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The Effect of Glucagon-Like Peptide-1 on Target Organs

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Prof. Dr. Michael A. Nauck

We say hello to everyone i’m here to talk about glucagon-like peptide number one and the abbreviation is glp-1 and it has numerous effects on different target organs but let me start with the description what is called the increase in effect the ink return effect is the fact that if you stimulate insulin secretion in healthy subjects with oral glucose as we normally

Do or with intravenous glucose that then you have a much higher insulin secretory response in healthy subjects with the oral administration of glucose and the control experiment is the intravenous infusion of glucose aiming at exactly the same plasma excursions of glucose concentrations as you have seen in the previous experiment with oral glucose and in healthy

Subjects oral glucose will trigger a three-fold higher insulin response than intravenous glucose and this is because oral glucose goes through the stomach to the gut is a job there and during that process encrypts and hormones from the gut are released that stimulate beta cell secretion if you perform the same experiment in patients with type 2 diabetes you don’t

See as much of an increase in effect so there is a defect in the ink return system in type 2 diabetic patients and that is expressed by the fact that you have almost the same insulin secretory response with oral glucose and intravenous glucose so the question arises what causes this defect the reduced incursion effect in patients with type 2 diabetes and there are

Two possibilities possibility number one is that the hormones are not adequately secreted from the gut but that does not appear to be the case according to more recent studies in the field so there is enough gop one and gip around but still the increase in effect is app defect and the reason is that the moment you have diabetes the moment your fasting glucose

Is in the diabetic range you lose the ability of your beta cells to respond to gip and once this is lost you lose your incursion effect and since glp-1 is an increase in hormone it was studied looking for experiments that as a secret agog it can stimulate insulin secretion also in type-2 diabetic patients and yes it was found that in contrast to gip glp-1 still

Works in such patients and after that it was found that it has multiple activities in different organ systems even within the endocrine pancreas it does not only stimulate insulin secretion it also suppresses glucagon secretion it leads to insulin biosynthesis and in some rodent experiments and in cell lines it can induce proliferation of beta cells that in the

End you have an increased beta cell mass and the other mechanism is the inhibition of apoptosis with glp-1 so if you incubate beta cells with high glucose concentrations with a lot of free fatty acids with cytokines with hydrogen peroxide that will induce cell death and you could prevent that with glp-1 other effects are on gastrointestinal motility primarily

Gastric emptying which is very much delayed with glp-1 and with appetite regulation and i want to stress that it is glp-1 entering the great circulation that has access to receptors in the brain and tells the brain know the appetite is lower you have more satiety you don’t want to eat as much so in the end exposed to glp-1 people will lose weight then there are

Cardiovascular effects of g-o-p one which i will talk about in a minute in more detail and last there is biochemical effect of elevation in insulin and reduction in glucagon concentrations which will affect metabolism at the level of the liver muscle and adipose tissue to have less glucose production by the liver and more uptake of glucose into tissue which both

Lowers glucose concentrations with respect to insulin secretion there is one very special feature of glp-1 and that is that it is acting in a very much glucose dependent manner so when glucose concentrations are low there is no stimulation of insulin secretion the moment you elevate glucose concentrations then it has a very profound effect stimulating insulin

Secretion and this is very much different from sulfonylureas like lemon clem ide which also stimulates insulin while glucose concentrations are low and this is complicated by hypoglycemia which is never provoked by even an overdose of glp-1 in the clinical situation regarding beta cell mass there are rodent experiments that exposure of animals for a short period

As two days is enough to increase measurably beta cell mass other experiments have shown that after ten days or six weeks so relatively short periods of time we believe that it takes a lot longer time in humans before you can even expect a change in beta cell mass with glp-1 light agents the effect on gi motility is mainly on gastric emptying also on intestinal

Motility and the effect on gastric emptying can be very profound almost leading to a standstill and gastric emptying which means no nutrients leave the stomach no nutrients are absorbed so there is no increase in postprandial concentrations of glucose and triglycerides for example but this effect is lost over time when you expose patients to high concentrations

Of glp-1 receptor agonists for a long period of time overall in fasting type 2 diabetes no matter how high their degree of hypoglycemia is to begin with we can normalize glucose concentrations within a few hours by stimulating insulin secretion and suppressing glucagon in the cardiovascular system there have been studies with glp-1 itself with eggs and tied with

Liraglutide and they have been performed in different species like rats like pigs and dogs and i am showing you experiments with eggs annotate and dogs and they have been performed the following way an acute myocardial infarction has been induced by occluding a coronary artery but through this artery a die was delivered to the myocardium so that you could calculate

The area at risk and after the experiment the real necrotic area was also quantified and then the degree of myocardial infarction was expressed as dead myocardium relative to the area at risk and if you do this with examine id and with placebo you see a smaller myocardial infarction with eggs and tight with riskier p1 receptor stimulation than without and this is

The uniform result that has been represent species and with different glp-1 receptor agonists there is also experiments on blood pressure pressure regulation if you expose humans to x and tide on regular tight treatment blood pressure falls by approximately 3 to 5 millimeters mercury there is vasodilation in patients with type 2 diabetes exposed to glp-1 receptor

Agonists and so there is reason to believe that there are multiple beneficial actions on the cardiovascular system of g-o-p one and all the other gop one receptor agonists one interesting last feature is that in recent time there have been experiments not only looking for expects of the intact molecule glp-1 7 to 36 a might as it is secreted from the gut and as

It binds the classical pancreatic type glp-1 receptor but what has been found out is that in the cardiovascular system you can have effects of g-o-p one also in receptor knockout mice so there must be some other signal transmission there is also effects of the degradation product after tpp four has acted on geo p1 and this degradation product is known not to

Stimulate the pancreatic type glp-1 receptor so we believe that there is a good chance that there will be a second receptor on cardiovascular tissue that maybe binds this degradation product preferentially and not so much of the intact original g-o-p one and such a receptor would probably be a very good target for preventing cardiovascular disease in patients with

And without type 2 diabetes based on these activities of g-o-p one several ways of using it as a anti diabetic treatment have been devised number one is the inhibition of the degrading enzyme dipeptidyl peptidase-4 abbreviated tp before under this circumstance it is still the endogenous lee released gut hormones gop one that is active in treating diabetes and the

Last approach is incurred in my metics which is other peptides that share some similarity with glp-1 that are able to bind to the receptor but are not degraded by dp before and have a longer half-life than the original molecule gop one the half-life of which is in the order of magnitude of one and a half minutes so this is the prospect for treating diabetes with

Help of properties that were discovered for the original endogenous gut peptide gop one thank you very much for your attention

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The Effect of Glucagon-Like Peptide-1 on Target Organs By EMEDCOIL