November 06, 2024
Not so long ago, seeing patients with obesity and type 2 diabetes used to elicit a yawn that was difficult to suppress from the physician, and longing and guilt from the patient. Now, however, the situation has changed dramatically. It is difficult to find an adult who has not heard the word Ozempic and would not be surprised by the sudden slimness of the "stars"
It is time to review in general terms what discoveries of digestive hormones we owe to therapeutic advances and what new things have been learned about the regulation of carbohydrate metabolism.
The main trigger for the synthesis and release of insulin by pancreatic β-cells is an increase in plasma glucose . However, there are other substances that can also stimulate this process. Their research dates back to the beginning of the 20th century.
The term incretin was first mentioned in 1932 by La Barre to describe substances synthesized in the small intestine in response to food intake and causing a hypoglycemic effect. It was suggested that these substances were hormonal in nature, but it was not possible to establish the details of their action for a long time because of imperfect methods of accurately determining the amount of insulin secreted in response to stimulation by them.
Interest in incretins was renewed in the late 1950s (Yalow and Berson, Nobel Price 1977), when radioimmunoassay was used to quantify extremely low concentrations of biological molecules, including insulin. The radioimmunoassay helped to detect differences in insulin secretion depending on the route of glucose administration.
When glucose was administered orally, Perley and Kipnis found additional delayed insulin secretion, which was not observed with i.v glucose administration. This phenomenon is called the incretin effect, and its contribution in healthy individuals is up to 70% of the postprandial insulin response. The strength of the response depends on the amount of glucose in the food.
In patients with type 2 DM this effect was for some reason not observed or was significantly reduced.
To date, two polypeptide hormones of incretin have been discovered:
glucose-dependent insulinotropic polypeptide 1969
glucagon‐like peptide‐1
end 1980's
General info about incretins
GIP is produced by enteroendocrine K cells in the proximal small intestine.
However, observations and experiments with removal of the distal small intestine revealed a decrease in the incretin effect. In the 1980s, another polypeptide GLP-1 was found to act synergistically with GIP.
This discovery was facilitated by advances in cloning and sequencing of mammalian genes(Svetlana Mojsov), in particular the proglucagon gene, as well as studies of peptide structure. Together with GLP-1, it was possible to obtain other peptides, which were added to the list of the friendly glucagon superfamily.
Both hormones are synthesized by endocrine cells in the intestinal wall and have a very short period of activity, being broken down in minutes by the same enzyme, DPP-4 (dipeptidyl peptidase-4). It is important to remember that DPP-4 is a widespread enzyme that has many points of application besides the incretins. Hormones are excreted mainly by the kidneys.
Incretins interact on the surface of β-cells with G-protein-coupled receptors, triggering several signaling pathways. The main one in β-cells is the cAMP-dependent pathway. Ultimately, there is an increase in intracellular calcium concentration and release of insulin and amylin from the secretory granules of β-cells. It is important to emphasize that this process is glucose-dependent, it is triggered by an increase in blood glucose levels.
The two-phase effect of incretins is explained by the fact that after ingestion of food (especially carbohydrates) their secretion increases in response to mediated stimulation of intestinal hormonal cells by neuronal factors (N.vagus), and then - as a consequence of direct contact with food (lipids). The first phase lasts about 15 min and the second phase about an hour.
Incretins activate not only insulin secretion from granules, but also its synthesis by β-cells due to activation of proinsulin gene transcription, thus preventing the depletion of the latter. The ability of incretins to stimulate proliferation and increase the apoptosis threshold of β-cells has been noted.
As mentioned, the incretins belong to the glucagon superfamily, whose members are united on the basis of their precursors related to glucagon. Here is perhaps a partial list:
Glucagon superfamily
glucagon famlily
- glucagon
- glucagon‐like peptide GLP-1 and GLP-2
- glicentin-related pancreatic peptide
- different combinations of all above
secretin family
- secretin
- GIP
- Vasoactive intestinal peptide (VIP)
- Growth hormone–releasing hormone (GHRF)
- Pituitary adenylate cyclase-activating polypeptide (PACAP)
- peptide histidine methionine/isoleucine (PHM/PHI)
What is interesting about glucagon family?
