title: 10-year trajectory of β-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study.
abstract: BACKGROUND
  The relative contributions of β-cell function and insulin sensitivity in the pathogenesis of type 2 diabetes are not fully understood. We investigated the longitudinal change in β-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 β-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 β-cell function and insulin sensitivity.
  
  
  RESULTS
  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 μU/mmol [95% CI 0·5-56·1] vs 7·9 μU/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 μU/mmol [6·5-7·2] vs 11·7 μU/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 × 10(-7)).
  
  
  CONCLUSIONS
  Decreased β-cell function, which might be determined partly by genetic factors, and impaired β-cell compensation for progressive decline in insulin sensitivity are crucial factors in the deterioration of glucose tolerance.
  
  
  BACKGROUND
  South Korean Ministry of Health & Welfare.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
authors.forename: Jung Hun
authors.initials: JH
authors.lastname: Ohn
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Soo Heon
authors.initials: SH
authors.lastname: Kwak
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
authors.forename: Soo
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
authors.forename: Hak Chul
authors.initials: HC
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea. Electronic address: kspark@snu.ac.kr.
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Preventive Medicine, Ajou University School of Medicine, Suwon, South Korea. Electronic address: chnaha@ajou.ac.kr.
authors.forename: Nam H
authors.initials: NH
authors.lastname: Cho
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D001786:Blood Glucose; D007328:Insulin