Two novel glucagon receptor antagonists prove effective therapeutic agents in high‐fat‐fed and obese diabetic mice

O’Harte, Finbarr; Franklin, Zara J.; Irwin, Nigel

doi:10.1111/dom.12360

Cited by 26 publications

(22 citation statements)

References 32 publications

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“…Furthermore, glucagon receptor knockout mice are resistant to diabetes upon streptozotocin (STZ)-induced ␤-cell destruction (42). In addition, recent work using a peptide-based glucagon receptor antagonist reported improved metabolic control of genetically or directly induced obesity-related diabetes in mice (43). Therefore, our discovery may potentiate glucagon regulation in diabetes through Mafb gene regulation.…”

Section: Discussionmentioning

confidence: 93%

MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic α Cells In Vivo

et al. 2018

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The MafB transcription factor is expressed in pancreatic α and β cells during development but becomes exclusive to α cells in adult rodents. -null ( ) mice were reported to have reduced α- and β-cell numbers throughout embryonic development. To further analyze the postnatal function of MafB in the pancreas, we generated endocrine cell-specific ( ) and tamoxifen-dependent ( ) knockout mice. mice exhibited reduced populations of insulin-positive (insulin) and glucagon cells at postnatal day 0, but the insulin cell population recovered by 8 weeks of age. In contrast, the Arx glucagon cell fraction and glucagon expression remained decreased even in adulthood. mice, with deleted after pancreas maturation, also demonstrated diminished glucagon cells and glucagon content without affecting β cells. A decreased Arx glucagon cell population in mice was compensated for by an increased Arx pancreatic polypeptide cell population. Furthermore, gene expression analyses from both and islets revealed that MafB is a key regulator of glucagon expression in α cells. Finally, both mutants failed to respond to arginine, likely due to impaired arginine transporter gene expression and glucagon production ability. Taken together, our findings reveal that MafB is critical for the functional maintenance of mouse α cells , including glucagon production and secretion, as well as in development.

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Section: Discussionmentioning

confidence: 93%

MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic α Cells In Vivo

et al. 2018

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“…Targeting the glucagon receptor may therefore be a promising approach for decreasing hepatic glucose production and reducing fasting plasma glucose levels 110 . In support of this approach, two glucagon receptor peptide antagonists decreased blood glucose and improved insulin sensitivity in ob/ob and diet-induced obese mice 111 . In mice expressing human glucagon receptor, the glucagon antagonist compound 1 decreased blood glucose in response to glucagon administration 112 .…”

Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismmentioning

confidence: 90%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

295

244

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Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis resulting in hyperglycemia. Although current diabetes treatments have exhibited some success in lowering blood glucose, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycemia. Novel diabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver in order to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

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“…The glucose tolerance test (GTT) and other terminal testing like glycated haemoglobin HbA 1c , blood biomarkers were conducted between day 28 and 35. The CLAMS analysis was performed between days 36 and 38 where mice were give 24 h to acclimatise and a further 24 h for measurements, as described previously [ 35 ]. Terminal blood samples and tissue retrieval was completed on day 40.…”

Section: Methodsmentioning

confidence: 99%

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice

et al. 2018

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Previous studies have shown that modified apelin analogues exhibited enzyme resistance in plasma and improved circulating half-life compared to apelin-13. This study investigated the antidiabetic effects of chronic administration of stable long acting fatty acid modified apelin analogues, namely, (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide, in high-fat fed obese-diabetic mice. Male NIH Swiss mice (groups n = 8) were maintained either on a high-fat diet (45% fat) from 8 to 28 weeks old, or control mice were fed a normal diet (10% fat). When diet induced obesity-diabetes was established after high-fat feeding, mice were injected i.p. once daily with apelin analogues, liraglutide (25 nmol/kg) or saline (controls). Administration of (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide for 28 days significantly reduced food intake and decreased body weight. Non-fasting glucose was reduced (p<0.01 to p<0.001) and plasma insulin concentrations increased (p<0.01 to p<0.001). This was accompanied by enhanced insulin responses (p<0.01 to p<0.001) and significant reductions in glucose excursion after oral (p<0.01) or i.p. (p<0.01) glucose challenges and feeding. Apelin analogues also significantly improved HbA1c (p<0.01), enhanced insulin sensitivity (p<0.01), reduced triglycerides (p<0.001), increased HDL-cholesterol (p<0.01) and decreased LDL-cholesterol (p<0.01), compared to high-fat fed saline treated control mice. Cholesterol levels were decreased (p<0.01) by pGlu(Lys8GluPAL)apelin-13 amide and both apelin treated groups showed improved bone mineral content, reduced fat deposits and increased plasma GLP-1. Daily treatment with liraglutide mirrored many of these changes (not on bone or adipose tissue), but unlike apelin analogues increased plasma amylase. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were improved by apelin analogues. These results indicate that long-term treatment with acylated analogues (Lys8GluPAL)apelin-13 amide and particularly pGlu(Lys8GluPAL)apelin-13 amide resulted in similar or enhanced therapeutic responses to liraglutide in high-fat fed mice. Fatty acid derived apelin analogues represent a new and exciting development in the treatment of obesity-diabetes.

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Two novel glucagon receptor antagonists prove effective therapeutic agents in high‐fat‐fed and obese diabetic mice

Abstract: These data indicate that peptide-based glucagon receptor antagonists can reverse aspects of genetically and dietary-induced obesity-related diabetes.

Cited by 26 publications

References 32 publications

MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic α Cells In Vivo

MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic α Cells In Vivo

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice

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