Insulin sensitivity and beta-cell function in the offspring of type 2 diabetic patients: impact of line of inheritance.
BACKGROUND
What defects in glucose metabolism are present in offspring of type 2 diabetic patients (FHD(+) with a positive family history of diabetes) and to what extent they depend on line of inheritance are uncertain.


OBJECTIVE
The objective of this study was to assess clinical phenotype, insulin sensitivity, and β-cell function in FHD(+) by line of inheritance.


METHODS
The subjects included 1221 nondiabetic men and women aged 30-60 yr, of whom 343 were FHD(+), who participated to the Relationship between Insulin Sensitivity and Cardiovascular Disease Investigators study, a multicenter European collaboration.


METHODS
The main outcome measures included the following: insulin sensitivity by the euglycemic clamp; total insulin secretion, β-cell glucose sensitivity, rate sensitivity, and potentiation by C-peptide deconvolution and oral glucose tolerance test modeling; and acute insulin response to i.v. glucose.


RESULTS
Older age, increased adiposity, and dyslipidemia were the dominant features of FHD(+) clinical phenotype. FHD(+) subjects had a 13% reduction in insulin sensitivity [95% confidence interval (CI) of 6,19], which in males was more pronounced (17%, CI: 5,24 vs. 10%, CI: 2,20) and influenced by maternal inheritance (21%, CI: 5,38 vs. 14%, CI: 0,28 paternal). After adjusting for confounders, β-cell glucose sensitivity and rate sensitivity were reduced by 13% (CI: 3,20) and 18% (CI: 5,35), respectively (P < 0.01 for both); the former defect was more severe with maternal (16%, CI: 4,26) than paternal (9%, CI: -2,22) transmission. Independently of line of inheritance, both fasting and total oral glucose tolerance test insulin secretion were increased in proportion to the insulin resistance, whereas acute insulin response and rate sensitivity were not.


CONCLUSIONS
Diabetic inheritance is expressed as a characteristic clinical phenotype associated with defects in insulin sensitivity and β-cell glucose sensitivity, which are accentuated along maternal inheritance. β-Cell rate sensitivity is reduced and β-cell dynamic responses to insulin resistance are lost independently of the line of inheritance.
Natali
Andrea
A
Department of Internal Medicine, University of Pisa, Pisa, Italy. anatali@ifc.cnr.it
Muscelli
Elza
E
Mari
Andrea
A
Balkau
Beverley
B
Walker
Mark
M
Tura
Andrea
A
Anderwald
Christian
C
Golay
Alain
A
Ferrannini
Ele
E
D056044:Actigraphy; D000328:Adult; D032721:Adult Children; D002648:Child; D016241:Child of Impaired Parents; D003924:Diabetes Mellitus, Type 2; D005192:Family Health; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D040582:Inheritance Patterns / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged