The incretins are peptide hormones secreted from the gut in response to food. They increase the secretion of insulin. The incretin response is reduced in patients with type 2 diabetes, so drugs acting on incretins may improve glycaemic control. Incretins are metabolised by dipeptidyl peptidase, so selectively inhibiting this enzyme increases the concentration of circulating incretins. A similar effect results from giving an incretin analogue that cannot be cleaved by dipeptidyl peptidase

Prins, Johannes B.

Australian Prescriber

Johannes B Prins

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Experimental and clinical pharmacology: Incretin mimetics and enhancers: mechanisms of action

University of Queensland eSpace

102 | Volume 31 | NumBeR 4  | AuGuST 2008 
Experimental and clinical pharmacology
Incretin mimetics and enhancers: mechanisms of action
Johannes B Prins, University of Queensland Diamantina Institute for Cancer, Immunology and 
Metabolic Medicine, and the Centres for Health Research, Princess Alexandra Hospital, Brisbane
Summary
The incretins are peptide hormones secreted 
from the gut in response to food. They increase 
the secretion of insulin. The incretin response 
is reduced in patients with type 2 diabetes, so 
drugs acting on incretins may improve glycaemic 
control. Incretins are metabolised by dipeptidyl 
peptidase, so selectively inhibiting this enzyme 
increases the concentration of circulating 
incretins. A similar effect results from giving 
an incretin analogue that cannot be cleaved by 
dipeptidyl peptidase.
Key words: diabetes, dipeptidyl peptidase, glucagon-like peptide, 
glucose-dependent insulinotropic polypeptide.
(Aust Prescr 2008;31:102–4)
Introduction
It has been known for many decades that an oral glucose load 
causes a greater release of insulin than a similar glucose load 
given intravenously. This difference (40–60% in the area-under-
the-curve of the insulin time-concentration graph) is due to the 
'incretin effect'. By increasing insulin secretion, the incretins 
lower blood glucose.
Physiology
The incretins are peptide hormones. They are released into the 
circulation, in response to luminal nutrients, within minutes of 
eating. In humans, the major incretins are glucagon-like peptide-1 
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). 
GLP-1 is secreted by the L cells in the ileum and colon, while GIP 
is secreted by the K cells in the duodenum.
Both incretins have hormonal effects on multiple organs, 
notably the endocrine pancreas, the gut and the brain (Table 1). 
Their predominant role is regulation of energy homeostasis. 
They stimulate insulin secretion in a glucose-dependent manner, 
delay gastric emptying and suppress appetite. This combination 
of effects makes a significant contribution to glucose 
homeostasis, particularly the control of postprandial glucose. 
Subsequent studies have identified other actions including 
improvement in pancreatic β cell glucose sensitivity and, in 
animal studies, promotion of pancreatic β cell proliferation and 
reduction in β cell apoptosis.
The circulating incretins act via specific G-protein-coupled 
receptors. There are clinically important differences in the tissue 
distribution of these receptors. The GLP-1 receptor is expressed 
in pancreatic islet a and β cells, heart, central nervous system, 
kidney, lung and gastrointestinal tract. The GIP receptor is 
expressed predominantly in the pancreatic islet β cells and less 
so in the central nervous system and adipose tissue.
Table 1
Incretins and their actions
Glucagon-like peptide-1 (GlP-1) Glucose-dependent insulinotropic polypeptide (GIP)
Secreted by L cells in the distal gut (ileum and colon) Secreted by K cells in the proximal gut (duodenum)
Stimulates glucose-dependent insulin release Stimulates glucose-dependent insulin release
Suppresses hepatic glucose output by inhibiting glucagon 
secretion in a glucose-dependent manner
Enhances β cell proliferation and survival in animal models and 
isolated human islets
Enhances β cell proliferation and survival in islet cell lines
Delays gastric emptying Delays gastric emptying
Cleared by dipeptidyl peptidase 4 inactivation and renal 
elimination
Cleared by dipeptidyl peptidase 4 inactivation and renal 
elimination
Anorexic
Controls fasting glycaemia
| Volume 31 | NumBeR 4  | AuGuST 2008 103
The incretin response to a meal lasts approximately 2–3 hours 
because, despite rapid metabolism and the short half-life  
(1–2 minutes) of each incretin molecule, the stimulus of 
nutrients in the gut persists and so there is ongoing production 
of incretins. The major mechanism of metabolism of the incretins 