The family of proglucagon gene peptides (proglucagon-derived peptides) shares a common structure with glucagon. Of all of them, GLP-1 (48%) has the greatest similarity with it. In general, the sequence of amino acids in glucagon and GLP-1 remains stable in many species. Thus human glucagon resembles glucagon of the sea devil (anglerfish) by 75%, and GLP-1 by 79%. Perhaps such conservatism in structure is worked out by evolution and is important for maintaining important processes of growth, transmission of nerve impulses and regulation of metabolism.
The above list is quite long, and the last family members will tell many people nothing at all. The question arises, should we look at it and forget about it?
However, we can look at these polypeptides from another angle. At the moment, even a person far from medicine knows about the existence of analogs of receptors to GLP-1 in the therapy of type 2 diabetes and obesity. Perhaps in the future there will be new drugs that complement the therapy by mimicking the action of other hormonal peptides synthesized in the gastrointestinal tract. It is logical to assume that we are dealing with a very complex interconnected system, the knowledge of which is only becoming clearer.
On the other hand, it is interesting that despite similarities in the constituent amino acid building blocks, family members differ greatly in their properties. As in the case of GLP-1, which despite the name "glucagon-like", has in most cases the exact opposite effect to the related glucagon.
Let us take a closer look at a subgroup of glucagon-like peptides whose structure is encoded by the same proglucagon gene located in chromosome 2.
Proglucagon-derived peptides (PGDPs)
The primary regulator of proglucagon gene expression is food intake. Based on the code of this gene pre-proglucagon is formed (like in pre-proinsulin). When its signal peptide (S) is cleaved off pre-proglucagon is converted to proglucagon.
(grpp + glucagon + ip1)
(glp1 + ip2 + glp2)
(glucagon + ip1)
The fate of proglucagon further depends on posttranslational processing in cells, where it is converted by tissue-specific proteases (convertases).
In pancreatic α-cells proglucagon will be converted to glucagon, glycentin-related polypeptide (GRPP), intervening peptide-1 (IP-1) and major proglucagon fragment (MPGF). GLP-1 is formed in minimal amounts.
In L-cells of the intestine, brainstem and hypothalamus other peptides, GLP-1, GLP-2, oxyntomodulin, glicentin and IP-2, will be libirated from it. Note that L-cells are located mainly in the distal small intestine and colon but could be found in smaller numbers throughout all intestine.
Glicentin The physiological effect of these large molecules is unclear; in rodents, its trophic effect on the small intestine has been noted.
Oxyntomodulin Suppresses GI motility and intestinal secretion, but stimulates exocrine pancreatic secretion and glucose absorption. Possible role in the regulation of satiety and heart rate.
Other proglucogon-derived peptides considered to play a complementary role.
GLP-1, which is an incretin, and GLP-2 have been the most studied so far. Let's take a closer look at them (and the other incretin GIP).
GLP-1
GLP-1 и pancreas
As mentioned above, food intake stimulates the expression of the proglucagon gene in endocrine L-cells of the distal small intestine. This triggers the synthesis of GLP-1 incretin, which in turn stimulates the β-cells of the PG to release insulin. Since this process is glucose-dependent, there is no risk of hypoglycemia.
Given the very rapid deactivation of GLP-1 in blood, it is hypothesized that insulin secretion by β-cells occurs not only through direct action with the receptor, but also indirectly through the neuronal activation pathway (efferent pathways of N.vagus).
GLP-1 has an inhibitory effect on glucagon secretion. This probably occurs through glucose-dependent stimulation of somatostatin secretion through receptors to GLP-1 on δ-cells of the PG. Somatostatin in turn inhibits both glucagon and GLP-1 production.
