The new hypoglycemic path is discovered!Insulin hundred years of domineering status or challenge!

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The new hypoglycemic path is discovered!Insulin hundred years of domineering status or challenge!

2022-01-15 06:04:26 10 ℃

"Diabetes is an unprecedented disease, worse, the situation may be out of control."

In the 21st century, diabetes have long been swept around the world, and with the change of life and eating habits, it has become a third largest factor affecting human health after the heart of cerebral vascular disease and malignant tumors. In China, adults have more than 114 million diabetic patients, accounting for one quarter of patients with diabetes around the world.

This is an ancient disease. In the Chinese medicine books earlier than 2000 years, there is a record of this disease. The diaper described in the book is sweet, and there is a thirst, drink, multiple urine, and more clinical symptoms, and later patients tend to be tired and thin. Obesity is closely related to diabetes.

However, the understanding of the ancients and the essence of the disease, there is still a small gap until the 19th century. In 1869, a German doctor, Paul Langerhans, found that there is "islet" in the human pancreas, and can secrete insulin. This uncovered the sequence of diabetes in modern times.

In 1922, Frederick Banting et al. First successfully extracted insulin from the animal pancreas and applied to the clinical, saved the lives of countless diabetes, and Banstea also won the Nobel Medicine Award. . Insulin discovery and use, the door to life and hope is opened for millions of diabetes patients. Since then, insulin produced in the pancreas is considered to be the main strategy for treating diabetes.

In the next 100 years, insulin is always in the status of "hegemony" in diabetes treatment. In the near future, another hormone molecule derived from fat "challenges this overlord status."

On January 4, 202, the researchers of the Solk Institute of the United States were published on the Cell Sub-magazine CELL Metabolism. They found that a substance-exogenous fibroblast growth factor 1 (FGF1) produced in adipose tissue can regulate blood sugar by inhibiting fat decomposition. It does different mechanisms with insulin so that FGF1 can reduce blood sugar in patients with insulin resistance in patients with insulin resistance.

With people's eating, fat and glucose into blood, insulin is transported from blood into muscle and adipose tissue to utilize or store. When insulin deletion or sensitivity is insufficient, the patient's blood in the blood is abnormally increased, exacerbating diabetes and obesity.

The previous studies have shown that the injection of FGF1 can significantly reduce the blood glucose level of mice, and chronic FGF1 treatment can alleviate insulin resistance, but the working principle is a mystery. The research team investigated the mechanism behind these phenomena and the links between them.

First, they found that FGF1 and insulin can inhibit fat decomposition and regulate the production of liver glucose. These similarities have made the research team can't help but doubt: Does FGF1 and insulin use the same signal path to regulate blood sugar?

It is well known that insulin inhibits fat decomposition by PDE3B. Considering that PDE3B is an enzyme that starts signaling pathway, a series of similar enzymes were tested for this study group, surprisingly, FGF1 was found to use a different path -PDE4 to inhibit CAMP-protein kinase A axes. This is separated from the inhibitory effect of insulin by PDE3B.

Image Source: Cell Metabolism

Finally, the researchers conducted research on the molecular mechanisms, and found that FGF1 regulatory fat decomposition was achieved by inducing specific phosphorylation of PDE4D S44 sites, and the site was adjusted by the feed-fast cycle.

Insulin and FGF1 regulates blood sugar mechanism

(Source: Cell Metabolism)

"This mechanism can be counted as a second cycle pathway with all the advantages of the parallel path." The first author, the Evans Laboratory Postdoctoral researcher Peencer Sancar said, "in insulin resistance The signal conduction of insulin is affected. However, by using different signal cascading, one of them can be operated normally. "In the case of insulin resistance, the FGF1 will inhibit PDE4 Fat decomposition reduces blood glucose levels.

(Source: Solk Institute)

It has to be said that this research "refreshing" people have awareness of blood sugar regulation, so that diabetes treatment has moved towards a new journey.

Although the molecular mechanism of blood glucose regulation has been placed by scientists, therapeutic drugs are still a significant difficulty in diabetes treatment. Among them, the treatment of type 2 diabetes is likely to use insulin, and the treatment is just tricky.

TIRZEPATIDE is a new type of glucose-dependent promotulin polypeptide (GIP, also known as a gastric inhibitory polypeptide) receptor and glucagon-like peptide-1 (GLP-1) receptor dual agonist. GIP and GLP-1 are hormones secreted into intestinal secretion, which can promote insulin secretion. TIRZEPATIDE integrates the effects of two promotulin to a single molecule, representing a type of new type of drug for treating type 2 diabetes. (Source: Diabetes Metab Syndr Obes.)

Recently, TIRZEPATIDE Treatment of Type 2 Diabetes Phase 3 SURPASS-4 (NCT03730662) clinical trials were published in the international top medical period "willow knife", and the study found that in a population of type 2 diabetes and high heart, and sweet Compared with the long-term treatment of spermulin, TirzePatide has a more significant blood glucose in long-term treatment, and the incidence of hypoglycemia is lower, and the safety is higher!

This 3-phase trial was carried out in 187 centers in 14 countries, and eventually included in 2002 adult patients. These patients have received any combination of metformin, sulfonylurea drugs or SGLT2 inhibitors, but HBA1C does not meet the standard (7.0% -10.5%) and have determined that there is an increase in cardiovascular disease or cardiovascular event. Patients were randomly packets, and 3 of them received a weekly subcutaneous injection of TirzePAtide 5 mg, 10 mg, and 15 mg, and the other group received a subcutaneous injection of sweet insulin.

At 52 weeks, the HBA1C reduction rate of different dose injection groups in TirzePatide was significantly higher than that of the metexin group. Moreover, the TirzePAmeDe treatment group HBA1C level continued to decrease for up to 104 weeks. Compared with Ganzuzin, the Tirzepath group daily, pre-meal and post-meal average blood sugar levels lower than baseline. These results indicate that TIRZEPATIDE has better efficacy than gum insulin.

In addition, at 52 weeks, the average systolic pressure and diastolic pressure of the TIRZEPATIDE group were reduced, while the meteoridin is high. The serum triglyceride, low density lipoprotein cholesterol and non-high density lipoprotein cholesterol levels were reduced in dose dependence. Compared to the sweet insulin group, the Trirzepath group did not increase the risk of MACE-4 events (cardiovascular death, myocardial infarction, stroke, unstable angina).

(Source: The Lancet)

In general, TIRZEPATIDE exhibits superiority and sustainability in overall blood glucose control and weight loss than mellitus and highly blood vessel risk. It is reported that Li Jing Company has submitted the New Drug Application (NDA) of TirzePatide (LY3298176) to the US Food and Drug Administration (FDA), and the company also submitted a marketing authorization application for TIRZEPATIDE to the European Drug Administration (EMA). MAA).

We hope that researchers in the future researchers are safe and effective as TIRZEPATIDE, and benefiting millions of diabetes patients.

references:

[1] fgf1 and insulin control lipolysis by convevergent Pathways. Cell Metab. 2022 Jan 4; 34 (1): 171-183.E6. DOI: 10.1016 / J.cmet.2021.12.004.

[2] Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial Lancet 2021 Nov 13; 398 (10313):.. 1811 --1824. DOI: 10.1016 / S0140-6736 (21) 02188-7.

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