The Glucagon Receptor Antagonist LY2409021 has No Effect on Postprandial Glucose in Type 2 Diabetes
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The Glucagon Receptor Antagonist LY2409021 has No Effect on Postprandial Glucose in Type 2 Diabetes. / Hædersdal, Sofie; Lund, Asger; Maagensen, Henrik; Nielsen-Hannerup, Elisabeth; Gasbjerg, Lærke S; Rosenkilde, Mette M; Forman, Julie Lyng; van Hall, Gerrit; Holst, Jens J; Knop, Filip K; Vilsbøll, Tina.
In: European Journal of Endocrinology, Vol. 186, No. 2, 2022, p. 207-221.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Glucagon Receptor Antagonist LY2409021 has No Effect on Postprandial Glucose in Type 2 Diabetes
AU - Hædersdal, Sofie
AU - Lund, Asger
AU - Maagensen, Henrik
AU - Nielsen-Hannerup, Elisabeth
AU - Gasbjerg, Lærke S
AU - Rosenkilde, Mette M
AU - Forman, Julie Lyng
AU - van Hall, Gerrit
AU - Holst, Jens J
AU - Knop, Filip K
AU - Vilsbøll, Tina
PY - 2022
Y1 - 2022
N2 - OBJECTIVE: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate consequences of hyperglucagonemia in type 2 diabetes.DESIGN: A double-blinded, randomized, placebo-controlled crossover study was conducted.METHODS: Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity towards related incretin receptors was determined in vitro.RESULTS: Compared to placebo, LY2409021 lowered fasting plasma glucose from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P<0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data.CONCLUSIONS: LY2409021 lowered fasting plasma glucose concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.
AB - OBJECTIVE: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate consequences of hyperglucagonemia in type 2 diabetes.DESIGN: A double-blinded, randomized, placebo-controlled crossover study was conducted.METHODS: Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity towards related incretin receptors was determined in vitro.RESULTS: Compared to placebo, LY2409021 lowered fasting plasma glucose from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P<0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data.CONCLUSIONS: LY2409021 lowered fasting plasma glucose concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.
U2 - 10.1530/EJE-21-0865
DO - 10.1530/EJE-21-0865
M3 - Journal article
C2 - 34863038
VL - 186
SP - 207
EP - 221
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
SN - 0804-4643
IS - 2
ER -
ID: 287118698