Glucagon receptor signaling in metabolic diseases

Albrechtsen, Nicolai J. Wewer

doi:10.1016/j.peptides.2017.11.016

Cited by 24 publications

(23 citation statements)

References 63 publications

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“…Proglucagon has 160 amino acids and is expressed in certain neurons of the brain stem, in intestinal L cells, and in pancreatic alpha cells [17]. Several bioactive peptides, including glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), are cleaved from proglucagon by prohormone convertase(s) in a tissue-specific (or perhaps more accurately enzyme-specific [18]) manner (Figure 1). The differential processing of proglucagon appears to reflect the enzymatic activities of the two prohormone convertases: prohormone convertase 1/3 (PC1/3) and 2 (PC2) [19].…”

Section: Processing Of Proglucagonmentioning

confidence: 99%

“…The absolute selectivity of PC1/3 and PC2 remains a matter of discussion. It has been speculated that metabolic stressors such as type 2 diabetes, obesity, and Roux-en-Y gastric bypass surgery may alter the processing profile of proglucagon both in the pancreas and in the gut, but the extent to which this occurs in humans and the clinical relevance of such changes remain unknown [18].…”

Section: Processing Of Proglucagonmentioning

confidence: 99%

“…Hyperaminoacidemia is therefore suggested as the factor leading to alpha cell hyperplasia [121,135,141]. This endocrine feedback loop, in which glucagon induces hepatic amino acid metabolism and amino acids in turn stimulate glucagon secretion, has been named the liver–alpha cell axis [7,18]. The glucagonotropic amino acids, alanine and glutamine, may be of particular importance in this feedback loop in mediating alpha cell secretion and growth, respectively [142].…”

Section: Glucagon Receptor Signalingmentioning

confidence: 99%

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Glucagon Receptor Signaling and Glucagon Resistance

Janah

Kjeldsen

Galsgaard

et al. 2019

IJMS

134

102

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Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.

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Section: Processing Of Proglucagonmentioning

confidence: 99%

Section: Processing Of Proglucagonmentioning

confidence: 99%

Section: Glucagon Receptor Signalingmentioning

confidence: 99%

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Glucagon Receptor Signaling and Glucagon Resistance

Janah

Kjeldsen

Galsgaard

et al. 2019

IJMS

134

102

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“…Upregulated gcg mRNA levels, increased glucagon levels, and α‐cell mass were observed. Glucagon is an α‐cell‐derived hormone that increases blood glucose levels via the promotion of hepatic glucose production, and similar to insulin, it plays a key role in metabolic diseases . Excess glucagon plays an important role in the development of diabetes .…”

Section: Discussionmentioning

confidence: 99%

Maternal Supplementation with β‐Carotene During Pregnancy Disturbs Lipid Metabolism and Glucose Homoeostasis in F1 Female Mice

Guo

Zuo

et al. 2019

Molecular Nutrition Food Res

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Scope: β-Carotene (BC), a substitute for vitamin A, is widely used for its benefits. The present study investigates whether in-utero BC administration can alter lipid and glucose homoeostasis in offspring. Methods and results: Pregnant mice are supplemented with BC (1 mg kg −1 weight) by oral gavage once every 3 days, for a total of six doses. Increased visceral fat may be caused by up-regulated PPARγ (peroxisome proliferator-activated receptor gamma) and RXRα/β (retinoid X receptors) in liver and adipose tissue, and glucose intolerance is observed in F1 adult females prenatally supplemented with BC, while F1 males do not exhibit these symptoms. In females, increased serum leptin, resistin, and IL-6 and reduced adiponectin, caused by visceral obesity, may result in downregulated insulin receptor signaling in muscle and further account for glucose intolerance. Increased pancreatic β-cell mass might compensate for the downregulated insulin gene (ins2). Increased glucagon and α-cell mass, accompanied by upregulated glucagon gene (gcg), might also be risk factors for the development of diabetes. Conclusions: Maternal supplementation with BC disturbs lipid metabolism and induces glucose intolerance in F1 female mice, suggesting that BC supplementation during pregnancy should be used with caution.

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“…Recent trials investigating glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RAs) for the treatment of NAFLD have shown promising results. Furthermore, GLP-1R/glucagon receptor dual agonists are being investigated for the treatment of NAFLD ( 12 ). In addition to its effects on glucose metabolism, glucagon is suggested to induce body weight loss, by increasing satiety and enhancing hepatic lipid oxidation and whole-body energy expenditure ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD

et al. 2018

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Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.

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Glucagon receptor signaling in metabolic diseases

Cited by 24 publications

References 63 publications

Glucagon Receptor Signaling and Glucagon Resistance

Glucagon Receptor Signaling and Glucagon Resistance

Maternal Supplementation with β‐Carotene During Pregnancy Disturbs Lipid Metabolism and Glucose Homoeostasis in F1 Female Mice

Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD

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