GLP-1 could increase sensitivity of β-cells with initial resistance to glucose stimulation, which is realized through increased expression of glucose transporters.
GLP-1 interaction with exocrine and epithelial cells of the pancreas in experiments stimulated their transformation to β cells
As noted, postprandial GLP-1 levels are reduced in obese people with type 2 DM. The reason for this has not yet been established.
Central (CNS) and peripheral nervous system
GLP-1 are relatively small molecules that can cross the blood-brain barrier and directly interact with CNS cells. In reality, however, it is unlikely that L-cell peptides can quickly reach higher neurons.
There are cells in the CNS that are capable of synthesizing GLP-1 themselves. The main source of GLP-1 are cells of the nucleus tractus solitarius (NTS) and the reticular formation of the medulla oblongata. Destruction of these neurons leads to a significant decrease in GLP-1 levels in the hypothalamus, brainstem and spinal cord.
GLP-1 secretion in central neurons is stimulated by leptin and gastric distension during ingestion.
As for GLP-1 receptors (GLP-1R), they are possessed by a much larger number of cells in the central and peripheral nervous system. The following is a far from complete list of areas that have receptors for GLP-1.
- Hypothalamus, responsible for eating behavior and maintenance of homeostasis
- Cells of the caudal part of the floor of the IV ventricle - area postrema (brain stem, chemoreceptor trigger zone), which are connected with vomiting centers and vagus nerve nuclei.
- The central nucleus of the amygdala, which is related to the emotions of fear and anxiety.
- Vagus nerve ganglion, whose afferent pathways end in the nuclei of the trunk solitary tract, which in turn are connected with the hypothalamus.
GLP-1 and its receptor agonists have anorexogenic effects. There is probably a link between GLP-1 secretion in the intestine, activation of signal transmission through afferent fibers of the vagus nerve, central neurons of the medulla oblongata and hypothalamus, resulting in the formation of the feeling of satiety and facilitating the decision to "eat no more ".
GLP-1 also has an anti-apoptosis effect on neurons, stimulate outgrowth and support differentiation triggered by nerve growth factor.
GLP-1 and Intestinal motility
GLP-1 inhibits gastric emptying and acid secretion. This probably occurs not only through direct effects on gastric cells, but also indirectly through activation of central neurons and transmission of their inhibitory signals via the vagus nerve. The hormone also increases the tonic contraction of the pyloric section of the stomach, which delays the entry of food into the intestine.
Patients with diabetes type 1 treated with GLP-1 receptor agonists may experience more smooth postprandial peak of blood glucose due to a slower entry of food from the stomach into the intestine.
GLP-1 and cardiovascular system, muscle and adipose tissue.
In rodent studies, GLP-1 increased blood pressure and heart rate. However, this was not observed when the receptor agonists were administered in humans.
In patients with type 2 DM during long-term GLP-1 receptor agonists therapy, a slight decrease in blood pressure was noted, possibly due to stimulation of water and sodium excretion with the kidneys. No decrease in blood pressure was noted in patients with type 2 DM and overweight due to antipsychotic therapy (despite significant weight loss)
GLP-1 enhances insulin-stimulated glucose uptake in skeletal muscle (and liver). GLP-1 interaction with its receptor on muscle cells follows cAMP independent path.
In animal models, the effect of GLP-1 on the activation of thermogenesis via interleukin-6 in fat cells has been observed. The detailed mechanism is the subject of research. Data on this in humans are very limited.
GLP-1 and thyroid
GLP-1 stimulates TSH and release of calcitonin from thyroid gland.
GLP-1 and kidney
GLP-1 promotes diuresis and sodium secretion
GLP-2
GLP-2 is formed in equimolar amounts with GLP-1 in intestinal L-cells, as well as in some CNS neurons. In contrast to GLP-1, the palette of tissues with receptors for GLP-2 is somewhat narrower, and they are found mainly in the intestine and CNS.
The effect of GLP-2 on insulin secretion has not yet been detected, but it may have an anti-inflammatory effect on islet cells.