is cleavage by dipeptidyl peptidase 4 (DPP4), an enzyme that is 
ubiquitously expressed, including in endothelial cells.
Incretins in diabetes
The clinical relevance of the incretin system came to light 
when it was recognised that the incretin response is markedly 
attenuated in people with type 2 diabetes. The lack of 
nutrient-induced release of GLP-1 contributes significantly to 
hyperglycaemia in these patients through a relative reduction 
in postprandial insulin response, the subsequent failure of 
glucagon suppression and a lack of appetite suppression. The 
concentration of GIP is near normal, but its effect on insulin 
secretion is diminished. These observations uncovered a new 
therapeutic strategy for type 2 diabetes – that of promoting the 
activity of the incretin system. 
Two pharmacological approaches have been taken to enhance 
the incretin effect in type 2 diabetes. One approach is to 
administer GLP-1 'analogues' (GLP-1 receptor agonists) that are 
resistant to cleavage by DPP4. The other approach is to inhibit 
DPP4 activity. This effectively increases the half-life and therefore 
the circulating concentrations of the incretins. The effectiveness 
of both approaches suggests that there is no significant 
reduction in GLP-1 sensitivity in subjects with diabetes.
GlP-1 receptor agonists
The administration of an incretin analogue resistant to cleavage 
by DPP4 has been successfully pursued by a number of 
pharmaceutical companies. Two drugs are now in clinical use 
or late stage clinical trial. As they are peptides they need to be 
given by subcutaneous injection, but long-acting formulations 
are being developed to see if once-weekly injections are 
possible.
Exendin is a peptide with approximately 50% homology to  
GLP-1. It is found in the saliva of a lizard known as the Gila 
monster. The molecule is a potent activator of the GLP-1 receptor 
and is resistant to cleavage by DPP4 and other peptidases 
so it has a long circulating half-life. The clinical formulation 
(exenatide) is in use in many parts of the world. 
Another analogue of human GLP-1 has been made by adding a 
C-16 fatty acid. The resultant compound (liraglutide) is resistant 
to DPP4 cleavage and has a long circulating half-life. It maintains 
normal activity at the GLP-1 receptor. 
The incretin effect on insulin secretion is glucose-dependent; 
insulin production is only enhanced by GLP-1 in the presence 
of hyperglycaemia. This is therapeutically highly advantageous 
because hypoglycaemia is not an effect of treatment. 
A therapeutically beneficial additional effect of the GLP-1 
analogues is significant weight loss (of up to 3 kg in clinical 
trials). This results from the combined effect of delayed gastric 
emptying and central effects to induce anorexia and (possibly) 
nausea. Additionally, the delayed gastric emptying causes 
nausea and vomiting in some patients.
The incretin analogues show direct effects which preserve β cell 
mass in animal models. They also have in vitro and in vivo effects 
which promote β cell proliferation and reduce β cell apoptosis.
The 'downsides' of the analogue approach are that there is 
no alteration or restoration in GIP concentrations or activity, 
administration is via injection, and the long-term consequence 
(if any) of prolonged GLP-1 receptor activation is unknown. 
Inhibition of dipeptidyl peptidase 4
DPP4 is a member of a large family of peptidases which have 
a wide range of actions. As GLP-1 and GIP are the only known 
substrates of DPP4, it is important for drugs to selectively inhibit 
this enzyme and not the other peptidases to limit adverse effects 
on other systems. Of particular relevance is the need to avoid 
inhibiting DPP8 and 9 as this can cause renal and skin toxicity, 
and immunosuppression.
Sitagliptin and vildagliptin are two DPP4 inhibitors that are 
highly specific for DPP4. They have long half-lives, allowing 
once-daily oral therapy. Two hours after a single dose there is 
almost complete inhibition of DPP4 and at 24 hours there is 
approximately 85% inhibition. In patients with type 2 diabetes, 
the drugs effectively restore GLP-1 circulating concentrations 
and the postprandial response of GLP-1 to that of a non-diabetic 
person. Fasting incretin levels remain low, but detectable, and 
the drugs also reduce fasting blood glucose in patients with 
type 2 diabetes, predominantly by reducing glucagon secretion. 
They also return the impaired β cell glucose sensitivity towards 
normal, an action that contributes to postprandial glucose 
control. 
In animal models of type 2 diabetes, sitagliptin and vildagliptin 
preserve β cell mass (and function). If this effect also occurs in 
