Treating diabetes can start with teaching insulin "chat"

Author: Zhu Lei (Hefei Institutes of Physical Science, Chinese Academy of Sciences)

Sometimes, too much enthusiasm is never appreciated.

For example, some insulins may have tried very hard but still cannot be recognized by the cells.

A picture of insulin and cells "talking to death" (Source: Fuyan's own)

When insulin cannot "chat" well with cells, it will cause problems in the transport of various energy metabolism raw materials, which is one of the main causes of type 2 diabetes. In medicine, this condition is called "insulin resistance."

So, can diabetes be cured by solving the problem of "insulin resistance"?

Insulin kills conversation - Insulin resistance

Insulin resistance occurs when the body becomes less responsive to normal levels of insulin in the blood.

Taking the liver as an example, insulin resistance causes the liver to be unable to respond to insulin signals, which weakens the inhibitory effect of insulin on glycogenolysis and gluconeogenesis, thereby causing blood sugar to rise; for muscles, it will cause the muscles to be unable to absorb blood sugar normally; in fat cells, insulin resistance will not only weaken the ability of fat cells to absorb glucose, but also cause the hydrolysis of triglycerides stored in the cells, thereby increasing the content of free fatty acids in plasma.

Insulin (Image source: homemade by the author)

Simple insulin resistance does not necessarily lead to diabetes, because high blood sugar stimulates pancreatic beta cells to secrete more insulin to maintain normal physiological functions. However, if other factors such as obesity, high blood lipids, inflammation and other factors damage pancreatic beta cells, there will be no way to secrete enough insulin, which will lead to a weakened absorption and utilization of glucose by human tissues, and it will be impossible to control blood sugar at a low level, so people will develop type 2 diabetes.

Why do existing diabetes treatments only treat the symptoms and not the root cause?

Diabetes itself is not fatal, but a series of complications caused by persistent high blood sugar are the main cause of death for diabetic patients, including acute diabetic ketoacidosis, lactic acidosis, hyperosmolar non-ketotic coma, etc.; chronic ones include diabetic nephropathy, cardiovascular disease, retinopathy, neuropathy, hypertension, diabetic foot, etc. Once complications occur, doctors can usually only take corresponding symptomatic treatments for certain special symptoms.

Therefore, the fundamental way to prevent and delay complications of diabetes is to control blood sugar. Currently, diabetes drug treatment focuses on controlling blood sugar and delaying the occurrence of related complications, but it cannot completely cure diabetes. The main reason is that the mechanism of action of most diabetes treatment drugs revolves around the blood sugar lowering function of insulin, reducing sugar intake and increasing sugar excretion.

For example, insulin, which accounts for the largest market share of diabetes drugs, is still regarded as the most direct and effective way to control blood sugar. This is because after developing type 2 diabetes, the pancreatic beta cells in the patient's body may have been damaged and unable to secrete enough insulin to control blood sugar.

The most popular DDP4 inhibitors currently work by inhibiting the degradation of the glucagon-like peptide GLP-1 in the body, which is a key factor in stimulating pancreatic beta cells to secrete insulin. In addition, there are GLP-1 analogs that can mimic the function of GLP-1 without being so easily inactivated. If the patient's pancreatic beta cells are severely damaged, SGLT-2 inhibitors can allow more blood sugar to be excreted through urine. If you want to control sugar intake, α-glucosidase inhibitors such as acarbose can reduce the absorption of sugars in the intestine.

However, these treatments do not address the root cause of type 2 diabetes - insulin resistance.

The mechanism of action of existing drugs for the treatment of type 2 diabetes (Image source: Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

Fortunately, there are still "emotional intelligence experts" who can guide insulin that can't "chat" - the High Magnetic Field Science Center of the Hefei Institutes of Physical Science, Chinese Academy of Sciences, has used advanced technology to transform the protein FGF21 that has the function of counteracting insulin resistance. The resulting protein variants have broad prospects in medicinal use and provide the possibility of "curing the root cause".

Let this protein teach insulin to "learn to chat"

In 2005, scientists discovered a protein called FGF21 that has the potential to reverse diabetes. It is an endocrine protein inherent to the human body, mainly secreted by tissues and organs such as the liver, and is involved in the regulation of human glucose and lipid metabolism. For diabetes treatment, FGF21 is like a generalist:

It can promote the expression of glucose transport receptor Glut1 in liver, fat and muscle tissues, and regulate oxidative stress response, promoting their uptake and oxidative utilization of excess blood glucose; it can act on the brain and is also a good hand in treating obesity; it can protect the function and survival of pancreatic beta cells.

