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-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests
1Consiglio Nazionale delle Ricerche Institute of Biomedical Engineering, Padua; 2Department of Internal Medicine and Consiglio Nazionale delle Ricerche Institute of Clinical Physiology at the University of Pisa, Pisa, Italy; and 3Department of Medicine M (Endocrinology and Diabetes), University Hospital, Aarhus, Denmark
Submitted 19 April 2004 ; accepted in final form 25 October 2004
To investigate early secretory defects in prediabetes, we evaluated 
-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. -Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 ± 6 vs. 87 ± 6 pmol· min–1·m–2, P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, 
= –0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5·M1.23), compensation for insulin resistance was impaired in FDR (10.8 ± 1.0 vs. 13.4 ± 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 ± 0.08 vs. 1.62 ± 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters (P < 0.05 or less). -Cell function parameters were also related to mean 24-h glucose levels (r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, -cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a -cell defect in the amplifying pathway of insulin secretion.
insulin secretion; insulin sensitivity; glucose tolerance; mathematical models
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