patients, then the drugs may delay or prevent the characteristic 
β cell deterioration seen in type 2 diabetes.
Future directions
The development of drugs to manipulate the incretin system 
is fascinating. It teaches us much about the pathophysiology of 
glucose homeostasis and type 2 diabetes. Based on currently 
available evidence, these drugs will provide additional therapies 
for type 2 diabetes.
A key set of data that will become available over the next few 
years will highlight the effect of these drugs on the pancreatic 
islet, with particular emphasis on their ability to prevent or delay 
secondary β cell failure. Should this be apparent in patients with 
type 2 diabetes, a strong case could be made for starting these 
104 | Volume 31 | NumBeR 4  | AuGuST 2008 
drugs very early in the disease, perhaps even in the pre-diabetic 
phase. This therapy would depend on favourable outcomes in 
long-term studies.
Further reading
Drucker DJ, Nauck MA. The incretin system: glucagon-like 
peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors 
in type 2 diabetes. Lancet 2006;368:1696-705.
Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response 
to oral and intravenous glucose administration. J Clin 
Endocrinol Metab 1964;24:1076-82.
Holst JJ, Orskov C. The incretin approach for diabetes treatment: 
modulation of islet hormone release by GLP-1 agonism. 
Diabetes 2004;53 Suppl 3:S197-S204.
Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. 
Normalization of fasting hyperglycaemia by exogenous 
glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-
dependent) diabetic patients. Diabetologia 1993;36:741-4.
Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin 
effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia 
1986;29:46-52.
Professor Prins has received research funding and/or honoraria 
for lectures or Advisory Board membership from Merck Sharp & 
Dohme, NovoNordisk and Novartis. 
Self-test questions
The following statements are either true or false  
(answers on page 111)
7. Stimulating the receptor for glucagon-like peptide causes 
weight gain.
8. Incretin analogues cause hypoglycaemia in patients with 
type 2 diabetes.
Incretin mimetics and enhancers: clinical applications
Anne T Reutens, Endocrinologist and Clinical researcher, and Jonathan E Shaw, Deputy Director, 
International Diabetes Institute, Melbourne
Experimental and clinical pharmacology
Summary
mimicking or enhancing the actions of incretin 
can help to control type 2 diabetes. exenatide 
and liraglutide are injectable glucagon-like 
peptide-1 receptor agonists, while vildagliptin 
and sitagliptin are oral dipeptidyl peptidase 4 
inhibitors. These drugs have their main effects on 
postprandial glucose, but also lower fasting glucose 
concentrations. Glucagon-like peptide-1 agonists 
lower glycated haemoglobin by about 1–1.7% and 
induce weight loss, but frequently cause transient 
nausea. Dipeptidyl peptidase 4 inhibitors reduce 
glycated haemoglobin by 0.5–1%. They have 
infrequent adverse effects, but no effect on weight. 
longer-term data are required to establish their full 
adverse event profile and their efficacy in reducing 
the macro- and microvascular complications of 
diabetes.
Key words: dipeptidyl peptidase, glucagon-like peptide, exenatide, 
liraglutide, sitagliptin, vildagliptin.
(Aust Prescr 2008;31:104–8)
Introduction
The incretin effect is a normal physiological response involving 
gut hormones. These incretins, glucose-dependent insulinotropic 
polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), stimulate 
pancreatic β cells to increase insulin secretion in response to 
oral carbohydrates. In type 2 diabetes, the secretion of GIP 
remains normal but the insulin response to it is impaired. GLP-1 
concentrations are reduced in type 2 diabetes but the pancreatic 
response is relatively preserved. Using agonists to mimic the 
action of incretin, or inhibiting incretin metabolism to enhance the 
effect, are new strategies to treat type 2 diabetes.1 The main effect 
of the drugs is to lower postprandial glucose. This is particularly 
attractive, as postprandial glucose concentrations are more 
strongly linked to cardiovascular disease than is fasting glucose.2
GlP-1 receptor agonists (mimetics)
GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase 4 
(DPP4), so its potential as a drug is very limited. However, 
drugs which are synthetic agonists at the GLP-1 receptor resist 
cleavage by DPP4.
Exenatide
Exenatide is an agonist which is administered twice daily before 
meals by subcutaneous injections from a pre-filled pen. The 


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