lactoferrin and Diabetes-Mellitus

Lactoferrin and lysozyme are two important, naturally occurring antibacterial proteins found in saliva, nasal secretions, milk, mucus, serum and in the lysosomes of neutrophils and macrophages. Both proteins bind specifically to glucose-modified proteins bearing advanced glycation endproducts (AGEs). Exposure to AGE-modified proteins blocks the bacterial agglutination and bacterial killing activities of lactoferrin and also inhibits the bactericidal and enzymatic activity of lysozyme. Peptide mapping by AGE ligand blot revealed two AGE-binding domains in lactoferrin, and a single AGE-binding domain in lysozyme. None of these AGE-binding domains displayed any significant homology in their primary sequences; however, a common 17-18 amino acid cysteine loop motif (CX15-16C) was identified among them, which we named an ABCD motif (AGE-Binding Cysteine-bounded Domain). Similar domains are also present in other antimicrobial proteins such as defesins. Hydrophilicity analysis indicated that each of these ABCD loops is markedly hydrophilic. Synthetic peptides, corresponding to these motifs in lactoferrin and lysozyme, exhibited AGE-binding activity. Since diabetes is associated with abnormally high levels of tissue and serum AGEs, the elevated AGEs may inhibit endogenous antibacterial proteins by binding to the conserved ABCD motif, thereby increasing susceptibility to bacterial infections in diabetic individuals. These results may provide a basis for the development of new approaches to prevent diabetic infections.

Topics: Amino Acid Sequence; Bacterial Infections; Diabetes Complications; Diabetes Mellitus; Glycosylation; Humans; Lactoferrin; Ligands; Molecular Sequence Data

Topics: Adult; Asthma; Bifidobacterium; Breast Feeding; Child, Preschool; Diabetes Mellitus; Dietary Supplements; Enterocolitis, Necrotizing; Female; Gastrointestinal Microbiome; Health; Humans; Infant; Infant, Newborn; Lactobacillus; Lactoferrin; Microbiota; Milk, Human; Neonatology; Oligosaccharides; Parturition; Pregnancy; Probiotics; Proteobacteria

Immunodiffusion assays were used to examine lactoferrin (LF) in the mixed saliva of 1026 patients and 553 apparently healthy individuals. Elevated salivary LF levels were found in respiratory and digestive diseases and diabetes. It is concluded that this non-invasive immunochemical assay is promising in the screening and monitoring of persons during their health examination.

Topics: Adult; Biomarkers; Diabetes Mellitus; Digestive System Diseases; Female; Humans; Lactoferrin; Male; Middle Aged; Neoplasms; Respiratory Tract Diseases; Saliva; Young Adult

Why diabetes is associated with abnormally high susceptibility to infection remains unknown, although two major antibacterial proteins, lysozyme and lactoferrin, have now been shown to specifically bind glucose-modified proteins bearing advanced glycation end products (AGEs). Exposure to AGE-modified proteins inhibits the enzymatic and bactericidal activity of lysozyme, and blocks the bacterial agglutination and bacterial killing activities of lactoferrin. Peptide mapping revealed a single AGE binding domain in lysozyme and two AGE binding domains in lactoferrin; each domain contains a 17- to 18- amino acid cysteine-bounded loop motif (CX15-16C) that is markedly hydrophilic. Synthetic peptides corresponding to these motifs in lysozyme and lactoferrin exhibited AGE binding activity, and similar domains are also present in other antimicrobial proteins. These results suggest that elevated levels of AGEs in tissues and serum of diabetic patients may inhibit endogenous antibacterial proteins by binding to this conserved AGE-binding cysteine-bounded domain 'ABCD' motif, thereby increasing susceptibility to bacterial infections in the diabetic population.

Topics: Amino Acid Sequence; Animals; Anti-Infective Agents; Binding Sites; Conserved Sequence; Diabetes Mellitus; Glycation End Products, Advanced; Humans; Lactoferrin; Molecular Sequence Data; Muramidase; Protein Binding

Using immunofluorescence, it has been shown that leukocyte thermostable alpha-glycoprotein (LTAG) and leukocyte beta-globulin (LBG) are, like lactoferrin, components of polynuclear leukocytes. These proteins were found in the perinuclear zone, cytoplasm membrane and extracellularly. Serum LTAG concentration increases in immune inflammatory diseases. In severe forms of diabetes and glomerulonephritis there is a rise in LBG concentration. The biological role of LTAG and LBG is unknown.

Topics: Beta-Globulins; Blood Proteins; C-Reactive Protein; Diabetes Mellitus; Fluorescent Antibody Technique; Glomerulonephritis; Glycoproteins; Granulocytes; Humans; Lactoferrin; Neutrophils

Reduced bacterial killing by polymorphonuclear leucocytes has been reported in patients with diabetes mellitus. Whether this is due to reduced content of bactericidal granular proteins has not been determined. We therefore immunochemically measured the content of myeloperoxidase, lactoferrin, lysozyme, cathepsin G and elastase in polymorphonuclear leucocytes from 50 insulin-treated diabetic patients. The peroxidase activity was also measured. Normal contents of myeloperoxidase and lactoferrin as well as normal peroxidase activity were found. The average contents of cathepsin G, elastase and lysozyme were 2.5, 3.2 and 2.6 micrograms/10(6) polymorphonuclear leucocytes, respectively, and thus 14, 45 and 18% higher than the contents of normal polymorphonuclear leucocytes. The results indicate that reduced intracellular killing of bacteria demonstrated in previous studies in diabetic patients does not appear to be related to a reduction in the content of bactericidal proteins.

Topics: Age Factors; Blood Bactericidal Activity; Cathepsin G; Cathepsins; Diabetes Mellitus; Humans; Lactoferrin; Muramidase; Neutrophils; Pancreatic Elastase; Peroxidase; Serine Endopeptidases; Time Factors

During the active phase of chronic recurrent parotitis there is a marked elevation in the parotid concentration of lactoferrin (Lf), and iron-binding glycoprotein with antibacterial properties. The Lf concentration decreases during the recovery period, but still remains above normal levels. The changes of Lf in parotitis parallel recent findings in mastitis and pancreatitis. Elevations in Lf were also noted in five of six subjects with Sjögren's disease, but not in subjects with sarcoidosis, diabetes or "dry mouth" without sialographic changes. The source of the Lf has not been determined; it could arise in part from disrupting polymorphonuclear leucocytes and in part from epithelial cells that synthesize Lf in the salivary glands. Inflammatory stimulation of Lf synthesis would suggest a basic protective mechanism in exocrine glands and should be fully explored.

Topics: Albumins; Chronic Disease; Diabetes Mellitus; Humans; Lactoferrin; Lactoglobulins; Parotitis; Recurrence; Saliva; Sarcoidosis; Secretory Rate; Sjogren's Syndrome; Xerostomia