The main role of GLP-2 consists in intestinotrophic effect, which consists in increasing cell proliferation in the crypts of the intestine and increasing their depth, improving blood flow in the intestine and portal system. Under its influence, glucose and lipid absorption improves, intestinal barrier function is restored, appetite and intestinal motility are suppressed, nerve cell proliferation and survival are activated.
In animal experiments, the effect of GLP-2 on central neurons via afferent pathways of the vagus nerve was demonstrated.
The question about the effect of GLP-2 on fat metabolism in obesity remains open.
A GLP-2 analog (teduglutide) has now been synthesized to treat short bowel syndrome and Crohn's disease. There may be drugs to cure other inflammatory bowel diseases and chemotherapy-induced mucositis in the future.
GIP
The glucose-dependent insulinotrophic peptide GIP was discovered earlier than the GLP-1 incretin. It is synthesized mainly in endocrine K-cells of the 12th intestine and jejunum.
GIP is encoded by a gene located on chromosome 17. Like many other members of the glucogonin superfamily GIP belongs to very conservative peptides, 90% of its amino acid sequences are the same in many mammals. However, the stimulation of hormone release varies. In humans, there is a greater response to fatty food intake, and in rodents, GIP is more intensely produced to carbohydrates.
The main application point of the peptide is β-cells, where it activates insulin synthesis and secrition.
β-cells of patients with DM 2 are less sensitive to GIP. Administration of GIP in physiologic doses does not stimulate insulin secretion in these patients. The possible reason for this may be the damaging effect of hyperglycemia and hyperlipidemia on receptors to GIP (and to GLP-1) and recovery upon correction of these conditions.
The effect of GIP is not limited to the pancreas alone. Receptors to GIP are found in adipose tissue, osteoblasts, on cells of the adrenal cortex and, as already mentioned, in the brainstem.
The role of GIP in the regulation of fat metabolism is possibly comparable to its regulation of carbohydrate metabolism. It enhances lipogenesis and blood flow in adipose tissue and decreases glucagon-stimulated lipolysis. The exact mechanisms of GIP's effect on adipose tissue (brown fat vs white fat) are still unknown and vary depending on the presence of insulin and baseline status (presence or absence of obesity). In obesity, hyperplasia of K cells and increased GIP release are often observed.
In bone tissue, GIP activates the proliferation of osteoblasts and inhibits their apoptosis.
GIP stimulates glucagon release, but this process is inhibited in healthy people when blood glucose rises. In patients with type 2 DM this does not happen. The reason for this phenomenon has not yet been established. Combined therapy of patients with GIP and GLP-1 receptor analogs shows neutral effect on glucagone release.
It is noted that combination therapy may result in better weight loss and glucose normalization than GLP-1 analogues alone. The addition of GIP allows the use of higher doses of GLP-1 analogs while reducing the likelihood of side effects such as nausea. (GIP causes the opposite effect of GLP-1 against area postrema cells in the CNS).
| # | GLP-1 | GIP | GLP-2 |
|---|---|---|---|
| T 1/2 | 1-2 min | 7 min* | 7 min |
| synthesis | brain, L-cells distal ileum и colon | K-cells duodenum and jejunum | brain, L-cells distal ileum и colon |
| incretin | yes | yes | no |
| deactivation | ← | DPP-4 | → |
| interaction with glucagon | inhibits | activates | |
| clearance | ← | urine | → |
Note: * GIP is less sensitive to DPP-4, so its biological activity time is longer than that of GLP-1. In patients with type 2 DM, the half-life of active incretins is reduced. The half-life of other proglucagon peptide derivatives is longer compare to incretins.
Human homeostasis is ensured by the coordinated work of a huge orchestra of ancient hormone peptides. In this review I wanted to highlight not only their remarkable qualities, but also potential problems associated with attempts to mimic their action with drugs. Obviously, such attempts have hidden consequences of which we are not yet aware.