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

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 Z 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.