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

Abstract

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.

Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes

“…However, the glucose-lowering efficacy tailed off with higher doses (30 mg, 60 mg qd) [ 94 ]. This is consistent with the observation that the same compound (100 mg) given as a single dose, demonstrated no improvement in glucose tolerance in patients with T2DM [ 95 ]. Mechanistic studies further confirmed that though being glucotropic, glucagon is also a potent insulinotropic hormone with antidiabetic potential [ 96 ].…”

Glucagon in type 2 diabetes: Friend or foe?

“…Further clinical development of GRAs was hampered by long‐term adverse events such as increased BW, liver fat content, systolic blood pressure, LDL‐cholesterol, and transaminase levels, associated with α‐cells hyperplasia and severe hypoglycaemia 131,134 . Also, GRA LY2409021 did not improve PPG following a mixed meal test 135 and paradoxically reduced glucose tolerance following an oral glucose tolerance test without restoring the incretin effect compared to placebo in 10 T2D patients 136 . GCGR antagonism was associated with stable fasting insulin levels, despite the amelioration of glucose control, and increased insulin levels during oral glucose tolerance test with a subsequent greater post‐load decrease in glucose, suggesting improved insulin sensitivity both in the fasting and fed states 134 .…”