Lixisenatide Peptide

Its molecular structure has been finely modified to bind and activate the GLP-1 receptor (a classic B-class G protein coupled receptor) on the cell membrane with high specificity and affinity, GPCR). Once it binds to the extracellular domain of the receptor, it will cause a profound change in the receptor conformation, thereby activating the coupled excitatory Gs protein. The Gs protein subsequently activates the adenylate cyclase (AC) on the cell membrane, catalyzing the conversion of ATP into a second messenger, resulting in a sharp and dose-dependent increase in intracellular cyclic adenosine monophosphate (cAMP) levels.

The massive accumulation of cAMP is the hub of the entire signal transduction, which subsequently activates two extremely critical downstream pathways in parallel: the protein kinase A (PKA) pathway and the exchange protein 2 (Epac2) signaling pathway directly activated by cAMP. The synergistic effect of these two pathways not only rapidly regulates the activity of various ion channels to promote vesicle release, but also promotes the expression of iletin genes at the transcriptional level and participates in the proliferation and anti apoptotic protection of pancreatic islet cells.

Within pancreatic islet cells, induction of elevated cAMP by liraglutide triggers a series of complex biochemical cascade reactions. It first promotes the release of calcium ions (Ca2+) from intracellular calcium storage pools such as the endoplasmic reticulum, while closing ATP sensitive potassium channels (K-ATP) on the cell membrane through PKA phosphorylation, leading to depolarization of the cell membrane. This potential change further promotes the extensive opening of voltage dependent calcium channels (VDCC) on the cell membrane, leading to rapid influx of extracellular Ca2+.

The surge of local Ca2+concentration finally triggered the migration of iletin containing microbubbles to the cell membrane and fusion efflux (exocytosis), which effectively restored the early (first phase) iletin secretion that was generally damaged in type 2 diabetics.

The key point here is that the secretion promoting process of Lysimab is strictly regulated by the "glucose dependent" mechanism.

This means that only when there is an abnormal increase in glucose concentration in the blood (such as after consuming carbohydrates), can the amplified cAMP signal be truly converted into the driving force for iletin secretion when the cells produce sufficient ATP due to glucose metabolism. On the contrary, when patiets are on an empty stomach or have normal or low blood sugar levels, this biochemical pathway is naturally "dormant", and its iletin secretion promoting effect will be extremely weakened or even stopped. This inherent 'intelligent braking' mechanism fundamentally reduces the risk of fatal hypoglycemia in clinic practice.

Type 2 diabetics is not only a disease of insufficient iletin secretion, but also a disease of abnormal hyperglucagon secretion. In pancreatic islet cells, improper secretion of glucagon is also inhibited in a strict glucose dependent manner. At present, the academic community believes that this inhibitory effect includes both direct action of pharmaceuticals on GLP-1 receptors on the cell surface and local paracrine inhibition by stimulating adjacent cells to secrete iletin and somatostatin.

Lixisenatide peptide strongly promotes glycogen breakdown and gluconeogenesis in the liver under physiological conditions. By effectively suppressing the surge of postprandial glucagon, the excessive output of endogenous glucose from the liver is cut off. This dual hormone regulatory valve of "insulinotropic+hypoglycemic" is crucial for controlling postprandial blood glucose peaks from the source.

This is its most proud 'core weapon' as a short acting GLP-1 receptor agonist. Unlike long-acting GLP-1 receptor agonists, which act continuously on receptors for 24 hours, long-acting formulations can cause rapid desensitization and rapid tolerance of the gastrointestinal vagus nerve receptors (Tachyphylaxis) within a few weeks. Their intermittent daily administration perfectly avoids this tolerance, allowing their ability to delay gastric emptying to be maintained for a long time. Mainly by activating the vagus nerve related nerves in the gastrointestinal tract, the satiety signal is transmitted to the brainstem.

And then the vagus nerve strongly inhibits the peristalsis and contraction of gastric smooth muscle, thereby significantly and persistently slowing down the rate of gastric contents being discharged into the duodenum. This physical "throttling" effect greatly prolongs the rate at which carbohydrates in food are broken down, absorbed, and enter the portal vein system by digestive enzymes in the small intestine. The absorption curve of postprandial glucose has been smoothed from a "steep peak" to a "gentle hill", effectively reducing the violent fluctuations of postprandial blood glucose (glucose drift), thereby greatly reducing the metabolic burden on pancreatic islet cells.

In addition to its role in peripheral organs such as the pancreas and gastrointestinal tract, Liraglutide also has the ability to cross the BBB (BBB) or directly act on periventricular organs with incomplete BBB, such as the posterior area (Area Postrema). It can deeply act on key energy metabolism and satiety regulation centers such as the arcuate nucleus (ARC) in the hypothalamus. At the synaptic level of neurons, on the one hand, POMC/ART (melanocortin/cocaine amphetamine regulated transcript) neurons that produce signals of anorexia and satiety are directly activated.

And on the other hand, NPY/AgRP neurons that produce signals of hunger are indirectly inhibited. By regulating this dual central nervous system circuit, patiets can effectively enhance their sense of fullness during the eating process, prompt them to terminate their eating behavior in advance, and psychologically reduce their desire for high calorie foods such as high sugar and high fat. This mechanism of reducing total calorie intake from top to bottom through the "brain gut axis" not only helps to further maintain the blood glucose homeostasis of the whole body, but also brings about clinically beneficial light to moderate weight loss for most type 2 diabetics patiets with overweight and obesity.