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Insulin secretion

GLP 1 facilitates insulin release in response to a meal. This Incretin effect is expressed as the ratio between the integrated insulin response to an oral glucose load and an isoglycaemic intravenous glucose infusion. The incretin effect contributes to up to 60% of the insulin secreted in response to meals.  The insulinotropic effect of GLP-1 is glucose dependent, which ensures that insulin secretion is not stimulated in the presence of hypoglycaemia.  Nature. 1993 Jan 28;361(6410):362-5.   This glucose-dependency for its action makes GLP-1 extremely desirable as a therapeutic agent in diabetes. Despite this, GLP-1 agonists tend to attain supraphysiological levels of GLP-1 and do have the potential to produce hypoglycaemia. Clin Ther. 2005 Feb;27(2):210-5.  Also, combining GLP-1 agonists with sulphonylureas, as is likely to happen in clinical practice, would result in compromising the benefits of the glucose-dependent GLP-1 action.

 


Administration of  2.5 nmol GLP-1 in type 2 diabetics produces an insulin response comparable to that of 1 mg glucagon or a 566 calorie meal.   Diabetes Care. 2000 Jun;23(6):807-12.   This effect was produced with lower side effects compared to glucagon and could be translated clinically as a means to assess beta cell function.  The effect on fasting hyperglycemia seems to be different with intravenous and subcutaneous GLP-1 administration as described elsewhere at this site. Exendin 9-39 amide, a potent GLP-1 antagonist inhibits insulin secretion from the human pancreas in the postprandial state, but not in the euglycaemic fasting state suggesting the normal physiological role of GLP-1 in maintaining post prandial glycaemia.


Measurement of the insulin response to GLP-1 treatment in healthy humans has to be interpreted with caution. This stems from the glucose dependency of GLP-1 action.  Hyperglycaemic type 2 diabetic subjects thus demonstrate obvious insulin responses, while healthy individuals who maintain normoglycaemia may not show a major insulin response to GLP-1 administration in the absence of glucose stimulation.  Am J Physiol. 1997 Nov;273(5 Pt 1):E981-8.  While GLP-1 increases pre-hepatic insulin secretion, studies using fractional clearance of C-peptide seems to suggest that GLP-1 may decrease endogenous insulin clearance as well. Diabetologia. 2005 Oct;48(10):2140-6  While the incretin effect produces improvement in postprandial hyperglycaemia in type 2 diabetics as well as normal people, improvement in fasting hyperglycaemia in type I diabetics by GLP1  is attributable to its action of reducing glucagon secretion, as well as effects on gastric emptying (see below).
Glucagon secretion

Although peripheral glucose uptake by insulin-dependent tissues is altered in type 2 diabetic patients, it does not appear to be the major cause of the post prandial hyperglycemia.  Instead postprandial hyperglucagonaemia is the defect in T2 diabetes which predominantly contributes to postprandial hyperglycaemia. This hyperglucagonaemia persists despite exogenous insulin therapy as peripherally injected insulin does not attain the higher portal circulation levels seen with physiological insulin secretion. GLP-1 suppresses glucagon secretion in healthy subjects,  J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46 probably mediated by direct activation of GLP-1 receptors on alpha cells with reduction of hepatic glucose output postprandially. The glucagon reduction does not seem to be secondary to an increase in insulin secretion, as this effect was demonstrable in type I diabetics as well.  


Reversal of the influence on gastric emptying effect by GLP-1 using  erythromycin resulted in increased glucagon levels despite increased insulin levels,  Diabetes. 2005 Jul;54(7):2212-8  demonstrating a modulation of glucagon, independent of the insulinotropic effect. Despite the glucagon suppressive effect by GLP-1, the counter-regulatory rise of glucagon in response to hypoglycaemia remains thankfully preserved. J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46  Glucagon suppression by GLP-1 may be mediated via GLP-1 receptors which have been demonstrated in pancreatic alpha cells in rats. Diabetes. 1997 May;46(5):785-91 Experiments using Exendin 9-39 amide, a potent antagonist of GLP-1 showed an increase in glucagon levels in both euglycaemic and hyperglycaemic states suggesting that GLP-1 may exert a tonic inhibitory effect on glucagon secretion from the pancreatic alpha cells in man. J Clin Invest.1998 Apr 1;101(7):1421-30. 


