Glucagon-Like Peptide 1 (GLP-1), a strong stimulator of insulin secretion belongs to a group of glucagon gene-derived peptides. Mature GLP-1 is stored in intracellular vesicles on the basolateral side of neuroendocrine L-cells, which are localized mainly in the distal part of the intestine.
Incretin hormones are produced by the gastrointestinal tract in response to nutrient entry and are necessary for the maintenance of glucose homeostasis. Two major incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are thought to be responsible for the incretin effect. GIP is a 42-amino acid polypeptide secreted from the endocrine K-cells of the duodenum and proximal jejunum after ingestion of carbohydrates, fat and amino acids. GIP acts through a specific GIP-receptor on pancreatic β-cell which enhances exocytosis of insulin containing granules. It has been shown that decreased incretion effect of GIP in diabetic patient is not due to impaired secretion but due to decreased effect on pancreatic β cells.
Glucagon-like peptide-1(GLP-1) GLP-1, another incretin hormone, was identified after the cloning and sequencing of the cDNA and genes encoding human proglucagon. The proglucagon gene encodes two peptides that share about 50% sequence homology to glucagon. The two peptides were named glucagon-like peptide-1 (GLP-1) and glucogan-like peptide-2 (GLP-2). After tissue-specific proteolytically posttranslational processing, GLP-1 is released from L cell of lower intestine and colon in response to nutrient ingestion. GLP-1 stimulates glucose-dependent insulin secretion in isolated islets as well as in human, whereas GLP-2 was unable to stimulate insulin secretion and is not an incretin hormone.
There are four forms of GLP-1 secreted in vivo: the inactive form of GLP-1(1-37) and GLP-1(1-36)-NH2, and the biologically active form of GLP-1(7-37) and GLP-1(7-36)-NH2. Both GLP-1(7-37) and GLP-1(7-36)-NH2 are produced from their full-length precursors by the action of PC enzyme and show the equipotent ability to stimulate glucose-dependently insulin secretion. It was found that GLP-1(7-36)-NH2 is the major form of GLP-1 in the circulation in humans. It was also reported that addition of the amide group (NH3) to GLP-1(1-36) is associated with prolonged survival of GLP-1(7-36) in plasma. The concentration of total GLP-1 (including GLP-1(7-36)-NH2 and GLP-1(9-36)-NH2) levels in fasting plasma is 10-20 pM in healthy Caucasians, while it peaks at 30-60 pM 30 min after 75-g glucose or mixed meals loading. In vivo, biologically active forms of GLP-1 [GLP-1(7-37) and GLP-1(7-36)-NH22] through dipeptidyl peptidase-4 (DPP-4)-mediated cleavage of the alanine residue at position 2, with a half life of less than 2 minutes.
GLP-1 has multiple roles in glucose regulation. At the pancreatic islet level, it increases insulin secretion, inhibits glucagon secretion, and stimulates somatostatin release. Over long term, GLP-1 increases beta-cell mass by stimulating beta-cell growth and proliferation and by inhibiting apoptosis. It is also possible that GLP-1 contributes to glucose regulation by promoting insulin-independent glucose disappearance. GLP-1 inhibits gastric emptying, intestinal motility and gastric acid secretion. By acting on the central nervous system, it inhibits food and water intake and promotes satiety.
Glucose and fatty acids in food are the primary physiologic stimuli for GLP-1 secretion. Administration of mixed meals or individual nutrients such as glucose or other sugars, fatty acids, essential amino acids, and dietary fiber all can stimulate GLP-1 secretion. In humans, oral but not intravenous glucose administration stimulates GLP-1 secretion. It was also reported that zein hydrolysate (a hydrolysate prepared from zein: a major corn protein) stimulated GLP-1 secretion directly in the ileum and indirectly in the duodenum in rat. It was found that nutrients stimulated GLP-1 secretion through two alternative pathways: one is via direct contact with L cells and the other is through indirect information transfer. GLP-1 secretion generally includes two phases: an early phase occurred at 10 to 15 minutes and the second phase occurred at 30 to 60 minutes after oral nutrient ingestion. It seems that the second phase of GLP-1 secretion is caused by direct contact of nutrients with L cells in the distal small intestine, while it is unlikely that the early phase of GLP-1 secretion is caused by the same mechanism since it takes more than 15 minutes for nutrients to get to the distal small intestine after oral meal uptake. This suggests that the existence of a proximal gut signal regulating GLP-1 release from the L cells of the distal small intestine.
Reference: KANG, Zhanfang. Impaired Incretin Effects in Type 2 Diabetes: Mechanism and Therapeutic Implication