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GCGR

Official Full Name
glucagon receptor
Organism
Homo sapiens
GeneID
2642
Background
The protein encoded by this gene is a glucagon receptor that is important in controlling blood glucose levels. Defects in this gene are a cause of non-insulin-dependent diabetes mellitus (NIDDM).[provided by RefSeq, Jan 2010]
Synonyms
GGR; GL-R; MVAH;
Bio Chemical Class
GPCR secretin
Protein Sequence
MPPCQPQRPLLLLLLLLACQPQVPSAQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQCQMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFASFVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLVEGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFWWILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFVTDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERNTSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF
Open
Disease
Acute diabete complication, Diabetes mellitus, Hypo-glycaemia, Non-alcoholic fatty liver disease, Obesity, Pancreatic internal secretion disorder, Type 2 diabetes mellitus
Approved Drug
2 +
Clinical Trial Drug
19 +
Discontinued Drug
5 +

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Detailed Information

A metabolic disease characterized by persistent hyperglycemia from either insulin deficit (type 1 diabetes, T1D) or a mix of insulin resistance and inadequate insulin production (type 2 diabetes, T2D), diabetes is a metabolic condition. Research, nevertheless, indicates that hyperglucagonemia exists in both kinds, hence stressing the major influence of glucagon in the course of diabetes. Blocking glucagon or GCGR has been shown in studies to lower hyperglycemia in both animal models and human patients, hence supporting the relevance of glucagon signaling in the development of diabetes.

A 29-amino-acid linear peptide, glucagon is released by pancreatic alpha cells and mostly targets liver cells. By binding to GCGR, it activates processes that drive gluconeogenesis and glycogen breakdown, hence raising blood glucose levels. Derived from the same proglucagon precursor, glucagon-like peptide 1 (GLP-1) also stimulates the GLP-1 receptor (GLP-1R) to control glucose metabolism. Glucagon and GLP-1 acting together affect bile acid and lipid metabolism, thereby suggesting their participation in diabetes.

Theories on Glucagon's Role in Diabetes

For decades, diabetes management has been centered around insulin. The insulinocentric hypothesis, which ascribed all diabetes-related metabolic problems to insulin deficit, was born from the discovery of insulin in 1921. Initially, glucagon was not thought to be relevant to diabetes pathogenesis; therapies were created only to substitute insulin.

Unger et al. put forward the bihormonal hypothesis in 1975, which held that glucagon and insulin both control glucose homeostasis. Insulin insufficiency causes more lipolysis, proteolysis, and lower glucose use; glucagon excess causes more glycogenolysis, gluconeogenesis, and ketogenesis. According to this view, too much glucagon activity as well as insulin deficit cause hyperglycemia in diabetes. As a result, glucagon suppression has been looked at as a complementary treatment for diabetes.

By implying that hyperglucagonemia, rather than insulin deficit, is the main cause of the condition, the glucagonocentric theory underlines glucagon's involvement in diabetes even more. This theory suggests that all forms of diabetes show excess glucagon. Research on GCGR-knockout (Gcgr -/-) mice has shown that these creatures display normal or lower fasting glucose levels, better glucose tolerance, and higher insulin sensitivity. Furthermore, these animals do not develop hyperglycemia even when beta-cells are destroyed until GCGR activity is restored, therefore supporting the idea that glucagon is the main factor in diabetes etiology.

Notwithstanding these results, GCGR suppression presents problems. Total GCGR activity inhibition could cause compensatory alpha-cell hyperplasia and hyperglucagonemia. Thus, GCGR antagonism has to be carefully adjusted to offset its therapeutic benefits and reduce negative effects.

Mechanisms of Glucagon-Induced Insulin Secretion

In healthy individuals, glucagon secretion is suppressed by high blood glucose levels and stimulated by low glucose levels, ensuring glucose homeostasis. However, hyperglucagonemia persists in patients with T1D and T2D due to impaired insulin-mediated inhibition of glucagon secretion.

Glucagon also exerts a paracrine effect within pancreatic islets. Studies have shown that glucagon enhances insulin secretion by binding to both GCGR and GLP-1R on β-cells.

Figure 1 depicts how the activation of GCGR and GLP-1R receptors stimulates insulin secretion in pancreatic islet Beta cells through a series of biochemical interactions involving glucagon, glucose, and various intracellular signaling pathways.Figure 1. Activation of GCGR and GLP-1R to promote insulin secretion in islet β cells.

Activated these receptors engage the G-protein Gαs, which causes more cyclic adenosine monophosphate (cAMP) generation and insulin exocytosis. Experimental studies indicate that especially under situations of nutritional excess, GCGR is very important for glucose-stimulated insulin release.

Moreover, glucagon signaling alters GLUT2, a glucose transporter required for glucose-stimulated insulin secretion (GSIS). Studies show that GCGR-knockout mice had less GLUT2 expression, which could compromise insulin release. Developing focused diabetic therapies depends on knowing the exact function of GCGR in beta-cell activity given these relationships.

GCGR Mutations and Their Association With Diabetes

Multiple genes shape the complicated hereditary condition T2D. Genetic research has linked a location on chromosome 17q25, where the GCGR gene resides, to T2D. Linked to GCGR mutations include hyperglucagonemia, compromised glucagon auto-feedback, and higher liver glucose production, all of which drive diabetes development.

T2D risk has been linked to one significant GCGR mutation, Gly40Ser (c.118G>A). Among T2D sufferers in French and Sardinian communities, the mutation was found in 5–8%, much more common than in non-diabetic people. Research in the United Kingdom revealed the Gly40Ser mutation in 15 of 691 T2D patients but in only 1 of 425 control subjects, indicating a substantial genetic susceptibility. Though this mutation is uncommon in Asian populations—including Japanese, Finnish, and Dutch cohorts—it suggests population-specific genetic risk factors.

Though their functional effects are unknown, additional GCGR variants than Gly40Ser have been found in other ethnic groupings. Certain mutations could cause hepatic glucagon resistance, which would compromise glucose homeostasis by lowering glucagon's downstream signaling. These mutations' function in diabetes progression has to be clarified by further study as well as their possible use as treatment targets.

References:

  1. Bailey CJ, Flatt PR, Conlon JM. An update on peptide-based therapies for type 2 diabetes and obesity. Peptides. 2023;161:170939.
  2. Jia Y, Liu Y, Feng L, et al. Role of Glucagon and Its Receptor in the Pathogenesis of Diabetes. Front Endocrinol (Lausanne). 2022;13:928016.
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