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Insulin Sensitivity and beta-Cell Function in the Offspring of Type 2 Diabetic Patients: Impact of Line of Inheritance

Lookup NU author(s): Professor Mark Walker


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Context: 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 beta-cell function in FHD+ by line of inheritance. Subjects: 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. Main Outcome Measures: The main outcome measures included the following: insulin sensitivity by the euglycemic clamp; total insulin secretion, beta-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, beta-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 beta-cell glucose sensitivity, which are accentuated along maternal inheritance. beta-Cell rate sensitivity is reduced and beta-cell dynamic responses to insulin resistance are lost independently of the line of inheritance. (J Clin Endocrinol Metab 95: 4703-4711, 2010)

Publication metadata

Author(s): Natali A, Muscelli E, Mari A, Balkau B, Walker M, Tura A, Anderwald C, Golay A, Ferrannini E, Insulin Sensitivity Cardiovasc Dis

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2010

Volume: 95

Issue: 10

Pages: 4703-4711

Print publication date: 01/10/2010

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: The Endocrine Society


DOI: 10.1210/jc.2009-2721


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AstraZeneca (Sweden)
QLG1-CT-2001-01252European Union