When it comes to how type 2 diabetes is caused, there are two main factors that come to mind:
First, the islet β cells in the pancreas cannot effectively secrete enough insulin to lower blood sugar--- insulin secretion is insufficient.
Second, the "sensitivity" of blood glucose regulatory organs other than the pancreas, such as the liver and muscles, to insulin decreases, resulting in "reduced work efficiency" of insulin --- insulin resistance.
There is no doubt that very few people associate type 2 diabetes directly with our gut.
But in fact, medical research in recent years has found that a significant proportion of type 2 diabetes is related to "gut factors". In addition, several new classes of hypoglycemic drugs that specifically act on this pathway are playing an increasingly important role in the treatment of type 2 diabetes!
In this article, we will introduce you to this important new knowledge about type 2 diabetes.
An important subtype of type 2 diabetes mellitus --- incretin insufficiency
In fact, medical experts have long observed a very interesting phenomenon: at the same blood sugar concentration, [oral glucose] stimulates the secretion of much more insulin than [intravenous glucose]!
This phenomenon means that in addition to the "increase in blood sugar" itself, which can stimulate insulin secretion, there should be some other factors in our body's digestive tract that can stimulate insulin secretion.
Later medical studies have confirmed that the secretion of [incretin] by the intestine is the key substance that can stimulate insulin secretion. In physiological conditions, incretin contributes about 50% to 70% of total insulin secretion. It is no exaggeration to say that this is one of the most important substances in the body to promote insulin secretion!
It is not difficult to understand how incretin works in the human body: after the start of eating, the food in the gastrointestinal tract will directly stimulate the secretion of incretin, and incretin will further promote the secretion of insulin by β islet cells, so that the body will have enough insulin to lower blood sugar after meals.
In other words, the secretion of postprandial insulin not only depends on the effect of food to raise blood sugar, but also depends on the stimulation of incretin. If our digestive tract is unable to produce enough incretin after eating, the secretion of postprandial insulin will also be affected, resulting in a postprandial increase in blood sugar.
That's why we say that with type 2 diabetes, the problem can be in the "gut".
In fact, the latest medical concept in recent years believes that type 2 diabetes can be further subdivided into different subtypes, such as [insulin deficiency type], [insulin resistance type] and so on. Among them, there is a special subtype called "incretin insufficiency", which refers to this part of type 2 diabetes that causes postprandial blood sugar to rise because it cannot produce enough incretin.
Epidemiological surveys show that in mainland China, more than half of patients with type 2 diabetes mainly manifest themselves as "elevated blood sugar after meals". Among these patients, most of them actually have the problem of "incretin insufficiency".
Speaking of which, some people may ask: how can I know if I have the problem of [incretin insufficiency]?
At present, it is not clinically possible to directly detect the level of postprandial incretin secretion, and the so-called "incretin" does not specifically refer to a specific hormone, but includes [glucagon-like peptide-1 GLP-1] and [glucose-dependent insulin secretion peptide GIP].
Therefore, whether there is "incretin insufficiency" or not depends more on whether the secretion of insulin after meals is affected!
For example, the most typical scenario is that the fasting blood glucose is normal and the fasting C-peptide is at a normal level of ≥1.1 ng/mL, which means that the patient's basal insulin secretion is acceptable. However, if the postprandial blood glucose rises, and at the same time, the postprandial C-peptide secretion is insufficient or significantly delayed, then there is a high probability that there is insufficient secretion of postprandial incretin.
In addition to lowering blood sugar, incretin also plays an important role
The reason why incretin has received more and more attention in the field of diabetes treatment in recent years is that in addition to its blood sugar regulation effect, incretin also has some important roles in other aspects.
For example, in addition to pancreatic islet cells, GIP and GLP-1, two incretin receptors, are also widely distributed in areas of the central nervous system that are responsible for regulating energy balance.
For example, these receptors are distributed in the hypothalamus, which is responsible for regulating appetite, feeding behavior, and controlling gastric emptying, and when these receptors are activated by incretin, appetite and feeding behavior will be significantly reduced, and the emptying effect in the stomach will also be significantly reduced. In this way, it can bring significant weight loss to the human body.
Because of this, a variety of hypoglycemic drugs developed based on incretin have been shown to have significant weight loss effects, and some drugs have even been approved specifically for weight loss (such as semaglutide, liraglutide).
For example, incretin is also believed to have the effect of regulating blood lipids and protecting the cardiovascular and renal branches.
Studies have found that GLP-1, an incretin, can indirectly affect lipid metabolism processes in the body, improve insulin sensitivity in adipose tissue, and affect the level of free fatty acids in the body.
At the same time, GLP-1 also has the effect of reducing myocardial tissue damage and maintaining cardiac ejection function.
In addition, GLP-1 can also promote angiogenesis and vascular endothelial cell proliferation by increasing nitric oxide.
All in all, the research on incretin has led to the following inspirations:
First, in general, incretin is a class of substances that are "beneficial" to the body's metabolism.
