The glucagon receptor antagonist LY2409021 has no effect on postprandial glucose in type 2 diabetes

in European Journal of Endocrinology
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  • 1 Clinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark
  • | 2 Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
  • | 3 Danish Diabetes Academy, Odense University Hospital, Odense, Denmark
  • | 4 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • | 5 Department of Public Health, Section of Biostatistics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • | 6 Clinical Metabolomics Core Facility, Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
  • | 7 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • | 8 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Correspondence should be addressed to T Vilsbøll; Email: tina.vilsboell.01@regionh.dk
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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 the consequences of hyperglucagonemia in T2D.

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 toward related incretin receptors was determined in vitro.

Results

Compared to placebo, LY2409021 lowered the fasting plasma glucose (FPG) 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 FPG 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.

 

     European Society of Endocrinology

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