Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Ali, Safina; Lamont, Benjamin J.; Charron, Maureen J.; Drucker, Daniel J.

doi:10.1172/jci43615

Cited by 93 publications

(94 citation statements)

References 59 publications

(81 reference statements)

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“…However, the acute nature of the increase in circulating glucagon also suggests that partial blockade of the glucagon receptor is most likely driven by a direct systemic feedback loop but might also be impacted by decreased overall glucagon clearance. Studies in mice have provided conflicting results regarding the role of GLP-1 in the improved glucose metabolism observed in glucagon receptor knockouts (26,27). Our results suggest that GLP-1 is unlikely to contribute to the efficacy of LY2409021 because active hormone levels are unchanged.…”

Section: Discussionmentioning

confidence: 65%

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

Kazda¹,

et al. 2015

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OBJECTIVEType 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSThe efficacy (HbA 1c and glucose) and safety (serum aminotransferase) of oncedaily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTSLY2409021 produced reductions in HbA 1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA 1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA 1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] £10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONSIn patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA 1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

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Section: Discussionmentioning

confidence: 65%

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

Kazda¹,

et al. 2015

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“…The contribution of increased GLP-1 concentrations to the altered glucose tolerance in Gcgr -/-has been investigated in STZ-treated Gcgr -/-mice, and inhibition of GLP-1 action had no effect on glucose tolerance but eliminated the improvement found in the STZ-treated Gcgr -/-mice [19]. The double knockout mouse, Gcgr -/-Glp1r -/- [20] has normal random fed blood glucose levels and a normal i.p. glucose tolerance.…”

Section: Discussionmentioning

confidence: 99%

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

et al. 2015

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Aims/hypothesis Normal glucose metabolism depends on pancreatic secretion of insulin and glucagon. The bihormonal hypothesis states that while lack of insulin leads to glucose underutilisation, glucagon excess is the principal factor in diabetic glucose overproduction. A recent study reported that streptozotocin-treated glucagon receptor knockout mice have normal glucose tolerance. We investigated the impact of acute disruption of glucagon secretin or action in a mouse model of severe diabetes by three different approaches: (1) alpha cell elimination; (2) glucagon immunoneutralisation; and (3) glucagon receptor antagonism, in order to evaluate the effect of these on glucose tolerance. Methods Severe diabetes was induced in transgenic and wild-type mice by streptozotocin. Glucose metabolism was investigated using OGTT in transgenic mice with the human diphtheria toxin receptor expressed in proglucagon producing cells allowing for diphtheria toxin (DT)-induced alpha cell ablation and in mice treated with either a specific high affinity glucagon antibody or a specific glucagon receptor antagonist.Results Near-total alpha cell elimination was induced in transgenic mice upon DT administration and resulted in a massive decrease in pancreatic glucagon content. Oral glucose tolerance in diabetic mice was neither affected by glucagon immunoneutralisation, glucagon receptor antagonism, nor alpha cell removal, but did not deteriorate further compared with mice with intact alpha cell mass. Conclusions/interpretation Disruption of glucagon action/ secretion did not improve glucose tolerance in diabetic mice. Near-total alpha cell elimination may have prevented further deterioration. Our findings support insulin lack as the major factor underlying hyperglycaemia in beta cell-deficient diabetes.

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“…It was reported that plasma levels of GLP-1 and GLP-2 were dramatically increased in GCGR Ϫ / Ϫ mice ( 32,33 ).…”

Section: Effects Of Gra On Cholesterol Absorption In Hgcgr Micementioning

confidence: 97%

Glucagon receptor antagonism induces increased cholesterol absorption

Guan

Yang

et al. 2015

Journal of Lipid Research

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Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Cited by 93 publications

References 59 publications

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

Glucagon receptor antagonism induces increased cholesterol absorption

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