title: Characterization of beta-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests.
abstract: To investigate early secretory defects in prediabetes, we evaluated beta-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. beta-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 x min(-1) x m(-2), P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, rho = -0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5 x 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). beta-Cell function parameters were also related to mean 24-h glucose levels (r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, beta-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a beta-cell defect in the amplifying pathway of insulin secretion.
authors.affiliation: Consiglio Nazionale delle Ricerche Institute of Biomedical Engineering, Padua, Italy. andrea.mari@isib.cnr.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Natali
authors.forename: Torben
authors.initials: T
authors.lastname: Ostergard
authors.forename: Ole
authors.initials: O
authors.lastname: Schmitz
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D004032:Diet; D002149:Energy Intake; D005190:Family; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000097:blood; D011498:Protein Precursors / Q000097:blood
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon