Chronic treatment with a glucagon receptor antagonist lowers glucose and moderately raises circulating glucagon and glucagon-like peptide 1 without severe alpha cell hypertrophy in diet-induced obese mice

Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.

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Unraveling oxyntomodulin, GLP1's enigmatic brother

Journal of Endocrinology ◽

10.1530/joe-12-0368 ◽

2012 ◽

Vol 215 (3) ◽

pp. 335-346 ◽

Cited By ~ 77

Author(s):

Alessandro Pocai

Keyword(s):

Weight Loss ◽

Glycemic Control ◽

Glucose Tolerance ◽

Obese Mice ◽

Glucagon Receptor ◽

Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Diabetes And Obesity ◽

Dual Agonist

Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.

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Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice

Journal of Endocrinology ◽

10.1530/joe-15-0463 ◽

2016 ◽

Vol 229 (3) ◽

pp. 319-330 ◽

Cited By ~ 4

Author(s):

L M McShane ◽

N Irwin ◽

D O’Flynn ◽

Z J Franklin ◽

C M Hewage ◽

...

Keyword(s):

Receptor Antagonist ◽

Combined Treatment ◽

Receptor Activation ◽

Daily Injection ◽

Oral Glucose ◽

Receptor Signaling ◽

Obese Mice ◽

Glucagon Receptor ◽

Glucagon Receptor Antagonist ◽

Gip Receptor

Ablation of glucagon receptor signaling represents a potential treatment option for type 2 diabetes (T2DM). Additionally, activation of glucose-dependent insulinotropic polypeptide (GIP) receptor signaling also holds therapeutic promise for T2DM. Therefore, this study examined both independent and combined metabolic actions of desHis1Pro4Glu9(Lys12PAL)-glucagon (glucagon receptor antagonist) and d-Ala2GIP (GIP receptor agonist) in diet-induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis1Pro4Glu9(Lys12PAL)-glucagon displayed enhanced alpha-helical content compared with native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis1Pro4Glu9(Lys12PAL)-glucagon was devoid of any insulinotropic or cAMP-generating actions, and did not impede d-Ala2GIP-mediated (P<0.01 to P<0.001) effects on insulin and cAMP production. Twice-daily injection of desHis1Pro4Glu9(Lys12PAL)-glucagon or d-Ala2GIP alone, and in combination, in high-fat-fed mice failed to affect body weight or energy intake. Circulating blood glucose levels were significantly (P<0.05 to P<0.01) decreased by all treatments regimens, with plasma and pancreatic insulin elevated (P<0.05 to P<0.001) in all mice receiving d-Ala2GIP. Interestingly, plasma glucagon concentrations were decreased (P<0.05) by sustained glucagon inhibition (day 28), but increased (P<0.05) by d-Ala2GIP therapy, with a combined treatment resulting in glucagon concentration similar to saline controls. All treatments improved (P<0.01) intraperitoneal and oral glucose tolerance, and peripheral insulin sensitivity. d-Ala2GIP-treated mice showed increased glucose-induced insulin secretion in response to intraperitoneal and oral glucose. Metabolic rate and ambulatory locomotor activity were increased (P<0.05 to P<0.001) in all desHis1Pro4Glu9(Lys12PAL)-glucagon-treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment.

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Novel glucagon receptor antagonist peptides improve glycaemic control and partially protect against streptozotocin induced diabetes in mice

Endocrine Abstracts ◽

10.1530/endoabs.37.oc4.1 ◽

2015 ◽

Author(s):

Finbarr O'Harte ◽

Laura McShane ◽

Nigel Irwin

Keyword(s):

Glycaemic Control ◽

Receptor Antagonist ◽

Glucagon Receptor ◽

Diabetes In Mice ◽

Antagonist Peptides ◽

Glucagon Receptor Antagonist ◽

Streptozotocin Induced Diabetes

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An Allosteric Glucagon Receptor Antagonist, LGD-6972, Displays Biased Receptor Signaling

Diabetes ◽

10.2337/db18-1117-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1117-P ◽

Cited By ~ 2

Author(s):

ERIC G. VAJDA ◽

LIN ZHI ◽

KEITH MARSCHKE

Keyword(s):

Receptor Antagonist ◽

Receptor Signaling ◽

Glucagon Receptor ◽

Glucagon Receptor Antagonist

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Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00459.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. R595-R608 ◽

Cited By ~ 4

Author(s):

Jacob D. Brown ◽

Danielle McAnally ◽

Jennifer E. Ayala ◽

Melissa A. Burmeister ◽

Camilo Morfa ◽

...

Keyword(s):

Weight Loss ◽

Energy Expenditure ◽

Receptor Agonist ◽

Day Treatment ◽

Mtor Pathway ◽

Obese Mice ◽

Promote Weight Loss ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Long Acting

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

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