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A molecular link between the high blood sugar level and the infection control system of the body has been discovered. In uncontrolled diabetes, high blood sugar level restrains the destructive molecules that affect the natural defense mechanism of the body.
Blood sugar breaks down into harmful molecules such as dicarbonyls that interfere with the β-defensins, the infection controlling antimicrobial peptide.
A team of researchers, “The Case Western Reserve Team” discovered two important dicarbonyls methylglyoxal (MGO) and glyoxal (GO) that can alter the structure of the β-defensin-2 lessening their ability to fight with inflammations and infections.
These findings may provide a new approach to develop and enhance the antimicrobial peptide drugs for people with diabetes who are unable to control infections and their wounds heal slowly.
The senior author of this study, Wesley M. Williams from the Department of the Biological Science, Case Western Reserve University, said that in uncontrolled diabetes, these dicarbonyls weaken the hBD-2 function along with the human β-defensins.
Williams and co-author Kiselar performed a comparative analysis of Mass spectra, bacterial killing potential and the immune cell attracting potential of the dicarbonyl-treated human β-defensin-2 (hBD-2) with that of the untreated hBD-2.
During this analysis, hBD-2 was first exposed to the dicarbonyls MGO and GO. The mass spectral analysis reveals that the methylglyoxal was more reactive than the glyoxal and, therefore, subsequent bacterial killing experiment and chemotactic experiments were performed using the methylglyoxal-treated human β-defensin-2.
Dicarbonyls exposed to the hBD-2 binds to the several amino acid residues as well as irreversibly to the two Arginine residues located at the surface of the hBD-2 peptide and thus influencing its structure and function.
During a comparative study of the bacterial killing ability, researchers found that untreated hBD-2 was much more effective in killing the bacteria while dicarbonyls-treated hBD-2 was unable to prevent bacterial growth because of the impaired function of the hBD-2.
In the last steps, researchers compared the effect of methylglyoxal on the hBD-2’s role in the immune system. In the immune defense system, defensins not only inhibit the entry of microbes into the body but also alter the immune system of the invaders. These mechanisms constitute the adaptive and innate immune system that can identify and destroy the microbes.
In the immune defense system, defensins act as chemoattractants attracting specific types of immune cells to activate the immune response called adaptive immunity.
Therefore, Williams and Kiselar along with a professor of physiology and biophysics George Dubyak examined the chemo-attracting ability of the MGO-treated hBD-2 and untreated hBD-2. In which they found that untreated hBD-2 attracted the human immune cells while MGO-treated hBD-2 was unable to attract the human immune cells.
However, in the next step, it is necessary to carry out the experiments in an animal model or on human tissue to verify these harmful effects of the dicarbonyls on the β-defensins among the people with diabetes. In addition, dicarbonyls may also affect human antimicrobial peptides other than β-defensins and ultimately their antimicrobial and chemoattractive functions get altered.
Williams also said that our body has defense mechanisms to balance such dicarbonyls but in people with chronic diseases such as diabetes, these defense mechanisms may be overwhelmed. Disturbed mechanism of balancing the dicarbonyls results in the accumulation of dicarbonyls that eventually overwhelms the ability of β-defensins against the inflammation and infection.
For now, blood sugar levels can be controlled by diet and medicine that maintains the dicarbonyls-β-defensins at a particular level. Therefore, there is a great need to develop an effective antimicrobial peptide and antihyperglycemic drugs that are not affected by the dicarbonyls and also helps to neutralize the dicarbonyls.
Reference: Journal of Public Library of Science