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-cell function impairment in first-degree relatives of type 2 diabetic subjects. Modeling analysis of 24-hour triple-meal tests
1 C.N.R. Institute of Biomedical Engineering, Padova, Italy
2 Department of Internal Medicine, C.N.R. Institute of Clinical Physiology at the University of Pisa, Pisa, Italy
3 Department of Medicine M (Endocrinology and Diabetes), University Hospital, Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: andrea.mari{at}isib.cnr.it.
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-1m-2, p<0.05). ISR5 was inversely related to M in controls (ISR5=k.M-1.23, 
=-
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, while 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.
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