Basics Actions Mechanism Regulators Diabetes Analogues Enhancers
It has been known since as early as 1964, that oral glucose elicits higher insulin levels in blood than a similar amount of intravenous glucose despite the latter achieving higher blood glucose levels. J Clin Endocrinol Metab. 1964 Oct;24:1076-82 Factors in the gut were thought to be responsible for this glucose-mediated higher insulin response. GLP-1 and GIP were later found to be the major players in this entero-insular axis, facilitating insulin secretion by the pancreas at a lower glucose threshold.
GLP-1 is a gut hormone secreted from the L-cells in the distal ileum into the circulation. It qualifies as an incretin- a hormone secreted from the gut into the circulation in response to the presence of glucose, and stimulating insulin secretion only in the presence of glucose or in other words in a glucose dependent fashion. GIP was identified earlier in 1970 as the first incretin, but the total incretin effect could not be explained by GIP alone. Further research resulted in the description of GLP-1 in 1985 as the second incretin.
Proglucagon is metabolised in the pancreas to produce glucagon. But in the gut, proglucagon is metabolised to produce Glucagon-like peptides 1 and 2 and Oxyntomodulin - or in other words, tissue specific post-translational processing. But GLP-1 production is not restricted to the gut. Pre-proglucagon is found in the brainstem in a small population of nerve cells in the nucleus of the solitary tract (NTS) that process the pre-propeptide as in the gut to yield GLP-1 and GLP-2. Originally given the name "enteroglucagon", the above three (GLP-1, GLP-2 and Oxyntomodulin) are often collectively referred to as "proglucagon-derived peptides”. GLP-1 [7-37] and [7-36 amide], which are truncated forms of the full version of the secreted peptide are the active forms with both forms being biologically equipotent Diabet Med. 1998 Nov;15(11):937-45. The active forms constitute about 15-30% of the total immunoreactive peptide measured. Diabetes. 2001 Mar;50(3):609-13
The main effect of a lack of GLP-1 in mice is diabetes mellitus. Humans with Type 2 diabetes have low levels of GLP-1, Diabetes. 2001 Mar;50(3):609-13. but the ability of the pancreas to respond to GLP-1 is preserved, J Clin Endocrinol Metab. 2003 Jun;88(6):2706-13 making a therapeutic application potentially possible. Unfortunately GLP-1 has a short half life of about 1.5 minutes, J Clin Endocrinol Metab. 2000 Aug;85(8):2884-8 and is cleared from circulation within 30-60 minutes after subcutaneous injection. GLP-1 degradation is effected by the enzyme, Dipeptidyl peptidase IV (DPP-IV). Eur J Biochem.1993 Jun 15;214(3):829-35. This limits the clinical application of native GLP-1 in diabetic therapy. The discovery of DPP-IV resistant molecules and the development of DPP-IV inhibitors can potentially revolutionise diabetes treatment in coming years. If you would like to know more about the physiology of incretins, use the "Actions" link, but if you are in a hurry to know more about the clinical application of GLP-1 , click on "Analogues".
GLP-1 is a gut hormone secreted from the L-cells in the distal ileum into the circulation. It qualifies as an incretin- a hormone secreted from the gut into the circulation in response to the presence of glucose, and stimulating insulin secretion only in the presence of glucose or in other words in a glucose dependent fashion. GIP was identified earlier in 1970 as the first incretin, but the total incretin effect could not be explained by GIP alone. Further research resulted in the description of GLP-1 in 1985 as the second incretin.
Proglucagon is metabolised in the pancreas to produce glucagon. But in the gut, proglucagon is metabolised to produce Glucagon-like peptides 1 and 2 and Oxyntomodulin - or in other words, tissue specific post-translational processing. But GLP-1 production is not restricted to the gut. Pre-proglucagon is found in the brainstem in a small population of nerve cells in the nucleus of the solitary tract (NTS) that process the pre-propeptide as in the gut to yield GLP-1 and GLP-2. Originally given the name "enteroglucagon", the above three (GLP-1, GLP-2 and Oxyntomodulin) are often collectively referred to as "proglucagon-derived peptides”. GLP-1 [7-37] and [7-36 amide], which are truncated forms of the full version of the secreted peptide are the active forms with both forms being biologically equipotent Diabet Med. 1998 Nov;15(11):937-45. The active forms constitute about 15-30% of the total immunoreactive peptide measured. Diabetes. 2001 Mar;50(3):609-13
The main effect of a lack of GLP-1 in mice is diabetes mellitus. Humans with Type 2 diabetes have low levels of GLP-1, Diabetes. 2001 Mar;50(3):609-13. but the ability of the pancreas to respond to GLP-1 is preserved, J Clin Endocrinol Metab. 2003 Jun;88(6):2706-13 making a therapeutic application potentially possible. Unfortunately GLP-1 has a short half life of about 1.5 minutes, J Clin Endocrinol Metab. 2000 Aug;85(8):2884-8 and is cleared from circulation within 30-60 minutes after subcutaneous injection. GLP-1 degradation is effected by the enzyme, Dipeptidyl peptidase IV (DPP-IV). Eur J Biochem.1993 Jun 15;214(3):829-35. This limits the clinical application of native GLP-1 in diabetic therapy. The discovery of DPP-IV resistant molecules and the development of DPP-IV inhibitors can potentially revolutionise diabetes treatment in coming years. If you would like to know more about the physiology of incretins, use the "Actions" link, but if you are in a hurry to know more about the clinical application of GLP-1 , click on "Analogues".