Let's talk about hypoglycemic drugs.
Sigrenastat.
In the previous article (elaborating on the story behind the hypoglycemic drug - thiazolidinedione (TZD)), there was a mention of siglitadine, a new hypoglycemic drug.
Chiglitazar sodium, trade name "dilopin", is a new hypoglycemic drug independently developed by China (Chipscreen Biosciences) with independent intellectual property rights, which conducted phase clinical research in 2005, completed phase clinical trials in 2012, and was approved for marketing in China on October 19, 2021 for the treatment of type 2 diabetes.
What kind of medicine it is, let's talk about it in detail today.
The story of three grocery stores.
Before talking about siglitastat, tell a story.
In a crowded street, three grocery stores were opened, one selling rice and grain, one selling tea, and one selling snacks. With more and more people coming and going, the three grocery stores are somewhat in short supply. In order to meet the needs of consumers, a regulatory authority came up with a way to require stores that sell snacks to be open 24 hours a day. At the beginning, the owner of the snack seller felt that he could make more money and work hard to meet people's consumption needs. But day after day, the boss felt so tired and didn't want to do this, so he responded to the department and asked to shorten the business hours, but the leader did not approve it. Since then, the snack seller has started to go bad, selling some expired food, causing diarrhea among the buyers. After verification, the leaders decided to readjust the plan, that is, the rain and dew were evenly wet, so that each of the three stores worked overtime appropriately, and each store worked overtime for 2 to 3 hours a day, so as to decompose the market pressure, which not only met the needs of consumers, but also allowed the three stores to increase their revenue at the same time, and not to be overworked.
Peroxisome proliferators activate receptors.
Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that regulates glycolipid metabolism and energy metabolism in vivo, which contains three receptors, δ and the corresponding ligand to perform different functions, and their functions are both overlapping and different. Just like the three grocery stores in the story above.
PPAR- is mainly expressed in the liver, and PPAR- agonists induce the transcription of lipid metabolism-related genes in the liver, enhance the oxidation of fatty acids, and reduce triglyceride (TG) synthesis, thereby reducing the content of fatty acids and triglycerides in the liver.
PPAR- is mainly expressed in adipose tissue, and after PPAR- activation, it regulates the expression and phosphorylation of signaling molecules through phosphatidylinositol kinase, protein kinase, etc., inhibits hepatic gluconeogenesis, increases fatty acid catabolism and synthesis in adipose tissue, and thus increases insulin sensitivity in peripheral tissues.
PPAR-δ is predominantly expressed in skeletal muscle, and when PPAR-δ activated, lipid synthesis is reduced.
As shown in the figure above, the drugs targeting PPAR- are mainly fibrates (such as fenofibrate), which are mainly used to lower triglycerides;
The drugs for PAR- are mainly thiazolidinediones (TZD) drugs, which are mainly used to improve insulin resistance and lower blood sugar, and the corresponding mechanism has been discussed in the previous part;
As for PPAR-δ, there is currently no corresponding drug.
Siglitazide.
PPAR and δ are like three grocery stores, each with its own role and the same efficacy. If one of the receptors is activated for a long time, over time, the efficacy will inevitably decrease, and even bring corresponding adverse reactions, such as long-term use of large doses of TZDS, which may increase water and sodium retention, resulting in edema, fractures, congestive heart failure, etc., just like letting a grocery store not rest for a long time, and over time, it will be counterproductive.
Only when the rain and dew are evenly wet, everyone works overtime, and everyone gets a little benefit, can this kind of business be long-lasting.
Therefore, the advent of siglitat sodium is a trade-off, siglitazide sodium is a PPAR total agonist, which can moderately activate ppar, δ receptors at the same time, and the activation of the three subtypes is relatively balanced, which can not only improve insulin resistance, lower blood sugar, but also lower blood lipids, and more importantly, can also reduce the potential adverse effects caused by single and over-activation (such as edema, fracture and other risks).
Summary. In conclusion, siglitazide sodium, as a new hypoglycemic drug independently developed in China, has obvious advantages, which can not only improve blood glucose, but also regulate blood lipids at the same time, and has fewer adverse reactions than TZDS. However, there is still a lack of large-scale cardiovascular-related studies, and further observation is needed for further clinical application in the later stage.