Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade
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Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade. / Aulinger, Benedikt A; Bedorf, Anne; Kutscherauer, Gabriele; de Heer, Jocelyn; Holst, Jens Juul; Göke, Burkhard; Schirra, Jörg.
In: Diabetes, Vol. 63, No. 3, 03.2014, p. 1079-92.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade
AU - Aulinger, Benedikt A
AU - Bedorf, Anne
AU - Kutscherauer, Gabriele
AU - de Heer, Jocelyn
AU - Holst, Jens Juul
AU - Göke, Burkhard
AU - Schirra, Jörg
PY - 2014/3
Y1 - 2014/3
N2 - Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.
AB - Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.
KW - Blood Glucose
KW - C-Peptide
KW - Cross-Over Studies
KW - Diabetes Mellitus, Type 2
KW - Dipeptidyl-Peptidase IV Inhibitors
KW - Fasting
KW - Female
KW - Gastric Emptying
KW - Glucagon-Like Peptide 1
KW - Glucose Tolerance Test
KW - Humans
KW - Incretins
KW - Insulin
KW - Male
KW - Middle Aged
KW - Pyrazines
KW - Receptors, Glucagon
KW - Triazoles
U2 - 10.2337/db13-1455
DO - 10.2337/db13-1455
M3 - Journal article
C2 - 24296715
VL - 63
SP - 1079
EP - 1092
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -
ID: 117852947