[Nature] Hypoglycemic drugs are ineffective?

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Author: Daisy Guide: Acarbose is a commonly used anti-diabetic drug
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Recently, a study published in "Nature" showed that some bacteria in the mouth and intestines can inactivate it
.

Since most people have never been exposed to this drug, why do bacteria living in healthy people develop a very specific resistance mechanism to acarbose? Studies have found that the ability to inactivate acarbose may be due to competition between bacteria in the microbiota
.

A resistance mechanism that is very specific to the drug is widely spread among members of the human microbiome.
This mechanism may unexpectedly affect the response of diabetic patients to this drug and its impact on the microbiome
.

The human microbiome is a very interesting field of research, and we still have a lot to understand, how these bacteria interact and how they interact with us
.

Acarbose is a commonly used anti-diabetic drug
.

An α-glucosidase inhibitor is a complex oligosaccharide whose structure is similar to oligosaccharides.
This non-oligosaccharide "pseudo-oligosaccharide" can compete with oligosaccharides at the brush border of cells in the upper small intestine and compete with α -Glucosidase reversibly binds to inhibit the activities of various α-glucosidase enzymes such as maltase, isomaltase, glucoamylase and sucrase, and decompose starch into oligosaccharides such as maltose (disaccharide), maltotriose and The decomposition of dextrin (oligosaccharide) into glucose slows down, which slows down the decomposition of sucrose into glucose and fructose, thus slowing down the absorption of intestinal glucose, thereby alleviating postprandial hyperglycemia and reducing blood sugar
.

Now, new research in the laboratory of Princeton researcher Mohamed Donia shows that some bacteria in the mouth and intestines can inactivate acarbose and may affect the clinical manifestations of the drug and its effect on the bacterial members of the human microbiome
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The paper was published in "Nature" and an article entitled "The human microbiome encodes resistance to the antidiabetic drug acarbose" was published: https:// Mohamed Donia, associate professor of Princeton’s Department of Molecular Biology, said: “A large number of studies have clearly shown that the human microbiome, the collection of microorganisms that live in and within the human body, can affect our health, disease, and response to various therapeutic interventions.
Ability
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However, it is still relatively rare to define this effect at the molecular and mechanistic level, which is exactly what we set out to do in this research
.

"Acarbose was originally derived from living in the soil.
Isolated from bacteria
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These bacteria secrete acarbose to hinder the growth of other types of bacteria in their environment, giving them a competitive advantage
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Both natural bacteria and the drug acarbose can inhibit α-glucosidase, an enzyme expressed by humans and bacteria, to break down complex sugars into forms that can be metabolized into energy
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However, the bacteria that produce acarbose also express an antidote to it-an enzyme called acarbose kinase, which can modify acarbose to inactivate it
.

Donia and his colleagues, led by Dr.
Jared Balaich, hypothesized that the ability to inactivate acarbose may not be unique to soil bacteria, but may also be used by bacteria in the human microbiome
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With the help of Abhishek Biswas, a research software engineer working with Donia, the research team searched the human microbiome for DNA sequences to determine the enzymes they predicted would inactivate acarbose
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Balaich said: "Our search identified 70 potentially related genes
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" To explore the role of these newly identified genes, the researchers synthesized the DNA sequences of selected gene subsets and purified the nine enzymes produced
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Further studies have shown that, except for one test enzyme, all test enzymes have functions similar to acarbose kinase and block the activity of acarbose in a test tube
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When the most common gene of these newly discovered enzymes was added to an oral bacteria that usually lacked acarbose-inactivating enzymes, the bacteria became resistant to the effects of acarbose
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Finally, in collaboration with Princeton crystallography facility manager Philip Jeffrey and associate professor Alexei Korennykh researchers in the laboratory, the team used X-ray crystallography to study how this newly discovered enzyme interacts with acarbose and showed that it The structure is similar to acarbose kinase of soil bacteria
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Researchers refer to the newly discovered and characterized family of human microbial histone proteins as "microbiome-derived acarbose kinases," or Maks
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Bacteria expressing MAKs may be resistant to acarbose
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Researchers have shown that Maks are rich in bacteria in the human digestive tract: they are mainly found in the three major categories or phyla of oral and intestinal bacteria, all of which are widely present in people all over the world
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This suggests that many people may carry bacteria that can neutralize important anti-diabetic drugs
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Donia said: "It doesn't make sense to us: Given that most people have never been exposed to this drug, why do bacteria living in healthy people develop a very specific resistance mechanism to acarbose? "In the process of investigating this issue, Donia and colleagues discovered at least one type of bacteria in the human microbiome that can produce compounds similar to acarbose
.

This finding suggests that the ability to inactivate acarbose may be due to competition between bacteria in the microbiota
.

In order to explore whether Maks might affect the effectiveness of acarbose in treating diabetic patients, Donia enlisted the help of Liping Zhao, professor of applied microbiology at Rutgers University.
He recently completed a human clinical trial to explore diet and gut microbiome.
And type II diabetes
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Fortunately, a small percentage of patients in this trial were treated with acarbose without any additional intervention-this is an ideal data set to explore the potential impact of Maks on acarbose treatment
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"Re-analysis of the data in this [study] showed that the gut microbiome has the ability to inactivate acarbose through the kinase discovered in Dr.
Donia’s laboratory compared to the group of patients whose gut microbiome does not have this ability.
The group of patients get less benefit from the medicine,” Professor Zhao said
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Although this finding should be interpreted with caution due to the small number of patients, it may indicate an unexpected interaction between the human microbiome and clinically important drugs
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In the future, larger clinical trials will be needed to determine how the presence of MAKs in the microbiome affects the performance of acarbose on diabetes
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Donia said: "We have known for a long time that bacteria use acarbose to compete for carbohydrates in the soil, and we humans use this molecule to treat diabetes
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In our research, we found that bacteria seem to also use acarbose-like molecules to compete in the human body, leading to a very specific drug resistance mechanism that spreads widely among members of the human microbiome
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This mechanism may unexpectedly affect the response of diabetic patients to this drug and affect its effect on the microbiome
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The revelation of this complex story raises more questions than answers, and we are very excited to continue exploring its molecular details
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"Balaich said, "I think this study just shows that the human microbiome is a very interesting research area, and we still have a lot to understand how these bacteria interact and how they interact with us
.

"Reference material: https://medicalxpress.
com/news/2021-12-oral-gut-microbes-inactivate-antidiabetic.
html Note: This article is intended to introduce the progress of medical research and cannot be used as a reference for treatment plans
.

If you need health guidance , Please go to a regular hospital for treatment
.

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