Serum Enzymes in Diabetes Mellitus - Clinical Chemistry

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acid phosphatase, and amylase-that show increased activity correlat- ed with blood sugar concentration. Because lysoso- mal enzymes as well as liver amylase.

CLIN. CHEM. 19/5, 447-452 (1973)

Serum Enzymes in Diabetes Mellitus Francesco

Belt iore, Luigi Lo Vecchio,

and Elena Napoli

Serum enzymes that show changed activities in diabetes mellitus can be divided into four groups: Group I includes some lysosomal enzymes-f.3-glucuronidase N-acetyl-fl-glucosaminidase, acid phosphatase, and amylase-that show increased activity correlated with blood sugar concentration. Because lysosomal enzymes as well as liver amylase show latency and may be “activated” by several agents, their increased activity in the serum of diabetics might be a manifestation of an activation occurring in tissues. Group II includes alkaline phosphatase and trehalase, which are increased but not correlated with blood sugar concentration. Their enhanced activity may reflect tissue metabolic disorders. Group Ill includes enzymes that increase in the postketotic period almost regularly-phosphohexose isomerase -or in only the most severe cases-aminotransferases and several dehydrogenases-because of tissue damage caused by metabolic and circulatory alterations. Cholinesterase, on the other hand, is decreased. Group IV includes any of the above-mentioned enzymes, and still others, that may be more active in diabetics with complications such as hepatIc and renal involvement and obesity. In diabetes mellitus, several serum enzymes have been studied. The data reported are apparently unrelated and often conflicting. However, when they are considered together, a general scheme may be envisaged that provides an understanding of the changes seen in the activities of the various enzymes. The scope of this review is to present and discuss available data on serum enzymes in diabetes mellitus set in such a scheme, as well as to consider some special problems concerning particular enzymes. The serum enzymes investigated in diabetes mellitus can be divided into (1) enzymes whose activity is usually increased, and (2) enzymes whose activity is usually normal, but which may change in special conditions and in some patients. The first group, in turn, may be divided into (a) enzymes whose serum level is correlated with the concentration of blood sugar, and (b) enzymes that do not show such a correlation. The second group may be divided into (a) enzymes that change in the postketotic period, and (b) enzymes whose activity may increase in diabetics with complications. Therefore, altogether, four groups of enzymes are to be considered (Table 1). From the 10 Clinics Medica Generale e Terapia Medica della Universit#{224} di Catania, Ospedale Garibaldi, 95123 Catania, Italy. Received Jan. 22, 1973; accepted Feb. 27, 1973.

