Older subjects with β-cell dysfunction have an accentuated incretin release

TY - JOUR

T1 - Older subjects with β-cell dysfunction have an accentuated incretin release

AU - De Jesús Garduno-Garcia, José

AU - Gastaldelli, Amalia

AU - DeFronzo, Ralph A

AU - Lertwattanarak, Raweewan

AU - Holst, Jens J.

AU - Musi, Nicolas

PY - 2018

Y1 - 2018

N2 - Objective Insulin secretion (IS) declines with age, which increases the risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in older adults. IS is regulated by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Here we tested the hypotheses that incretin release is lower in older adults and that this decline is associated with β-cell dysfunction. Research Design A total of 40 young (25 ± 3 years) and 53 older (74 ± 7 years) lean nondiabetic subjects underwent a 2-hour oral glucose tolerance test (OGTT). Based on the OGTT, subjects were divided into three groups: young subjects with normal glucose tolerance (Y-NGT; n = 40), older subjects with normal glucose tolerance (O-NGT; n = 32), and older subjects with IGT (O-IGT; n = 21). Main Outcome Measures Plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15 to 30 minutes. We quantitated insulin sensitivity (Matsuda index) and insulin secretory rate (ISR) by deconvolution of C-peptide with the calculation of β-cell glucose sensitivity. Results Matsuda index, early phase ISR (0 to 30 minutes), and parameters of β-cell function were lower in O-IGT than in Y-NGT subjects but not in O-NGT subjects. GLP-1 concentrations were elevated in both older groups [GLP-1 area under the curve (AUC) 0-120 was 2.8 ± 0.1 in Y-NGT, 3.8 ± 0.5 in O-NGT, and 3.7 ± 0.4 nmol/L 120 minutes in O-IGT subjects; P < 0.05], whereas GIP secretion was higher in O-NGT than in Y-NGT subjects (GIP AUC 0-120 was 4.7 ± 0.3 in Y-NGT, 6.0 ± 0.4 in O-NGT, and 4.8 ± 0.3 nmol/L 120 minutes in O-IGT subjects; P < 0.05). Conclusions Aging is associated with an exaggerated GLP-1 secretory response. However, it was not sufficient to increase insulin first-phase release in O-IGT and overcome insulin resistance.

AB - Objective Insulin secretion (IS) declines with age, which increases the risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in older adults. IS is regulated by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Here we tested the hypotheses that incretin release is lower in older adults and that this decline is associated with β-cell dysfunction. Research Design A total of 40 young (25 ± 3 years) and 53 older (74 ± 7 years) lean nondiabetic subjects underwent a 2-hour oral glucose tolerance test (OGTT). Based on the OGTT, subjects were divided into three groups: young subjects with normal glucose tolerance (Y-NGT; n = 40), older subjects with normal glucose tolerance (O-NGT; n = 32), and older subjects with IGT (O-IGT; n = 21). Main Outcome Measures Plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15 to 30 minutes. We quantitated insulin sensitivity (Matsuda index) and insulin secretory rate (ISR) by deconvolution of C-peptide with the calculation of β-cell glucose sensitivity. Results Matsuda index, early phase ISR (0 to 30 minutes), and parameters of β-cell function were lower in O-IGT than in Y-NGT subjects but not in O-NGT subjects. GLP-1 concentrations were elevated in both older groups [GLP-1 area under the curve (AUC) 0-120 was 2.8 ± 0.1 in Y-NGT, 3.8 ± 0.5 in O-NGT, and 3.7 ± 0.4 nmol/L 120 minutes in O-IGT subjects; P < 0.05], whereas GIP secretion was higher in O-NGT than in Y-NGT subjects (GIP AUC 0-120 was 4.7 ± 0.3 in Y-NGT, 6.0 ± 0.4 in O-NGT, and 4.8 ± 0.3 nmol/L 120 minutes in O-IGT subjects; P < 0.05). Conclusions Aging is associated with an exaggerated GLP-1 secretory response. However, it was not sufficient to increase insulin first-phase release in O-IGT and overcome insulin resistance.

U2 - 10.1210/jc.2018-00260

DO - 10.1210/jc.2018-00260

M3 - Journal article

C2 - 29672742

AN - SCOPUS:85050124603

SN - 0021-972X

VL - 103

SP - 2613

EP - 2619

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 7

ER -