GLP-1 secretion determinants and regulators

Typical fasting levels of total GLP-1 are around 5 to 10 pmol/L and reaching peak levels of 25pmol/L after a mixed meal. Regul Pept. 2004 Nov 15;122(3):209-17.  While all the GLP-1 stored in the L cells is in the active (intact) form,  Endocrinology. 1999 Nov;140(11):5356-63.   less than 25% of the newly secreted GLP-1 leaves the gut in the active  form.   Further degradation in the liver   Am J Physiol. 1996 Sep;271(3 Pt 1):E458-64.     ensures that only about 10% of the newly secreted GLP-1 enters the systemic circulation in the active form.  GLP-1 is not normally synthesized in physiologically relevant amounts in normal islet A cells, where the proglucagon is predominantly processed into glucagon.

 GLP-1 is mostly released from the L cells in the intestines, with more GLP-1 (7-36) than GLP-1 (7-37) in a 5:1 ratio. Diabetes. 1989 Mar;38(3):338-42. The pancreatic alpha cells also secrete small amounts of GLP-1 (7-36) and (7-37) amide.  Am J Physiol. 1995 Dec;269(6 Pt 1):G852-60     Although L cells are widely distributed along the intestine, with numerous cells even in the gut as distally as the rectum, GLP-1 is predominantly secreted from the (mid-intestinal) ileal L cells.  The high duodenal cells may contribute to the initial early phase GLP-1 response to food which happens in 6-8 mins, a response that is unaltered by small intestinal resection.  Z Gastroenterol. 1996 Mar;34(3):159-66   Some L cells may co secrete PYY  Regul Pept. 1986 Feb;13(3-4):283-91.    while others may co-secrete GIP.  Regul Pept. 2003 Jul 15;114(2-3):189-96.  Infact up to half of ileal L cells produce both GIP and GLP-1 although little is known about this differential expression. L cells are open type cells with microvilli protruding into the lumen.  Sensors for glucose clearly lie on the luminal side of the intestines as evidenced by a lack of GLP-1 secretion in response to intravenous glucose administration.  Digestion. 1995;56(2):117-26. The L cells seem to be under intrinsic cholinergic control as shown by reduction in glucose stimulated GLP-1 secretion following atropine infusion. J Clin Endocrinol Metab. 1997 Mar;82(3):786-90.  although a control mediated through a delay in gastric emptying is possible. The sympathetic system has an inhibitory effect on GLP-1 secretion, mediated through nor epinephrine. Studies do not show a major role for extrinsic vagal innervation on GLP-1 secretion.   Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E939-47.    A lack of rise of GLP-1 levels during the cephalic phase of food ingestion well demonstrated by sham feeding   Scand J Gastroenterol. 1994 Jun;29(6):501-5.  and the fact that GLP-1 responses are normal (or exaggerated) after vagotomy  are in keeping with this. Studying the enteroendocrine L cells has still been painfully slow due to the lack  of an ideal model. Endocrinology. 2003 May;144(5):2025-33.

It has been noted that the presence of glucose distal to the stomach is necessary to stimulate GLP-1 release, with secretion being exaggerated in patients after total gastrectomy, Dig Dis Sci. 1991 Oct;36(10):1361-70.  which is thought to contribute to the features of the dumping syndrome.  Thus, the speed of gastric emptying can regulate the rapidity of GLP-1 secretion. Yet, GLP-1 release normally occurs within 8 minutes of food ingestion in healthy subjects. Digestion. 1995;56(2):117-26.    Neural and hormonal factors may well contribute to the initial period (15-30 minutes) of GLP-1 secretion, while the latter period (30-60 minutes) is contributed to by direct nutrient stimulation of L cells.  

The mere presence of nutrients in the lumen of the gut is not sufficient for GLP-1 stimulation, and it seems that glucose absorption is necessary to elicit secretion.  Digestion. 1994;55(1):24-8.   Calcium levels may have a primary role in GLP-1 secretion as shown by GLP-1 stimulation by increased intracellular calcium levels and its reduction by calcium channel blockers.  Endocrinology. 1988 Jul;123(1):220-6.  

