title: Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes.
abstract: OBJECTIVE
  The relative roles of insulin resistance and beta-cell dysfunction in the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes are debated. First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia.
  
  
  METHODS
  We evaluated the evolution of insulin sensitivity, beta-cell function, glucose effectiveness, and glucose tolerance over 7 years in 33 nondiabetic, first-degree relatives of type 2 diabetic individuals using frequently sampled tolbutamide-modified intravenous and oral glucose tolerance tests.
  
  
  RESULTS
  Subjects gained weight, and their waist circumference increased (P < 0.05). Insulin sensitivity, the acute insulin response to glucose, and glucose effectiveness did not change significantly. However, when we accounted for the modulating effect of insulin sensitivity on insulin release, beta-cell function determined as the disposition index decreased by 22% (P < 0.05). This decrease was associated with declines in intravenous and oral glucose tolerance (P < 0.05 and P < 0.001, respectively). Of the subjects with normal glucose tolerance at the first assessment, we compared those who progressed to IGT with those who did not. The disposition index was 50% lower in the progressors than in the nonprogressors at follow-up (P < 0.05).
  
  
  CONCLUSIONS
  The decline in glucose tolerance over time in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of beta-cell function. Thus, early interventions to slow the decline in beta-cell function should be considered in high-risk individuals.
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
authors.forename: Josep
authors.initials: J
authors.lastname: Vidal
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Utzschneider
authors.forename: Darcy B
authors.initials: DB
authors.lastname: Carr
authors.forename: Todd
authors.initials: T
authors.lastname: Schraw
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Boyko
authors.forename: Wilfred Y
authors.initials: WY
authors.lastname: Fujimoto
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D049628:Body Size; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D005190:Family; D005500:Follow-Up Studies; D018149:Glucose Intolerance / Q000453:epidemiology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008875:Middle Aged; D011236:Prediabetic State / Q000235:genetics*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin