participants who had NGT at 10 years showed a decrease in ISI (adjusted data 10.1 [9.9-10.3] vs 7.4 [7.3-7.6]: p<0.0001) but a compensatory increase in IGI60 (adjusted data 6.9 muU/mmol [6.5-7.2] vs 11.7 muU/mmol [11.2-12.1]: p<0.0001) compared with baseline. By contrast, participants who developed diabetes showed a decrease in ISI (adjusted data 8.4 [8.0-8.7] vs 3.0 [2.8-3.2]: p<0.0001) but no significant compensatory increase (p=0.95) in IGI60. A genetic variant near the glucokinase gene (rs4607517) was significantly associated with progression to prediabetes or diabetes (hazard ratio 1.27, 1.16-1.38: p=1.70 x 10(-7)). INTERPRETATION: Decreased beta-cell function, which might be determined partly by genetic factors, and impaired beta-cell compensation for progressive decline in insulin sensitivity are crucial factors in the deterioration of glucose tolerance. FUNDING: South Korean Ministry of Health & Welfare.