Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response

TY - JOUR

T1 - Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response

AU - Tura, A.

AU - Bagger, J. I.

AU - Ferrannini, E.

AU - Holst, J. J.

AU - Knop, F. K.

AU - Vilsbøll, T.

AU - Mari, A.

PY - 2017/12

Y1 - 2017/12

N2 - Background and aims The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. Methods and results Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). Conclusion Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.

AB - Background and aims The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. Methods and results Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). Conclusion Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.

KW - Glucagon-like Peptide-1

KW - Glucose-dependent insulinotropic peptide

KW - Incretin effect

KW - Incretin sensitivity

KW - Insulin secretion

KW - Mathematical model

KW - Oral glucose tolerance test

KW - Type 2 diabetes mellitus

U2 - 10.1016/j.numecd.2017.10.006

DO - 10.1016/j.numecd.2017.10.006

M3 - Journal article

C2 - 29162361

AN - SCOPUS:85034789034

SN - 0939-4753

VL - 27

SP - 1123

EP - 1129

JO - Nutrition, Metabolism & Cardiovascular Diseases

JF - Nutrition, Metabolism & Cardiovascular Diseases

IS - 12

ER -