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Reduced trypsin binding capacity of alpha 2-macroglobulin in diabetes
Abstract:
The plasma proteinase inhibitor, alpha 2-macroglobulin, is usually elevated in diabetes. The trypsin binding capacity and the concentration of alpha 2-macroglobulin in 90 diabetics sera were compared with 30 age- and sex-matched normal sera. The mean alpha 2-macroglobulin concentration determined by radial immunodiffusion was 313 mg/dl for the diabetics as compared to 240 mg/dl for the healthy subjects (significantly higher, p less than 0.01). The mean of the ratio, mol trypsin bound/mol alpha 2-macroglobulin (molar binding ratio) for the Type I diabetics (n = 54), 0.82, was significantly lower than the mean of the healthy subjects, 0.87, or the mean of the Type II diabetics, 0.87. No relationship between the molar binding ratios and the levels of glycosylated hemoglobin was found. The alpha 2-macroglobulin was isolated from the plasma of 11 Type I diabetics and 7 normals. The maximum molar trypsin binding capacities of the diabetic alpha 2-macroglobulin were significantly lower. The mean for the diabetic alpha 2-macroglobulin was 1.72 vs. 1.97 for the normal alpha 2-macroglobulin. These results indicate that the trypsin binding function of alpha 2-macroglobulin is moderately impaired in diabetes. No differences were found in the extent of proteolytic cleavage of the 'bait region' of diabetic alpha 2-macroglobulin, autolytic cleavage or the methylamine reaction at the thiolester site between diabetic and normal alpha 2-macroglobulin. Nonenzymatic glucosylation of normal alpha 2-macroglobulin did not lower the trypsin binding capacity. The nature of the modification of alpha 2-macroglobulin leading to reduced trypsin binding capacity or the physiological significance is not yet known.
Insights
In diabetes, alpha 2-macroglobulin levels are higher but its trypsin binding function is impaired. This study found reduced trypsin binding capacity in diabetic alpha 2-macroglobulin, suggesting functional changes in this important proteinase inhibitor.
Area of Science:
- Biochemistry
- Proteomics
- Clinical Chemistry
Background:
- Alpha 2-macroglobulin (A2M) is a key plasma proteinase inhibitor.
- Elevated A2M levels are commonly observed in diabetic patients.
- The functional integrity of A2M in diabetes requires further investigation.
Purpose of the Study:
- To compare trypsin binding capacity and concentration of A2M in diabetic and normal individuals.
- To investigate potential alterations in A2M function in diabetes mellitus.
- To explore the relationship between A2M function and glycemic control.
Main Methods:
- Radial immunodiffusion was used to quantify A2M concentration.
- Trypsin binding capacity was assessed by measuring the molar binding ratio.
- A2M was isolated from plasma for further functional analysis.
- Levels of glycosylated hemoglobin were measured.
Main Results:
- Diabetic sera showed significantly higher mean A2M concentration (313 mg/dl) compared to healthy controls (240 mg/dl).
- Type I diabetics exhibited a significantly lower molar binding ratio (0.82) compared to healthy subjects (0.87) and Type II diabetics (0.87).
- Isolated diabetic A2M demonstrated significantly lower maximum trypsin binding capacity (1.72) than normal A2M (1.97).
- No correlation was found between molar binding ratios and glycosylated hemoglobin levels.
Conclusions:
- The trypsin binding function of alpha 2-macroglobulin is impaired in diabetes.
- The impairment in A2M function is not explained by nonenzymatic glucosylation or alterations in specific cleavage sites.
- The precise mechanism and physiological implications of reduced A2M trypsin binding capacity in diabetes remain unknown.