GCG

Official Full Name

glucagon

Organism

Homo sapiens

GeneID

2641

Background

The protein encoded by this gene is actually a preproprotein that is cleaved into four distinct mature peptides. One of these, glucagon, is a pancreatic hormone that counteracts the glucose-lowering action of insulin by stimulating glycogenolysis and gluconeogenesis. Glucagon is a ligand for a specific G-protein linked receptor whose signalling pathway controls cell proliferation. Two of the other peptides are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms. Finally, the fourth peptide is similar to glicentin, an active enteroglucagon. [provided by RefSeq, Jul 2008]

Synonyms

GLP1; GLP2; GRPP; GLP-1;

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Detailed Information

Glucagon-like peptide 1 (GLP1) is a gastrointestinal peptide hormone that stimulates insulin secretion from pancreatic β-cells and promotes insulin synthesis. GLP1, encoded by the glucagon (GCG) gene, is produced by tissue-specific posttranslational proteolytic processing of a large precursor containing three independent peptides GCG, GLP1, and GLP2. Biologically active GLP1s consist of 30 or 31 amino acids, both of which have similar bioactivities and overall metabolism, although most GLP1 secreted from the gut is C-terminally amidated and 30 amino acids in length.

GLP1, secreted from L-cells in response to food intake, regulates blood glucose level through inducing insulin secretion in a glucose concentration-dependent manner, while it suppresses GCG release from pancreatic α-cells. The glucose-dependent action of GLP1 has the potential for the treatment of diabetes mellitus because it does not cause hypoglycemia under normal plasma glucose concentration conditions. Apart from its incretin activity, GLP1 stimulates proliferation and differentiation of pancreatic β-cells. GLP1 is also produced in neurons of the brainstem and is transported through axonal networks to diverse brain regions such as the cerebral cortex, thalamus, and hypothalamus. In the brain, GLP1 is known to promote satiety by regulating appetite and food intake, leading to body weight loss. GLP1 is also involved in neurite outgrowth and spatial learning ability in the central nervous system.

GLP-1 and type 2 diabetes

Type 2 diabetes mellitus is the most common form of diabetes ranging from insulin resistance with relative insulin deficiency to predominantly secretory defect in insulin secretion with insulin resistance. Postprandial levels of active GLP-1 are diminished in obese and insulin-resistant patients. Because GLP-1 elimination is similar in healthy, obese, and type 2 diabetic patients, the decrease in GLP-1 levels observed in obese and type 2 diabetic individuals is probably caused by reductions in GLP-1 secretion. Vollmer et al. suggested that GLP-1 secretion was not impaired in patients with well-controlled type 2 diabetes but it may become impaired in patients with diabetes of longer duration or those with poor glycemic control.

Lately, there has been growing interest in methods by which GLP-1 levels and action can be enhanced in diabetes. Two main adopted strategies are using GLP-1 receptor agonists and dipeptidyl peptidase-IV (DPP-IV) inhibitors. However, another alternative approach that is receiving increasing attention is direct stimulation of GLP-1 secretion from intestinal L cells. This approach provides some additional benefits, including simultaneous stimulation of peptide YY, oxyntomodulin, and GLP-2 and increases in GLP-1 9–36 concentration, a cleaved product of DPPIV, which is a weak insulinotropic agonist that inhibits hepatic glucose production and may play antioxidant actions in the heart and vasculature.

The effect of GLP-1 in type 3 diabetes

One study showed that GLP-1 mimetic drugs have neurotrophic, neuroprotective, and anti-inflammatory effects, which play a role in retardation of AD progression. Another study suggested that liraglutide, a GLP-1 receptor agonist, can alleviate spatial memory dysfunction and neuroinflammation that leads to cognitive impairment. GLP1 has been shown to act as a growth factor in the brain and promote neurite growth. GLP-1 receptor activators stimulate the differentiation of neuronal stem cells in a manner similar to nerve growth factor, therefore it may inhibit brain atrophy in AD patients. In addition, GLP1 receptor agonists such as liraglutide and exendin-4 attenuate endogenous levels of amyloid beta in the brain and prevent amyloid plaque accumulation in the AD brain. Moreover, stimulating glucose metabolism in AD patients through the administration of GLP-1 markedly improves cognitive dysfunction in the AD brain. Recent studies reported that GLP-1 could attenuate brain insulin resistance by decreasing c-Jun N-terminal kinase (JNK) signaling and increasing the expression of the B-cell lymphoma 2 gene (Bcl2) in the T2DM mouse. Several studies suggested that GLP-1 receptor agonists increase the proliferation of neural progenitor cells and increase neurogenesis in the dentate gyrus of the hippocampus. Earlier studies reported the impaired proliferation of neural stem cell in the AD mouse model and that GLP-1 and analogues of GLP-1 can promote neural stem cell proliferation in the brain. GLP-1 receptor activates neurogenesis in hippocampus through mitogen-activated protein kinases (MAPK), resulting in enhancement of learning and memory. More generally, GLP-1 could attenuate neuroinflammation and enhance neurogenesis and insulin resistance in diabetes-induced dementia, also known as type 3 diabetes.

References:

Mansour A, et al. Nutrients related to GLP1 secretory responses. Nutrition, 2013, 29(6):813-820.
Choon B, Juhyun S. The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. International Journal of Molecular Sciences, 2017, 18(11):2493-.
Hwang J I, et al. MOLECULAR EVOLUTION OF GPCRS: GLP1/GLP1 receptors. Journal of Molecular Endocrinology, 2014, 52(3):T15-T27.
Vangoitsenhoven R, Mathieu C, Van d S B. GLP1 and cancer: friend or foe? Endocrine Related Cancer, 2012, 19(5):F77-F88.

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