Incretin deficiency is one of the causes of type 2 diabetes.
Second, in addition to being beneficial to blood sugar control, incretin also has the effects of weight loss, lipid regulation and heart and kidney protection.
It is these effects other than sugar control that make the hypoglycemic drugs developed based on incretin gradually become the "star drugs" in the field of hypoglycemic therapy.
3 new types of hypoglycemic drugs based on incretin
At present, in the field of hypoglycemic therapy in the world, there are three main classes of drugs developed based on the path of incretin:
First, [DPP-4 inhibitors] represented by vildagliptin, sitagliptin, linagliptin, saxagliptin, alogliptin, etc., are also known as "liptin" hypoglycemic drugs.
These drugs are commonly used for postprandial blood glucose control by inhibiting DPP-4, thereby reducing the inactivation of GLP-1 in the body and increasing the level of endogenous GLP-1.
Second, the [GLP-1 receptor agonists] represented by liraglutide, exenatide, dulaglutide, benaglutide, lisinatide, losenatide, etc., are also known as "peptide" hypoglycemic injections.
This type of drug is mainly administered by subcutaneous injection, but among them, the oral version of semaglutide has just been approved for marketing in the mainland. These drugs do not increase the level of GLP-1, an incretin, in the body, but directly activate the receptors of GLP-1, so as to continue to exert the "benefits" that GLP-1 can bring.
As early as 2020, the "Chinese Expert Recommendations for the Clinical Application of Novel Antihyperglycemic Drugs to Improve Cardiovascular and Renal Outcomes" clearly pointed out that GLP-1 receptor agonists can significantly improve cardiovascular and renal clinical outcomes, and have a good safety profile. Today, it is recommended as one of the preferred hypoglycemic drugs for patients with type 2 diabetes with high heart and kidney risk!
Chinese Expert Recommendations on the Clinical Application of Novel Antihyperglycemic Drugs to Improve Cardiovascular and Renal Outcomes
On the other hand, the injectable and oral versions of semaglutide have been approved in many countries and regions around the world for weight loss in obese people.
Third, [dual agonist of GIP and GLP-1 receptors] represented by tirpatide.
Although this kind of drug has not yet been officially marketed in the mainland, it is characterized by drugs that can act on two kinds of incretin receptors at the same time, and it has shown the potential to surpass [peptide" hypoglycemic injection in terms of hypoglycemic and weight loss. Even, some people call this drug the "hypoglycemic ceiling".
Judging from the current clinical application status, among the above three types of drugs, because the "liptin" hypoglycemic drugs have been on the market at the earliest, the price and medical insurance policies are relatively "friendly", and they are also oral drugs, many "old patients" are still using them.
For patients with type 2 diabetes who are typically "incretin insufficiency" with postprandial blood sugar elevation, "liptin" oral drugs are actually a good choice to control postprandial blood sugar.
The ["peptide" hypoglycemic injection, represented by semaglutide, is undoubtedly one of the most popular "star drugs" in the treatment of type 2 diabetes at this stage.
According to the latest medical concepts, these drugs should be regarded as one of the "preferred hypoglycemic drugs" for patients with type 2 diabetes who are overweight/obese or who have a high risk of heart and kidney.
With the availability of an oral version of semaglutide, it is believed that more patients will start using this type of drug.
Finally, as of January 2024, the bienteral secretin receptor agonist --- "tirpatide", which has not yet been officially marketed in the mainland, is generally regarded as a strong competitor or even a potential surpass of ["peptide" hypoglycemic injections] in the world! In the future, this kind of drug may hope to bring more "surprises" to the treatment of type 2 diabetes.
To sum up, fasting blood glucose and fasting C-peptide are normal, but type 2 diabetes, which is mainly characterized by increased postprandial blood glucose and decreased or delayed postprandial C-peptide, mostly belongs to the subtype of "incretin insufficiency" in clinical practice!
In this part of the patient, insufficient secretion of postprandial incretin is often one of the important causes of type 2 diabetes.
In terms of treatment, the key at this stage is to make good use of new hypoglycemic drugs developed based on the incretin mechanism such as "liptin" hypoglycemic drugs and "peptide" hypoglycemic injections.
(Note: All prescription medications need to be used under the guidance of a doctor!)
[References]
1. Guidelines for the Management of Metabolic Diseases of the National Standardized Center for the Management of Metabolic Diseases (MMC) (Second Edition) Chinese Journal of Endocrinology and Metabolism, Vol. 39, No. 6, June 2023
2. Guidelines for the rational use of drugs in the primary level of type 2 diabetes mellitus, Chinese Journal of General Practitioners, June 2021, Volume 20, Issue 6
3. Guidelines for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition) Chinese Journal of Diabetes Mellitus, April 2021, Vol. 13, No. 4
4. Clinical application of new antihyperglycemic drugs to improve cardiovascular and renal outcomes, Chinese expert recommendations, Chinese Journal of Circulation, March 2020, Vol. 35, No. 3
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