A study in 8 healthy subjects using a pancreatic clamp (octreotide, insulin and glucose infusions) has shown glucose lowering without increase in the islet hormones. Am J Physiol Endocrinol Metab. 2003;285  Does GLP-1 then directly increase glucose uptake by various cells independent of insulin or glucagon? This issue of islet-independent action of GLP-1 still remains controversial. A direct effect byGLP-1 on glucose disposal in liver, muscle or adipose tissue has not yet been demonstrated. Neither has GLP-1 receptors been demonstrated in these tissues, but it is possible that as yet undescribed GLP-1 receptors of a different nature may exist at these sites.
Gastric emptying

Another mechanism by which improved glycaemia is effected by GLP-1 in type 2 diabetics (J Clin Endocrinol Metab. 1996 Jan;81(1):327-32.    as well as  type I diabetics  J Clin Endocrinol Metab. 2004 Jul;89(7):3469-73.    is  through inhibition ofgastric emptying,  possibly mediated via an inhibition of efferent vagal activity. Am J Physiol. 1997 Oct;273(4 Pt 1):G920-7   a property not possessed by the other incretin GIP. Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E621-5.    Inhibition of gastric emptying by GLP-1 is dose dependent and independent of glucose levels. 


GLP-1 inhibits antro-pyloro-duodenal contractility and gastric fundic tone, Gut. 2000 May;46(5):622-31.   while stimulating the pyloric tone,  Gut. 2002 Mar;50(3):341-8.     thus forming a component of the "ileal brake". In fact, gastric emptying deceleration is thought to be the major mechanism by which GLP-1 lowers glucose levels, more than its insulinotropic action,   Am J Physiol. 1997 Nov;273(5 Pt 1):E981-8.   although this observation might have been related to the fact that demonstrating an insulin response in healthy individuals capable of maintaining euglycaemia through their endogenous GLP-1 is difficult. see under "Insulin secretion" above.   Preventing the action of GLP-1 on gastric emptying using erythromycin (which accelerates gastric emptying probably through parasympathetic mechanisms) brings out the actual incretin action of the exogenously administered GLP-1 with higher insulin responses. Diabetes. 2005 Jul;54(7):2212-8.


Gastric emptying studies in the obese has produced different results probably attributable to the methodological variations, as well as subtle factors as glycaemic levels and weight stability. A scintigraphic study in 19 non-diabetic obese with mean BMI of 38.7 kg/m2 demonstrated no increase in gastric emptying time at 3 hours compared to controls. Int J Obes Relat Metab Disord. 2000 Jul;24(7):899-905. A mild increase in the early phase (first 30 mins) was demonstrable, but its clinical significance might be debatable. A further study using (13)C-octanoic acid breath test in  16 obese women compared to controls revealed significant delay in gastric emptying in the obese women (mean t(1/2)-values (+/-standard error of the mean) were 3.67 +/- 0.14 hours and 4.23 +/- 0.18 hours for lean and obese. GLP-1 may exert its pro-euglycaemic effects by further delaying  this gastric emptying, although this would have implications in the diabetic patient with existing gastroparesis.  GLP-1 also inhibits gastric acid secretion. Am J Physiol. 1997 Nov;273(5 Pt 1):E981-8

Read more about gastric emptying and gastric motility
Appetite

Pre-proglucagon is present in the brainstem in the nucleus of the solitary tract (NTS) that processes the pre-propeptide as in the gut to yield GLP-1 and GLP-2. Although synthesis is restricted to this site in the brain, GLP-1 is present in different parts of the peptidergic neurones of the brain including the forebrain and hypothalamus.  Neuroscience. 1997 Mar;77(1):257-70.   GLP-1 immunoreactive fibres from the NTS extensively innervate the hypothalamus. J Comp Neurol. 1988 May 22;271(4):519-32.

