Star targets for hypoglycemic & weight loss: GLP1R/GIPR/GCGR

Background

Type 2 diabetes has hundreds of millions of patients worldwide, accounting for about 90% of diabetes cases. It is a progressive disease. The patient's condition worsens over time. It is difficult to control blood sugar well for a long time using conventional drug treatment. This is different from the human pancreatic islet. Associated with progressive decrease in β-cell function. Anti-type 2 diabetes drugs currently used clinically are mainly divided into glucose regulators (such as α-glycosidase inhibitors), insulin secretion-promoting drugs (such as sulfonylureas and glinides), and insulin-increasing drugs according to their mechanisms of action. Sensitizers (such as biguanides, PPARγ agonists), incretin enhancers (such as GLP-1 analogs and DPP-4 inhibitors) and amylin analogs.

Among them, the new anti-diabetic drug GLP-1 receptor agonist has attracted great attention due to its significant hypoglycemic effect, weight loss, blood pressure reduction, and improvement of blood lipid profiles. At present, GLP-1R targeted drugs have accounted for half of the market in the field of hypoglycemic and weight loss, and competition is fierce. Target drugs such as GIPR and GCGR have also entered the market.

GLP-1R Introduction

GLP-1 Receptor (GLP-1R) belongs to G protein-coupled receptor and is a specific receptor for GLP-1. It is expressed in the pancreas, central nervous system, cardiovascular, gastrointestinal tract, lung, Kidney, thyroid, skin, lymphocytes, mesenchymal stem cells, etc. In pancreatic tissue, human pancreatic islet β cells normally express high levels of GLP-1R. GLP-1 binding to it can promote the synthesis and secretion of insulin, while also stimulating β cell proliferation and inhibiting apoptosis. GLP-1 receptor agonists are synthetic peptide preparations that have partial or complete homology with the natural GLP-1 amino acid sequence in the body, are not easily degraded, have a longer half-life, and have stronger biological activity. They have the properties of natural GLP-1 It is biologically active, so it can play the role of GLP-1. It can lower blood sugar without increasing the risk of hypoglycemia. It has good safety. It can inhibit β-cell apoptosis, lose weight, and reduce visceral fat. Long-term use can protect β-cell function and prevent clinical advantages such as the occurrence of cardiovascular events. The most significant advantage of this type of drug is that it is effective in controlling blood sugar and can help with weight loss. Obese patients benefit more from its use.

Introduction to CIPR

GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide) are both incretin polypeptides secreted by the human intestinal mucosa and are produced by K cells in the proximal intestine and distal intestine respectively. Produced by L cells. The former can bind to the GLP-1R receptor on pancreatic beta cells and stimulate insulin secretion, lowering blood sugar. It can also reduce food intake, delay gastric emptying, and control weight; the latter can regulate energy after binding to the GIPR receptor. Metabolism, inhibiting gastric acid and pepsin secretion, stimulating insulin release, inhibiting gastric motility and emptying and other functions can supplement the function of GLP-1R receptor. Existing research shows that the main functions of GIP are:

1. Stimulate insulin secretion;

2. Acts on the brain, increasing neuropeptide secretion and reducing brain activity;

3. Change energy metabolism and reduce fat oxidation and decomposition in muscles and liver;

4. Promote glucose to enter fat cells and convert into fat, promote postprandial inflammatory response of fat cells, and reduce blood sugar levels.

Although the role of GIP in regulating blood sugar by promoting insulin secretion and regulating glucagon secretion has been widely confirmed, researchers have been controversial about developing GIPR agonists or antagonists to treat diabetes and obesity. However, with the publication of clinical data and in-depth research on the mechanism of action of tirzepatide (a dual GIPR and GLP-1R agonist developed by Eli Lilly) in recent years, it has been shown that GIP can regulate glucagon by activating GIPR in pancreatic islet α cells. Secretion, inducing more insulin secretion through the interaction of pancreatic α and β cells, rather than just promoting insulin secretion by activating GIPR in pancreatic β cells. Phase III clinical data shows that tirzepatide has a significantly greater blood sugar and weight-lowering effect than semaglutide. GIPR agonists also reduce weight by reducing food intake and increasing energy consumption. In combination with GLP-1 receptor agonists, they have great efficacy. With good effects, it has been developed for the treatment of diabetes, obesity and non-alcoholic steatohepatitis, which has revitalized the development of GLP1R/GIPR/GCGR dual-target/triple-target agonist drugs.

Introduction to GCGR

Glucagon receptor (GCGR) is a G protein-coupled receptor mainly found on liver cells. This receptor binds to the glucagon hormone and can promote liver cells to decompose glycogen and increase blood sugar levels. rise. Under normal physiological conditions, glucagon secretion from α cells is inhibited by insulin and the like during hyperglycemia. When blood sugar levels drop, β cell secretion decreases, eliminating the inhibitory effect on α cells, and glucagon secretion increases. Existing research shows that in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM), plasma glucagon levels are too high, glucagon secretion is uncontrolled, leading to failure of blood glucose homeostasis and relatively low insulin secretion. or an absolute reduction, both of which together lead to a hyperglycemic state. Glucagon can also treat hypoglycemia under normal physiological conditions, so glucagon receptor drugs are important targets for the treatment of diabetes, obesity, and hypoglycemia.

GCGR protein is a type B G protein-coupled receptor. Glucagon can activate the GCGR-Gs signaling complex in liver cells. The Gs protein will interact with adenylate cyclase, thereby inducing the second messenger cyclic phosphate. The production of adenosine (cAMP) and the activation of downstream signaling pathways can also activate the GCGR-Gq signaling complex, which activates phospholipase C (PLC), leading to an increase in intracellular Ca2+ and activation of protein kinase C (PKC), both of which can promote glucose metabolism. Protolysis and gluconeogenesis cause blood sugar to rise.

Current status of drug research and development

Currently, clinical research on more than 40 GIPR target drugs is underway at home and abroad, including Eli Lilly, Amgen, Zhejiang Doyle Biotech, Huadong Medicine, Hangzhou Xianweida Biotech, etc. Drug forms include monoclonal antibodies, double antibodies, polypeptide drug conjugates (PDC), fusion proteins, etc.

On June 26 this year, Eli Lilly announced the latest phase II clinical data of the GLP-1R/GIPR/GCGR triple-target agonist Retatrutide in the treatment of obesity/overweight, and simultaneously published it in the New England Journal of Medicine, showing the weight loss effect of 48 weeks of treatment More than 20%, subverting the efficacy data of single-target and dual-target GLP-1 drugs.

In response to the development, production and research needs of GLP-1R, GIPR, and CGCR receptor agonist drugs, we have developed the following GPCR drug target cell lines, which simulate the relevant action mechanisms in vivo and can be quickly and conveniently detected through reporter gene methods, which can be used for candidate High-throughput screening of drugs, in vitro activity testing and QC testing at the release stage.