More importantly, FGF21 can fight against insulin resistance. Studies have shown that the combination of FGF21 and insulin can achieve the effect of 1+1>2. This is undoubtedly good news for patients with advanced diabetes who cannot control blood sugar well even with insulin.

FGF21 structural dynamics (Image source: provided by the author)

Since FGF21 is so good and it has been discovered for some time, what affects its clinical application?

So far, clinical trials of FGF21-related drugs for the treatment of diabetes have all stopped at the first phase. The fundamental reason is that the stability of the natural protein FGF21 is very poor and it does not have good pharmacokinetic properties in the body. Studies have shown that the half-life of FGF21 in the body is less than 30 minutes, so to maintain an effective concentration, a large dose and frequency of administration are required.

However, recently, the High Magnetic Field Science Center of the Hefei Institutes of Physical Science of the Chinese Academy of Sciences located on the Hefei Science Island has received good news. Researchers have used an advanced technology that can study protein structure and stability - nuclear magnetic resonance spectroscopy to analyze the three-dimensional structure of FGF21 and analyze the reasons for its low structural stability:

There is a β-hairpin structure region that participates in the interaction with the FGF21 receptor. Its folding is in a dynamically changing balance, which makes FGF21 have two states: activated and inactivated. This characteristic may be involved in important physiological regulation in the normal physiological process of the human body and has very important significance. However, when FGF21 is used as a drug, we hope that its stability and activity are as high as possible. This characteristic of natural protein obviously cannot meet the needs of medication.

The researchers used protein engineering to slightly modify the natural amino acid sequence of FGF21, adding a "lock" to the β-hairpin structure that undergoes conformational changes - introducing a pair of disulfide bonds, and obtained a new FGF21 variant with ultra-high stability without affecting its structure and function. Subsequent diabetic mouse experiments showed that the new FGF21 variant has better ability to lower blood sugar, reduce body weight and reduce serum insulin than FGF21 in the treatment of diabetes in obese mice, and can completely reverse insulin resistance in fat cells.

Protein engineering of novel FGF21 variants (Image source: provided by the author)

Since this new FGF21 variant has high thermal stability, its activity can remain unaffected at a high temperature of 90 degrees, which is conducive to the preparation, storage and transportation of drugs. At the same time, its hypoglycemic activity is greatly improved. In diabetic mouse experiments, one-sixth of the dosage can achieve the function of lowering blood sugar, so it can effectively reduce the number of dosing and greatly improve the treatment plan for diabetic patients. At present, the industrialization process of this drug is progressing steadily, and agreements have been reached with many companies to jointly carry out a series of preclinical experiments. It is expected to apply for clinical approval and carry out experiments in 2 years.

Prevention is the most important thing to fight diabetes

Although there is some hope for drug development, prevention is the most important thing in controlling diabetes.

Current scientific research believes that an unhealthy lifestyle is the main culprit for insulin resistance. Obesity (especially abdominal obesity), lack of exercise, frequent intake of high-fat and high-sugar foods (such as milk tea, fried and barbecued foods, various beverages, etc.), smoking, and being over 45 years old... If you have one or more of these factors, your body will be more likely to develop insulin resistance or even diabetes.

In addition, drugs such as steroids and antipsychotics can also cause insulin resistance. Mothers who have had gestational diabetes are also at a higher risk of developing the disease.

Therefore, to prevent type 2 diabetes, you must first control your weight. You can simply calculate your BMI value [equal to weight (kg) divided by height (m) squared]. If the BMI value is greater than 25, you are overweight, and greater than 30, you are obese. The most effective way to prevent diabetes is to lose weight, reduce the intake of high-fat and high-sugar foods, change your sedentary lifestyle, and actively exercise. You should also have regular physical examinations to monitor various physical indicators such as blood sugar, blood lipids, and blood pressure. If you find any abnormalities, seek medical attention in time.

So my friends, for the sake of your health, during the upcoming Spring Festival holiday, you still have to control your diet and move your legs~

References:

[1] Zhu, L. et al. Dynamic folding modulation generates FGF21 variant against diabetes. EMBO Rep, e51352 (2020).

[2] Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J Clin Invest 115, 1627-1635 (2005).

[3] Degirolamo, C., Sabba, C. & Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 15, 51-69 (2016).

[4] Diabetes. World Health Organization (2020). https://www.who.int/news-room/fact-sheets/detail/diabetes

[5] Tan, SY et al. Type 1 and 2 diabetes mellitus: A review on current treatment approach and gene therapy as potential intervention. Diabetes & metabolic syndrome 13, 364-372 (2019).