 Intraventricular administration of GLP-1 in fasted rats inhibits food intake.  Am J Physiol. 1996 Oct;271(4 Pt 2):R848-56.  This seemed to be a short term effect than a long term meal regulation effect as shown by 4 day infusion studies in rats .  Brain Res. 1998 Jan 1;779(1-2):75-83.  Exendin (9-39), a GLP-1 receptor antagonist blocks the  inhibitory effect of GLP-1 on food intake. Exendin(9-39) blocks the GLP-1 induced activation of c-fos in the PVN, suggesting the likely site of action of GLP-1.Nature. 1996 Jan 4;379(6560):69-72.    Ablation of the arcuate nucleus using monosodium glutamate in rats abolishes the GLP-1 induced inhibition of feeding (during intracerebroventricular administration).   Diabetes. 1998 Apr;47(4):530-7. 

GLP-1 inhibits while Exendin(9-39) augments NPY-induced feeding. Nature. 1996 Jan 4;379(6560):69-72. Exendin (9-39) blocks the Leptin induced inhibition of food intake suggesting that the anorectic effects of Leptin may partly be mediated through the GLP-1 pathway in the brain. Co-expression of GLP-1 mRNA and the Leptin receptor in the brainstem neurons FEBS Lett. 1997 Sep 29;415(2):134-8.   lends further credence to this point of view, although absence of feeding abnormalities in the GLP-1r knock out mice Nat Med. 1996 Nov;2(11):1254-8.   argues against a predominant role for this pathway in mediating Leptin action, although compensation by other regulatory pathways might maintain feeding in this scenario.  Eur J Pharmacol. 2002 Apr 12;440(2-3):269-79   


GLP-1 decreases appetite in healthy,   J Clin Invest. 1998 Feb 1;101(3):515-20.  obese   Int J Obes Relat Metab Disord. 1999 Mar;23(3):304-11    and diabetic humans. Am J Physiol. 1999 May;276(5 Pt 2):R1541-4.   Diabetes Care. 1999 Jul;22(7):1137-43.Whether this is mediated through direct action on central pathways or predominantly through peripheral actions (gastric distension due to delay in gastric emptying) remains to be clarified. The fact that GLP-1 reduces appetite even in fasted patients Gut. 1999 Jan;44(1):81-6.   argues for a significant role for central mechanisms. Yet, the fact that the half life of active GLP-1 is less than 2 minutes makes it likely that peripheral mechanisms as delayed gastric emptying would play a significant role.  GLP-1 does not seem to cross the blood brain barrier.    J Mol Neurosci. 2002 Feb-Apr;18(1-2):7-14. But Blood brain barrier deficient areas as area postrema and the subfornical organ show a localisation of I125-labeled GLP-1 within 5 minutes after injection into rats, and is compatible with the theory of a gut-released GLP-1 mediating satiety actions centrally.   Diabetes. 1996 Jun;45(6):832-5.     This could mean the possibility of GLP 1 turning out to be the only insulin secretagogue which does not facilitate weight gain.  The appetite reducing properties of GLP-1 seems to be synergistic with that of PYY another anorectic gut hormone. Exendin-4, a GLP-1 agonist  and PYY(3-36) independently decreased food intake in mice  significantly by 83% and 26% respectively, whereas combining the two resulted in further synergistic reduction of food consumption. GLP-1 receptors have been shown in high densities in all brain areas involved in drinking and water homeostasis. Neuroendocrinology. 1995 Aug;62(2):130-4.    Fluid intake also seems to be reduced by GLP-1 administration in rats  Am J Physiol. 1996 Oct;271(4 Pt 2):R848-56.   and humans, Gut. 1999 Jan;44(1):81-6.    although the effect is short lasting such that dehydration does not result with long term administration of GLP-1.  

