Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes.
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.
Cnop
Miriam
M
Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108, USA.
Vidal
Josep
J
Hull
Rebecca L
RL
Utzschneider
Kristina M
KM
Carr
Darcy B
DB
Schraw
Todd
T
Scherer
Philipp E
PE
Boyko
Edward J
EJ
Fujimoto
Wilfred Y
WY
Kahn
Steven E
SE
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
D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin