Single and multiple ascending-dose study of glucagon-receptor antagonist RN909 in type 2 diabetes: a phase 1, randomized, double-blind, placebo-controlled trial

Gumbiner, Barry M.; Esteves, Brooke; Dell, Vanessa; Joh, Tenshang; Garzone, Pamela D.; Forgie, Alison; Udata, Chandrasekhar

doi:10.1007/s12020-018-1597-1

Cited by 16 publications

(8 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Monoclonal antibodies that block glucagon receptor are beneficial to control diabetes in patients with T1D and T2D [67], [68]. However, a theoretical concern that might be associated to glucagon receptor blockade is development of pancreatic neoplasia, as patients with biallelic inactivating mutations in the glucagon receptor gene ( GCGR ) develop α-cell hyperplasia that may progress to neoplasia (Mahvash syndrome) [69].…”

Section: Relevance Of Glucagon In Patients With Diabetesmentioning

confidence: 99%

Metabolic effects of glucagon in humans

Adeva‐Andany¹,

Funcasta-Calderón²,

Fernández‐Fernández³

et al. 2019

Journal of Clinical & Translational Endocrinology

View full text Add to dashboard Cite

Diabetes is a common metabolic disorder that involves glucose, amino acids, and fatty acids. Either insulin deficiency or insulin resistance may cause diabetes. Insulin deficiency causes type 1 diabetes and diabetes associated with total pancreatectomy. Glucagon produces insulin resistance. Glucagon-induced insulin resistance promotes type 2 diabetes and diabetes associated with glucagonoma. Further, glucagon-induced insulin resistance aggravates the metabolic consequences of the insulin-deficient state. A major metabolic effect of insulin is the accumulation of glucose as glycogen in the liver. Glucagon opposes hepatic insulin action and enhances the rate of gluconeogenesis, increasing hepatic glucose output. In order to support gluconeogenesis, glucagon promotes skeletal muscle wasting to supply amino acids as gluconeogenic precursors. Glucagon promotes hepatic fatty acid oxidation to supply energy required to sustain gluconeogenesis. Hepatic fatty acid oxidation generates β-hydroxybutyrate and acetoacetate (ketogenesis). Prospective studies reveal that elevated glucagon secretion at baseline occurs in healthy subjects who develop impaired glucose tolerance at follow-up compared with subjects who maintain normal glucose tolerance, suggesting a relationship between elevated glucagon secretion and development of impaired glucose tolerance. Prospective studies have identified animal protein consumption as an independent risk factor for type 2 diabetes and cardiovascular disease. Animal protein intake activates glucagon secretion inducing sustained elevations in plasma glucagon. Glucagon is a major hormone that causes insulin resistance. Insulin resistance is an established cardiovascular risk factor additionally to its pathogenic role in diabetes. Glucagon may be a potential link between animal protein intake and the risk of developing type 2 diabetes and cardiovascular disease.

show abstract

Section: Relevance Of Glucagon In Patients With Diabetesmentioning

confidence: 99%

Metabolic effects of glucagon in humans

Adeva‐Andany¹,

Funcasta-Calderón²,

Fernández‐Fernández³

et al. 2019

Journal of Clinical & Translational Endocrinology

View full text Add to dashboard Cite

show abstract

“…Hence, low plasma glucose does not always associate with elevated glucagon levels, raising the possibility that hypoglycemia is not the primary driver of -cell secretory function. Furthermore, blocking glucagon action with genetic interruption (13,14) or pharmacological antagonism in mice (15), non-human primates (16), or humans (17,18) lowers glucose but does not necessary alter the susceptibility to hypoglycemia. On the other hand, a much tighter relationship is seen between glucagon levels and a subset of amino acids (19).…”

Section: B Does Glucagon Only Exist To Prevent Hypoglycemia?mentioning

confidence: 99%

Repositioning Glucagon Action in the Physiology and Pharmacology of Diabetes

2019

View full text Add to dashboard Cite

Glucagon is historically described as the counterregulatory hormone to insulin, induced by fasting/hypoglycemia to raise blood glucose through action mediated in the liver. However, it is becoming clear that the biology of glucagon is much more complex and extends beyond hepatic actions to exert control on glucose metabolism. We discuss the inconsistencies with the canonical view that glucagon is primarily a hyperglycemic agent driven by fasting/hypoglycemia and highlight the recent advances that have reshaped the metabolic role of glucagon. These concepts are placed within the context of both normal physiology and the pathophysiology of disease, and then extended to discuss emerging strategies that incorporate glucagon agonism in the pharmacology of treating diabetes.

show abstract

“…Accordingly, the mouse is an informative model to assess the potential beneficial responses to glucagon receptor manipulation. Despite improving the regulation of blood glucose, reported increases in hepatic triglyceride content, plasma total cholesterol ( 31 ), and liver enzymes ( 31 , 32 ) have led to questions regarding the safety and efficacy of such therapeutics. Global glucagon receptor knockout increases fasting serum nonesterified fatty acid (NEFA) and triglyceride (TAG) concentrations, and hepatic TAG secretion in mice ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Glucagon receptor signaling at white adipose tissue does not regulate lipolysis

Vasileva

Marx

Beaudry

et al. 2022

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Although the physiologic role of glucagon receptor signaling in the liver is well defined, the impact of glucagon receptor (Gcgr) signaling at white adipose tissue (WAT) continues to be debated. While numerous studies propose glucagon stimulates WAT lipolysis, we lack evidence that physiological concentrations of glucagon regulate WAT lipolysis. In turn, we performed studies in both wildtype and WAT Gcgr knockout mice to determine if glucagon regulates lipolysis at WAT in the mouse. We assessed the effects of fasting and acute exogenous glucagon administration in wildtype C57BL/6J and Gcgr Adipocyte+/+ vs GcgrAdipocyte-/- mice. Using an ex vivo lipolysis protocol, we further examined the direct effects of glucagon on physiologically (fasted) and pharmacologically stimulated lipolysis. We found that adipocyte Gcgr expression did not affect fasting induced lipolysis or hepatic lipid accumulation in lean or diet induced obese (DIO) mice. Acute glucagon administration did not affect serum non-esterified fatty acids (NEFA), leptin, or adiponectin concentration, but did increase serum glucose and FGF21, regardless of genotype. Glucagon did not affect ex vivo lipolysis in explants from either Gcgr Adipocyte+/+ or GcgrAdipocyte-/- mice. Gcgr expression did not affect fasting-induced or isoproterenol-stimulated lipolysis from WAT explants. Moreover, glucagon receptor signaling at WAT did not affect body weight or glucose homeostasis in lean or DIO mice. Our studies have established that physiological levels of glucagon do not regulate WAT lipolysis, either directly or indirectly. Given that glucagon receptor agonism can improve dyslipidemia and decrease hepatic lipid accumulation, it is critical to understand the tissue-specific effects of glucagon receptor action. Unlike the crucial role of hepatic glucagon receptor signaling in maintaining glucose and lipid homeostasis, we observed no metabolic consequence of WAT glucagon receptor deletion.

show abstract

Single and multiple ascending-dose study of glucagon-receptor antagonist RN909 in type 2 diabetes: a phase 1, randomized, double-blind, placebo-controlled trial

Abstract: RN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.

Cited by 16 publications

References 15 publications

Metabolic effects of glucagon in humans

Metabolic effects of glucagon in humans

Repositioning Glucagon Action in the Physiology and Pharmacology of Diabetes

Glucagon receptor signaling at white adipose tissue does not regulate lipolysis

Contact Info

Product

Resources

About