 Nutrient factors and the way they are presented to the gut may determine the  ability of an ingested meal to stimulate GLP-1 secretion. Liquid meals elicit higher secretion of GLP-1 than solid meals.  Nutrition. 1998 May;14(5):433-6.   The size of the meal elicits a proportionally high GLP-1 response  J Clin Endocrinol Metab. 2003 Jun;88(6):2706-13.    which is probably due to increased areas of L cell activation.    Smaller meal volumes may preferentially activate the upper intestinal incretin -GIP- while larger meals may stimulate lower intestinal L cells with more of GLP-1 output.  Regul Pept. 2005 Jun 15;128(2):97-107.   While glucose and galactose stimulate GLP-1 release, fructose and lactose do not,  Acta Endocrinol (Copenh). 1990 Oct;123(4):464-70.   and this is probably attributable to the mechanism of transport of the latter two which does not involve the sodium/glucose co-transporter on the brush border.  Free fatty acids from diet may stimulate GPR120, a G protein coupled receptor which is abundantly expressed in the intestines, to produce GLP-1 secretion and increased insulin levels.   Nat Med. 2005 Jan;11(1):90-4.  Monounsaturated long chain fatty acids may produce more GLP-1 stimulation than  short or medium chain polyunsaturated or saturated fatty acids.  Endocrinology. 1995 Dec;136(12):5593-9.    While undigested proteins and amino acids do not stimulate GLP-1 secretion, J Endocrinol. 1993 Jul;138(1):159-66.   peptones (protein hydrolysates) do. Diabetes. 1998 Jul;47(7):1038-45. 

Various other factors may influence the L cells of the ileum to modulate GLP-1 secretion. Men tend to have lower GLP-1 responses compared to women Diabetes. 2001;50:609-613;    Eur J Endocrinol. 1996 Oct;135(4):425-32.  and a hormonal effect is possible.   Increasing BMI decreases GLP-1 responses.  J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23,    Gut. 1996 Jun;38(6):916-9, which has been demonstrated to be be dependent on the nutrient ingested. Gut. 1996 Jun;38(6):916-9.   Euglycaemic Hyperinsulinaemic clamps have demonstrated GLP-1 secretion stimulation by oral glucose loads, suggesting that changes in blood levels of glucose and insulin are not necessary to elicit GLP-1 secretion,  Am J Clin Nutr. 1998 Sep;68(3):591-8  implying neural mechanisms in GLP-1 regulation. Vagotomy (in conjunction with gut transection)  abolishes  and vagal stimulation increases GLP-1 secretion. Endocrinology. 1999 Apr;140(4):1687-94.   Although vagal activity seems to be essential for GLP-1 secretion in rats,  patients with diabetic autonomic neuropathy seem to have no impairment of GLP-1 secretion. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23.       Alcohol when taken in combination with a fatty meal is associated with suppression of  the incretin response in type 2 diabetics. Metabolism. 2004 Jan;53(1):77-83.   NEFA (non-esterified fatty acid) levels, though suggested to decrease GLP-1 levels through effects on the L cell,   Clin Sci (Lond). 1999 Apr;96(4):335-42. did not vary significantly between diabetic and non-diabetic subjects despite different GLP-1 responses. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23.    Sulphonylurea Acta Diabetol. 1995 Oct;32(3):165-9.    or metformin treatment    J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23,     does not seem to produce an increased incretin response than diet alone.

