High blood sugar in diabetic patients can unleash destructive molecules that interfere with the body’s natural infection-control defenses, a new study has found.
The study by scientists from the Case Western Reserve University may have uncovered a molecular mechanism that sets into motion dangerous infection in the feet and hands often occurring with uncontrolled diabetes.
Researchers found that high blood sugar unleashes destructive molecules that interfere with body’s immune system. The harmful molecules – dicarbonyls – are breakdown products of glucose that interfere with infection-controlling antimicrobial peptides known as beta-defensins.
Scientists discovered how two dicarbonyls – methylglyoxal (MGO) and glyoxal (GO) – alter the structure of human beta-defensin-2 (hBD-2) peptides, hobbling their ability to fight inflammation and infection.
The findings could ultimately contribute important insights into developing and enhancing antimicrobial peptide drugs for people with diabetes who have hard-to-control infections and wounds that are slow to heal.
“If our findings hold up in future in vivo animal experiments and in human tissues, we will have solid evidence for how this dicarbonyl mechanism works in the setting of uncontrolled diabetes to weaken hBD-2 function, and that of other beta-defensins,” said senior author Wesley M Williams, from the Case Western Reserve University.
In experiments researchers compared the mass spectra, the bacterial-killing potential and the immune cell-attracting ability of dicarbonyl-treated hBD-2 with untreated hBD-2.
This beta-defensin was initially exposed to the activities of two key dicarbonyls – MGO and GO, both of which are known to increase in humans with high blood sugar.
First the investigators compared the mass spectra for the dicarbonyl-exposed hBD-2 with untreated hBD-2.
In the dicarbonyl-exposed hBD-2, they found that in addition to binding to several other amino acid residues, the dicarbonyl irreversibly binds to two positively charged arginine amino acids located near the surface of the hBD-2 peptide.
The importance of positive or negative charges in a protein is that they can influence the protein’s function.
Next, the investigators compared dicarbonyl-treated hBD-2 to untreated hBD-2 in their ability to kill gram-negative bacteria. The untreated hBD-2 is quite effective in killing gram-negative bacteria, while dicarbonyl-exposed hBD-2 greatly impaired this defensin’s ability to stop onslaught of bacteria.
“In the petri dish of hBD-2 treated with dicarbonyl, we saw a roughly 50 per cent reduction in the ability of hBD-2 to inhibit growth or kill the bacteria,” Williams said.
“Experiments were repeated multiple times using several bacterial strains, and we found a loss of function in all cases,” he said.
“It establishes that the antimicrobial function was being significantly impeded by the MGO dicarbonyl,” Williams said.