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Altered Homeostatic Adaptation of First- and Second-Phase ß-Cell Secretion in the Offspring of Patients With Type 2 Diabetes

Studies With a Minimal Model to Assess ß-Cell Function

¹ Division of Endocrinology and Metabolic Diseases, University of Verona and Azienda Ospedaliera di Verona, Verona, Italy
² Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany
³ Department of Internal Medicine, University Medical Center, Utrecht, the Netherlands

We adapted a minimal model to assess ß-cell function during a hyperglycemic glucose clamp and to uncover peculiar aspects of the relationship among ß-cell function, plasma glucose, and insulin sensitivity (IS) in offspring of Caucasian patients with type 2 diabetes (OfT2D). We pooled two data sets of OfT2D (n = 69) and control subjects (n = 45) with normal glucose regulation. Plasma C-peptide was measured during a hyperglycemic clamp (10 mmol/l) to quantify model-based first-phase secretion and glucose sensitivity of second-phase secretion (ß). IS was quantified during the hyperglycemic clamp. In the pooled data, first-phase secretion was linearly and negatively related to fasting plasma glucose, but not IS; OfT2D lay on a distinct line shifted to the left of the control subjects. In contrast, ß was negatively related to IS, and OfT2D lay on a distinct line shifted more and more to the left of the control subjects, as IS was worse. Thus, in OfT2D lower ß-cell adaptive responses exist between ambient glycemia and first-phase insulin secretion and between IS and second-phase secretion. Under conditions leading to decreased insulin sensitivity, these disturbed relationships may lead to progression to diabetes in OfT2D.

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