An orally available compound suppresses glucagon hypersecretion and normalizes hyperglycemia in type 1 diabetes
Farzad Asadi, Subhadra C. Gunawardana, Roland E. Dolle, David W. Piston
Farzad Asadi, Subhadra C. Gunawardana, Roland E. Dolle, David W. Piston
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Research Article Endocrinology

An orally available compound suppresses glucagon hypersecretion and normalizes hyperglycemia in type 1 diabetes

Abstract

Suppression of glucagon hypersecretion can normalize hyperglycemia during type 1 diabetes (T1D). Activating erythropoietin-producing human hepatocellular receptor type-A4 (EphA4) on α cells reduced glucagon hypersecretion from dispersed α cells and T1D islets from both human donor and mouse models. We synthesized a high-affinity small molecule agonist for the EphA4 receptor, WCDD301, which showed robust plasma and liver microsome metabolic stability in both mouse and human preparations. In islets and dispersed islet cells from nondiabetic and T1D human donors, WCDD301 reduced glucagon secretion comparable to the natural EphA4 ligand, Ephrin-A5. In diabetic NOD and streptozotocin-treated mice, once-daily oral administration of WCDD301 formulated with a time-release excipient reduced plasma glucagon and normalized blood glucose for more than 3 months. These results suggest that targeting the α cell EphA4 receptor by sustained release of WCDD301 is a promising pharmacologic pathway for normalizing hyperglycemia in patients with T1D.

Authors

Farzad Asadi, Subhadra C. Gunawardana, Roland E. Dolle, David W. Piston

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Figure 6

WCDD301 normalizes blood glucose levels in diabetic mouse models that is accompanied by improvement in glucose tolerance.

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WCDD301 normalizes blood glucose levels in diabetic mouse models that is...
(A) Treatment of diabetic NOD mice with moderate hyperglycemia using WCDD301 (n = 6–9, oral, 7.5 mg/kg) or placebo (n = 4) and monitoring blood glucose over 11 weeks. Values (mean ± SEM) in each week were compared with the values of before treatment (week 0) using 1-way ANOVA. **P < 0.01, ***P < 0.001. Plasma (B) glucagon and (C) insulin following treatment of the NOD mice; 1-way ANOVA; ***P < 0.001, n = 5; ND, nondiabetic; D, diabetic. (D) Intraperitoneal glucose tolerance in WCDD301-treated NOD mice; values expressed as mean ± SD (n = 3) and areas under the curves compared among groups using 1-way ANOVA. ***P < 0.001 compared with the nondiabetic placebo-treated mice. (E) Insulin tolerance in WCDD301-treated NOD mice; values expressed as mean ± SD (n = 4) and areas under curves compared among groups using 1-way ANOVA; ***P < 0.001 compared with the diabetic placebo-treated or diabetic WCDD301-treated mice. (F) Treatment of STZ-induced diabetic mice with early severe hyperglycemia using WCDD301 (10 mg/kg) and monitoring blood glucose over 4 weeks. Values of the placebo treated (n = 3) or WCDD301 treated (n = 4) in each week were compared with the corresponding values of before dosing using 1-way ANOVA; ***P < 0.001. (G) Glucose output from primary mouse hepatocytes in the presence or absence of 100 nM glucagon and/or 3 μM WCDD301 (n = 5). Each dot represents mean values of 1 mouse. Values of WCDD301-treated groups compared with the corresponding control using t test, α = 0.05.