Other Organ systems

GLP-1 in the brain can mediate hypothalamic-pituitary-adrenal axis activation as suggested by the dense innervation of CRH neurones by GLP-1 nerve terminals  Brain Res. 2003 Sep 26;985(2):163-8.  and the  ability of GLP-1 to activate neuroendocrine CRH neurones.   Endocrinology. 1997 Oct;138(10):4445-55.  Intracerebroventricular GLP-1 stimulates LH, TSH, corticosterone, and vasopressin secretion  in rats.    Yet, GLP-1 does not seem to be crucial to endocrine functions as demonstrated using GLP-1 receptor knock out mice.  Endocrinology. 2000 Feb;141(2):752-62.   GLP-1 has been shown to improve memory and learning behaviour.  Nat Med. 2003 Sep;9(9):1173-9  A reduction in the propensity to seizures and improvement of cognitive function has also been demonstrated by transfecting hippocampal neurons with a GLP-1 receptor expressing construct.   Nat Med. 2003 Sep;9(9):1173-9  A role in neuroprotection has been suggested by the invitro finding of GLP-1 mediated potentiation of Nerve Growth Factor-initiated cell differentiation.   J Pharmacol Exp Ther. 2002 Mar;300(3):958-66.   Beta-amyloid peptide formation in the brain of animals models of Alzheimer's disease has been shown to be decreased by GLP-1.   J Neurosci Res. 2003 Jun 1;72(5):603-12.



No cardiac effects have been noted with GLP-1 in humans   Diabetes Care. 1999 Jul;22(7):1137-43. despite some evidence of stimulatory effects in rat studies   Am J Physiol. 1994 Mar;266(3 Pt 1):E459-66, although studies in this respect are sparse. 

Intravenous GLP 1 infusion in the presence of intravenous salt loading has shown a natriuretic effect on the kidney with a mild reduction in GFR in both healthy and insulin resistant-obese individuals suggesting a possible physiological role for GLP-1 in water and salt homeostasis. J Clin Endocrinol Metab. 2004 Jun;89(6):3055-61.    

GLP-1 receptor (and its mRNA) are expressed in the lung (type II pneumocytes)   Endocrinology. 1996 Jul;137(7):2968-78.  and pulmonary arteries.  Am J Physiol. 1993 Oct;265(4 Pt 1):L374-81.  GLP-1 inhibits mucous secretion in the bronchial tree with relaxation of the bronchial smooth muscles, although its physiological significance remains unknown.



An insulin independent effect on glucose uptake in peripheral tissues (liver, muscle, adipose tissues) of healthy volunteers has been found to be present in some studies  J Clin Invest. 1994 May;93(5):2263-6.  but not in others. J Clin Endocrinol Metab. 1998 Jul;83(7):2399-404.  A study in type 2 diabetics who had insulin and glucagon varied using infusions to mimic basal and postprandial levels while being administered somatostatin and glucose intravenously shows similar effects in both saline and GLP-1 infusion groups, suggesting that GLP-1 may not have insulin-independent effects in diabetics.  Diabetes.2000 Apr;49(4):611-7.   In this regard, it has been noted that the whole-body glucose utilisation is not lower in GLP-1 receptor (-/-) knock out mice during basal or hyperinsulinaemic conditions.    Diabetes. 1998 Apr;47(4):632-9.  GLP-1 receptors havenot been demonstrated in the liver, muscles, or adipose tissue. Endocrinology. 1996 Jul;137(7):2968-78.  Yet, GLP-1 seems to suppress cAMP formation in adipocytes and myocytes   Biochim Biophys Acta. 1996 Jun 13;1312(2):132-6.  with glycogenicFEBS Lett. 1994 Aug 1;349(2):313-6.   and lipogenic  J Endocrinol. 1991 Aug;130(2):267-72.  actions in these tissues.   While the possibility of an as yet unidentified GLP-1 receptor exists, it is also possible that other receptors belonging to the glucagon-like-peptide-receptor superfamily might mediate these effects by altering their ligand specificity in the presence of other proteins . Receptor activity-modifying proteins (RAMPs) have in fact been identified,   tissue specific isoforms of which could alter the ligand-binding selectivity and affinity of various receptors.   Nature. 1998 May 28;393(6683):333-9.  A notable example in this regard is the interaction of the CGRP-R (Calcitonin Gene-Related Peptide Receptor) which binds to CGRP in the presence of RAMP-1 and with Adrenomedullin in the presence of RAMP-2. A similar alteration in ligand specificity for GLP-1 is possible.