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Insulin and Amylin Release Are Both Diminished in First-Degree Relatives of Subjects With Type 2 Diabetes

From the Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System, and the University of Washington, Seattle, Washington

OBJECTIVE—To determine whether first-degree relatives of individuals with type 2 diabetes, who are at high risk of subsequently developing hyperglycemia, manifest alterations in ß-cell function including an alteration in the co-release of insulin and amylin.

RESEARCH DESIGN AND METHODS—In 30 first-degree relatives and 24 matched subjects with no family history of diabetes, ß-cell function was measured as the intravenous glucose-induced acute insulin response (AIR_g) and acute amylin response (AAR_g). The insulin sensitivity index (S_I) was quantified and used to account for the role of insulin sensitivity to modulate ß-cell function (S_I x ß-cell function).

RESULTS—Fasting plasma glucose (5.3 ± 0.1 vs. 5.1 ± 0.1 mmol/l; means ± SEM), immunoreactive insulin (IRI) (68 ± 7 vs. 57 ± 6 pmol/l) and amylin-like immunoreactivity (ALI) (5.5 ± 0.6 vs. 4.7 ± 0.7 pmol/l) were similar in relatives and control subjects, respectively. Relatives were insulin resistant compared with control subjects (S_I: 4.86 ± 0.63 vs. 7.20 ± 0.78 x 10^-5 min^-1 · pmol^-1 · l^-1, P = 0.01), but their AIR_g (392 ± 59 vs. 386 ± 50 pmol/l) and AAR_g (5.9 ± 0.9 vs. 6.1 ± 0.8 pmol/l) did not differ. When ß-cell function was determined relative to insulin sensitivity, in the first-degree relatives, both AIR_g (S_I x AIR_g: 1.60 ± 0.23 vs. 2.44 ± 0.31 x 10^-2 min^-1, P < 0.05) and AAR_g (S_I x AAR_g: 2.39 ± 0.35 vs. 4.06 ± 0.56 x 10^-4 min^-1, P < 0.05) were reduced. The molar proportion of ALI to IRI was not altered in high-risk subjects (1.75 ± 0.16 vs. 1.71 ± 0.15%).

CONCLUSIONS—First-degree relatives of subjects with type 2 diabetes have diminished ß-cell function at a time when they are not hyperglycemic, and this reduction affects insulin and amylin responses proportionally. Thus, an altered amylin-to-insulin ratio is not likely to identify individuals at high risk of developing type 2 diabetes.

Abbreviations: AAR_g, intravenous glucose-induced acute amylin response • AIR_g, intravenous glucose-induced acute insulin response • ALI, amylin-like immunoreactivity • GEZI, glucose effectiveness at zero insulin • IRI, immunoreactive insulin • S_G, glucose effectiveness • S_I, insulin sensitivity index

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