GIP has been shown to increase GLP-1 secretion in rats, Endocrinology. 1991 Jun;128(6):3175-82.  but such an effect was not demonstrable in humans. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23.    Calcitonin gene related peptide (CGRP) as well as cholinergic agonists positively regulate GLP-1 secretion.     Endocrinology. 1991 Jun;128(6):3175-82.  Bombesin and Neuromedin C also strongly stimulate GLP-1 secretion. Glucagon has been found to have a positive correlation with GLP-1 response although this might have been dependent on the protein content of the meal used. J Clin Endocrinol Metab. 2001 Aug;86(8):3717-23    Insulin, possibly through a feedback loop,  Horm Metab Res. 1975 Nov;7(6):452-6.  and somatostatin   Scand J Gastroenterol Suppl. 1982;74:93-103. Am J Physiol Endocrinol Metab. 2000 Jun;278(6):E1010-8.  through a paracrine action,  inhibit GLP-1 release. Beta adrenergic stimulation by isoproterenol or epinephrine stimulates GLP-1 release in vivo   Surgery. 1981 Aug;90(2):186-94. and in vitro. Endocrinology. 1994 Dec;135(6):2398-403  

While GLP-1 is part of the enteroinsular axis, Leptin forms part of the adipoinsular axis. Leptin infusion increases GLP-1 secretion in rats.  [Surprisingly Leptin deficiency is associated with increased activity of ascending GLP1 and 2 neurones with increased pre-pro glucagon mRNA synthesis in ascending GLP-1 neurones]  In contrast to GLP-1, Leptin suppresses insulin secretion and gene expression, J Clin Endocrinol Metab. 1999 Feb;84(2):670-6.   but GLP-1 response to meals may over-ride the Leptin signal. J Clin Invest. 1997 Sep 1;100(5):1174-9.   Mice with GLP-1 (-/-) mutations show increased sensitivity to the insulin suppressing  actions of Leptin,    Diabetes. 1997 Dec;46(12):2029-34.   in keeping with the counter-regulatory actions of these peptides on insulin secretion.  Also, rats with mutated leptin receptors seem to show higher insulin responses to GLP-1.   Diabetes. 1995 May;44(5):495-500.

GLP-1 suppresses PYY release.  Am J Physiol. 1999 Sep;277(3 Pt 2):R910-6   As GLP-1 is co-secreted with PYY,   Regul Pept. 1986 Feb;13(3-4):283-91.  this suppression of PYY by exogenous GLP-1 suggests a negative feedback effect of exogenous GLP-1 infusion on the intestinal L cell, and probably its own regulation physiologically.  GLP-1 also diminishes the postprandial release of pancreatic polypeptide, a peptide closely related to PYY with positive effects on satiety induction.

After secretion, GLP-1 is rapidly cleaved by DPP-IV enzyme into GLP-1 (9-36).    J Clin Endocrinol Metab. 1995 Mar;80(3):952-7. This metabolite has a half life of 5 minutes Diabetes. 1995 Sep;44(9):1126-31.    and seems to be antagonistic at the GLP-1 receptor. J Biol Chem. 1997 Aug 22;272(34):21201-6.   The majority of GLP-1 entering the circulation has already been inactivated by DPP-IV. While most of the degradation happens in the hepato-portal circulation, excretion of GLP-1 is mainly effected by the kidneys through glomerular filtration and tubular catabolism Horm Metab Res. 1993 Dec;25(12):612-6.    and hence, GLP-1 levels are increased in uraemic states. J Clin Endocrinol Metab. 1992 Feb;74(2):379-84.  

While GLP-1 was set to be a therapeutic strategy for type 2 diabetics, the need for parenteral administration and the short half-life limited pursuing the native molecule itself as an option. GLP-1 has been administered as buccal tablets (400mcg glp-1 achieving ~100-150 pmol/L in 30 minutes of administration, and being cleared with a circulating half life of 26 minutes.  Diabetes Care. 1996 Aug;19(8):843-8    Although some success has been achieved with buccal mucosal tablets ( Diabetes Care. 1997 Dec;20(12):1874-9), a bioavailability of a mere 7% with oral administration ensured that satisfactory treatment modalities remained doubtful till GLP1 analogues came onto the scene. A new technology (eligen technology from emisphere) might enable administration of hormones including GLP-1 orally with efficacy.

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