The two major incretins in humans are GLP-1 and GIP. These incretins share a considerable amino acid identity.
10 They both increase insulin secretion; however, only GLP-1 suppresses glucagon secretion. Both GLP-1 and GIP are rapidly inactivated by the enzyme DPP-IV.
11-13
Endogenous GIP is a 42-chain amino acid peptide secreted by the lymphocyte K cells, which are located within the intestinal epithelium of the proximal duodenum and regulated predominantly with fat consumption.
10,15,16 Glucose-dependent insulinotropic peptide is reduced during the fasting state and increased after food ingestion. The primary action of GIP is to stimulate glucose-dependent insulin secretion. Thus, enhancement of GIP signaling may have beneficial effects in patients with T2DM, but these benefits remain to be determined in clinical practice.
10,15,16
Both GIP and GLP-1 are ubiquitous hormones. Their receptor distribution is located within several organs, including the brain, duodenum, kidneys, liver, lungs, pancreas, and stomach.
17 The receptors for these hormones are mediated through a G–protein-coupled adenylate cyclase, resulting in an increase of cyclic adenosine monophosphate and activation of protein kinase A.
17 These actions lead to increased insulin secretion. Other signaling mechanisms involving GIP and GLP-1 receptors have been described in β cells.
12,13,17 Figure 1 illustrates the progression of events involving GIP and GLP-1 leading to insulin secretion within β cells. Also noted in
Figure 1 is the tissue receptor distribution of both GIP and GLP-1.
17
Endogenous GLP-1 is a gastrointestinal hormone secreted from the L cells of the distal aspect of the small intestine. It is derived from a large proglucagon (ie, glucagon precursor) that also encodes for glucagon.
10,16 Like GIP, GLP-1 is reduced in the fasting state and increases rapidly after a meal. It has potent effects on the β-cell secretion of insulin and on gastrointestinal motility.
18 The increase in insulin secretion after a meal is only partially influenced by GLP-1 local activity. Most likely, influences that are hormonally and neurally mediated also exist.
18,19
The release of GLP-1 is attenuated in patients with T2DM after ingestion of a mixed meal. This attenuation has been demonstrated in patients with T2DM (N=54), with a significant reduction of the GLP-1 area under the curve during a period of 240 minutes after a meal, compared with individuals with normal glucose levels (
P<.05).
19 In addition, patients with impaired glucose tolerance in the study had a reduced GLP-1 response to a mixed meal. After a mixed meal, a reduction of GIP was also observed in patients with T2DM, but this reduction did not reach statistical significance.
19
The effect of GLP-1 action protects β-cell function.
20 The outcome of events of GLP-1 stimulation results in increased insulin secretion, as well as decreased glucagon secretion, gastric emptying, and food consumption.
20 These changes lead to improved glycemic control and a reduction of free fatty acids, which, in turn, may result in attenuation of both glucotoxicity and lipotoxicity in patients.
20 In addition, GLP-1 stimulation produces direct effects on β cells, resulting in proliferation of β cells, increased cell regeneration, and reduced cell apoptosis. These effects have been demonstrated only in animal studies. They remain to be demonstrated in human subjects.
20
Besides GLP-1 and GIP, there are several other substrates for DPP-IV inhibition. These substrates include glucagon, the clinical significance of which is not known. Many of the biologic effects of DPP-IV inhibition are currently under investigation.
In a crossover study, GLP-1 reduced hunger and increased early satiety in patients with T2DM (N=12) who received a GLP-1 infusion while consuming a mixed meal.
21 Hunger scores and satiety scores associated with GLP-1 infusion were compared with those associated with saline infusion. After the start of the meal, hunger and satiety were improved significantly (hunger
P=.026; satiety
P=.028) and, as a result, food consumption was less in patients who received GLP-1.
21