Disease relevance of GCG

• Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus [1].
• This system in human obesity is not altered by the approximately twofold elevation in plasma glucagon that occurs in this metabolic disorder [2].
• GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome [3].
• The observation of greatly increased postprandial plasma GLP-1 7-36 levels in patients with postgastrectomy dumping syndrome suggests that it may mediate the hyperinsulinaemia and reactive hypoglycaemia of this disorder [4].
• BACKGROUND & AIMS: The gut-derived peptide glucagon-like peptide 2 (GLP-2) has been suggested as a potential drug candidate for the treatment of various intestinal diseases [5].

Psychiatry related information on GCG

• The postprandial GLP-1 response is associated with activation of areas of the human brain previously implicated in satiation and food intake regulation [6].
• On the other hand, low GLP-1 levels in girls with anorexia nervosa are beneficial and promote appetite [7].
• GLP-1 as a satiety factor in children with eating disorders [7].
• Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness [8].
• GLP-1 concentrations are increased in overweight subjects, which may affect satiety responses in this group [9].

High impact information on GCG

• Recent studies have demonstrated that it is feasible to regenerate and expand the beta-cell mass by the application of hormones and growth factors like glucagon-like peptide-1, gastrin, epidermal growth factor, and others [10].
• In addition to the energetic or nutritional contributions of VFA to the body, the VFA may indirectly influence cholesterol synthesis and even help regulate insulin or glucagon secretion [11].
• We administered 1 mg of glucagon intravenously immediately before CT scanning to minimize the degree of smooth-muscle spasm and peristalsis and to reduce the patient's discomfort [12].
• Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy [13].
• Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor [14].

Chemical compound and disease context of GCG

• Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis [3].
• Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency of its antihyperglycemic effects should minimize any risk of severe hypoglycemia [15].
• Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-microg GLP-2 group (p < 0.01) [16].
• CONCLUSIONS: The results of this study suggest that apart from decreasing insulin resistance as a result of weight loss, orlistat may increase postprandial GLP-1 levels, thereby enhancing the insulin secretory response to the meal and blunting the postprandial rise in glucose in type 2 diabetic patients [17].
• Tubular carcinoids lacked argentaffinity and serotonin but were diffusely and strongly positive for glucagon [18].

Biological context of GCG

• The genomic sequence that includes GCG was found to have a long history of gene duplication events [19].
• Some members of the glucagon-like family of genes, GCG on chromosome 2 and GIP on chromosome 17, may be products of ancient genome duplications on the early vertebrate lineage [19].
• Recently, a processed pseudogene of the X-chromosome-linked gene TIMM8A was inserted downstream of GCG [19].
• The human proglucagon gene (GCG) is encoded within a finished 576-kb DNA sequence generated by the Human Genome Project. GCG is flanked by 18 kb and 65 kb of DNA, 5' and 3', respectively, that do not encode genes [19].
• Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37 [20].

Anatomical context of GCG

• Glucagon stimulated the production of cyclic adenosine monophosphate (cAMP) by human membranes with half-maximal activation elicited by 6 nM hormone [2].
• CONCLUSIONS: GLP-2 reduces gastric acid secretion but does not seem to have an influence on gastric emptying [5].
• GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine [3].
• The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine [3].
• Further studies demonstrated that hGLP-1, xenGLP-1A, -1B, and -1C stimulate comparable insulin release from the pancreas [21].

Associations of GCG with chemical compounds

• The pituitary adenylate cyclase-activating polypeptide (PACAP)/ glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors) [22].
• Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates [1].
• Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV) [3].
• Postprandial plasma concentrations of triglycerides and free fatty acids were significantly higher during GLP-2 infusion compared with placebo (P < .01), while glycerol concentrations were similar (P = .07) [5].
• METHODS: Fifteen healthy male volunteers were studied with the intravenous infusion of GLP-2 or placebo over 120 minutes in the fasting state, and pentagastrin-stimulated gastric acid output was assessed [5].

Physical interactions of GCG

• All three Xenopus GLP-1-like peptides bind effectively to the hGLP-1R and stimulate cAMP production [21].
• In addition, the glucagon receptor core domain (7TM helices and connecting loops) strongly determines specificity for the glucagon amino terminus [23].
• The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist [24].
• DPP-IV inhibitors stabilise endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects [25].
• Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line [26].

Enzymatic interactions of GCG

• The intestinal brush-border protease dipeptidyl peptidase IV (DPP IV) cleaves GLP-2 to an inactive form [27].
• Glucagon-mediated internalization of serine-phosphorylated glucagon receptor and Gsalpha in rat liver [28].
• Cathepsin B from both rat liver and bovine spleen was shown to hydrolyse glucagon by the same mechanism [29].

Co-localisations of GCG

• TFF3 immunoreactivity was colocalized with insulin and glucagon in distinct cell clusters in human fetal pancreas at wk 14 and in the newborn rat pancreas [30].
• IAPP was colocalized with insulin and glucagon in the immature and nondifferentiated cell granules in both species [31].

Regulatory relationships of GCG

• We infused somatostatin (SS) intravenously (500 or 1,000 microgram/h) in 13 healthy subjects to suppress insulin and glucagon secretion from the endocrine pancreas, together with infusion of either GLP-I (50 pmol / kg / h) or saline intravenously [32].
• Also, the metalloproteinase inhibitor GM6001 and an anti-BTC neutralizing antibody suppressed the GLP-1 proliferative effect [33].
• RESULTS: Gastric inhibitory polypeptide dose-dependently stimulated glucagon secretion ( p=0.019) with a maximal increment after 10 min [34].
• The glucagon-receptor antagonist also suppressed the potentiation of glucose-induced insulin release by addition of 10 nmol/l glucagon [35].
• DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide [36].

Other interactions of GCG

• In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity [1].
• Infusion of somatostatin, an inhibitor of glucagon secretion, in insulin-dependent diabetics resulted in a 75-100% reduction in the blood-glucose rise after oral glucose administration, but did not improve intravenous glucose tolerance [37].
• Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases [3].
• In 14 patients, dramatic decreases in the levels of circulating peptides (insulin, vasoactive intestinal polypeptide, gastrin, and glucagon) have been accompanied by major alleviations of symptoms [38].
• These results demonstrate that despite an average of nine amino acid differences between the predicted Xenopus GLPs and hGLP-1, all act as hGLP-1R agonists [21].

Analytical, diagnostic and therapeutic context of GCG

• Moreover, GLP-2 prevents intestinal hypoplasia resulting from total parenteral nutrition [39].
• Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short-lasting effects [15].
• To determine the amino acid sequence of the naturally occurring peptide we isolated GLP-1 from human small intestine by hydrophobic, gel permeation, and reverse-phase high performance liquid chromatography [40].
• Venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1 (total and intact), and GIP (total and intact; specific immunoassays) [41].
• The plasma half-lives of GLP-1 7-36 amide and GLP-1 7-37 were 5.3 +/- 0.4 vs. 6.1 +/- 0.8 min, and the metabolic clearance rates of the two peptides also were similar (14.6 +/- 2.4 vs. 12.2 +/- 1.0 pmol/kg x min) [42].

References