Short‐term administration of the glucagon receptor antagonist <scp>LY2409021</scp> lowers blood glucose in healthy people and in those with type 2 diabetes

Kelly, Raymond P.; Garhyan, Parag; Raddad, Eyas; Fu, Haoda; Lim, Chay Ngee; Prince, Melvin; Pinaire, Jane; Loh, M. T.; Deeg, Mark A.

doi:10.1111/dom.12446

Cited by 97 publications

(99 citation statements)

References 26 publications

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“…In contrast, Wang et al [21] recently showed that weekly administration of a monoclonal glucagon receptor-targeting antibody caused normalisation of blood glucose in severely diabetic mice. Perhaps chronic blockade of the glucagon receptor elicits changes in the pancreas similar to GCGRdeletion or antagonist administration [16]. In the present study, all of the three methods were supposed to cause immediate and near complete glucagon deficiency.…”

Section: Discussionmentioning

confidence: 50%

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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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Section: Discussionmentioning

confidence: 50%

“…These results further support the notion that presence or absence of glucagon did not matter for the hepatic glucose production during insulinopenia. This is in contrast to insulin-independent diabetes, where both glucagon antagonism and immunoneutralisation lowers blood glucose [8,16,17].…”

Section: Discussionmentioning

confidence: 91%

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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“…The positive results of these preclinical studies have begun to translate into clinical impact, with impressive glucose lowering with small molecule glucagon receptor antagonists in diabetic individuals [4,50]. This demonstrates the contribution increased glucagon signalling makes to the diabetic state and the potential for large effects on glycaemia with antagonism.…”

Section: Glucagon Antagonismmentioning

confidence: 93%

“…Following decades during which reduced insulin action was viewed as the exclusive cause of diabetes mellitus and hormonal replacement proved transformative to diabetic individuals worldwide, renewed interest in glucagon has resulted in a rediscovered appreciation of the role this hormone plays in the pathophysiology of impaired glucose homeostasis [1][2][3]. This recent excitement for glucagon antagonism as a viable therapeutic approach stems from the tantalising preclinical results suggesting that reducing glucagon action or secretion will exert potent reductions in the elevated hepatic glucose production present in both type 1 and 2 diabetes mellitus [4][5][6][7][8]. Glucagon is secreted by the pancreatic alpha cell in response to changes in the local concentration of glucose, amino acids or insulin.…”

Section: Glucagon: Hormonal Mediator Of Hepatic Metabolismmentioning

confidence: 99%

Glucagon: acute actions on hepatic metabolism

Miller

Birnbaum

2016

Diabetologia

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Type 2 diabetes mellitus is the result of impaired systemic control of glucose homeostasis, in part through the dysregulation of the hormone glucagon. Glucagon acts on the liver to increase glucose production through alterations in hepatic metabolism, and reducing the elevated glucagon signalling in diabetic patients is an attractive strategy for the treatment of hyperglycaemia. Here we review the actions of the hormone in the liver, focusing on the acute alterations of metabolic pathways. This review summarises

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“…58 Early clinical trials in patients with type 2 diabetes mellitus show promise. 59,60 Therefore therapies that modulate glucagon receptor signalling could potentially be used to treat the hyperglycaemia of type 1 diabetes mellitus. Potential limitations to this approach are early findings from studies in rodents that glucagon receptor modulation is associated with islet hyperplasia and disturbance in lipid metabolism in rodent studies, 61 clearly issues that need further investigation.…”

Section: Novel Drugs That Target the Glucagon Pathway And Alpha Cell mentioning

confidence: 99%

Alpha cell function in type 1 diabetes

Hughes

Narendran

2014

Br J Diabetes

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Our understanding of the pathogenesis of type 1 diabetes mellitus has traditionally revolved around the insulin deficiency that follows pancreatic beta cell loss. However, there is an increasing appreciation of defects in other glucoregulatory cells in type 1 diabetes mellitus. Oversecretion of glucagon from pancreatic alpha cells is characteristic of type 1 diabetes mellitus, and modulating these glucagon levels reduces hyperglycaemia. This article reviews alpha cell function in type 1 diabetes mellitus. We examine how its function is controlled and compromised, and review studies that target alpha cell function. Finally, we explore potential approaches to modulating alpha cell function in type 1 diabetes mellitus. Br J Diabetes Vasc Dis 2014;14:45-51

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Short‐term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes

Cited by 97 publications

References 26 publications

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

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

Glucagon: acute actions on hepatic metabolism

Alpha cell function in type 1 diabetes

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