Enzymes of Group I This group includes 3-glucuronidase,1 N-acetyl-glucosaminidase, acid phosphatase, and amylase, and is characterized by the occurrence of a correlation of enzyme activity with the blood sugar concentration, and therefore, approximately, with the degree of metabolic decompensation. The observation of an increased serum activity of fl-glucuronidase (1-5) and N-acetyl-f3-glucosamin. idase (4, 6) in diabetes mellitus, with higher values in women than in men (1, 3-5), has been given conflicting interpretations. Some workers (1, 4) have regarded the enzyme change as being linked to the diabetic condition. Others (2, 3), on the grounds of some data (7, 8) showing a correlation between the activity of these enzymes and atherosclerotic disease, have postulated that the increased activity is linked to the increased susceptibility of diabetics to atherosclerosis. Because 3-glucuronidase activity increases in hepatic diseases (9-11), its increased activity in diabetes has been also ascribed to underlying liver involvement (12). Further evidence would suggests that the serum activity of these two enzymes is linked to both the diabetic state (5, 6, 13) and the presence of vascular lesions in either the small or large vessels (5, 6). In fact, in severely decompensated diabetics with various degrees of ketoacidosis the activity of both enzymes in serum is markedly ele‘Trivial and nonstandard names used: -glucuronidase is $-Dglucuronide glucuronohydrolase, EC 3.2.1.31; N-acetyl-fl-glucosaminidase is chitobiose acetylaminodeoxyglucohydrolase, EC 3.2.1.29; acid phosphatase is orthophosphoric monoester phosphohydrolase, EC 3.1.3.2; amylase is a-1,4-glucan 4-glucanohydrolase, EC 3.2.1.1; alkaline phosphatase is orthophosphoric monoester phosphohydrolase, EC 3.1.3.1; trehalase is trehalose 1-glucohydrolase, EC 3.2.1.28; glucose-6-phosphatase is o-glucose-6-phosphate phosphohydrolase, EC 3.1.3.9; fructose-1,6-diphosphatase is D-fructose-1,6-diphosphate 1-phosphohydrolase, EC 3.1.3.11; phosphohexose isomerase is D-glucose-6-phosphate ketol-isomerase, EC 5.3.1.9; aspartate aminotransferase is L-aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1; alanine aminotransferase is L-alanine: 2-oxoglutarate aminotransferase, EC 2.6.1.2; sorbitol dehydrogenase is L-iditol:NAD oxidoreductase, EC 1.1.1.14; glutamate dehydrogenase is i.-glutamate : NAD(P) oxidoreductase, deaminating, EC 1.4.1.3; isocitrate dehydrogenase is threo-D9isocitrate:NADP oxidoreductase (decarboxylating) EC 1.1.1.42; malate dehydrogenase is L-malate : NAD oxidoreductase, EC 1.1.1.37; lactate dehydrogenase is L-lactate:NAD oxidoreductase, EC 1.1.1.27; cholinesterase is acylcholine acyl-hydrolase, EC 3.1.1.8; aldolase is fructose-1,6-diphosphate n-glyceraldehyde-3phosphate-lyase, EC 4.1.2.13; arginase is L-arglnine ureohydrolase, EC 3.5.3.1; lipase is glycerol-ester hydrolase, EC 3.1.1.3; creatine kinase is adenosine triphosphate:creatine phospho-transferase, EC 2.7.3.2.

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Table 1. Classification of Changes in Serum Enzyme Activity in Diabetes Mellitus Increased enzymes

Enzymes usually normal, which may change in the postketotic period or in diabetics with complications

Enzymes whose activity is correlated with glycemia (Group I)

Enzymes whose activity is moderately increased and not correlated with glycemia (Group II)

Enzymes that may change in the post-ketotic period (Group III)#{176}

Enzymes that may increase in diabetics with complications (Group IV)

Beta-glucuronidase N-Acetyl-beta-glucosaminidase Acid phosphatase Amylase#{176}

Alkaline phosphatase Trehalase

Phosphohexose isomerase Aspartate aminotransferase A lanine aminotransferase Sorbitol dehydrogenase Glutamate dehydrogenase I socitrate dehydrogenase Malate dehydrogenase Lactate dehydrogenase Cholinesterasec

Enzymes of group III Aldolase Creatine kinase Arginase Lipase Cholinesterase

a Enzymes of group I, being correlated with glycemla, are increased during ketotic episodes, but rapidly return to normal with the normalization cemlc level, while enzymes of group III remain elevated for some days in the postketotiC period. Amylase elevation becomes appreciable only in severely decompensated diabetics. C Cholinesterase Is decreased in the postketotic period, in contrast to the other enzymes of this group.

vated, with an increase of up to 283% for 3-glucuronidase and 140% for N-acetyl-3-glucosaminidase, and is clearly correlated with blood sugar concentration, so that it returns promptly toward normal as metabolic compensation is achieved (13). This indicates that the increased activity is linked to the condition of diabetic decompensation, and not, as postulated by some workers, to a possible presence of liver involvement (12) or to susceptibility to atherosclerosis (2, 3). This view is supported by the normal activity of other enzymes, including aspartate and alanine aminotransferases, observed in most instances (13). The correlation with the degree of glucose metabolic disorder is also confirmed by the statistically significant correlation between enzyme activity and sugar concentration found in large series of diabetics for both f3-glucuronidase (5) and N-acetyl-fl-glucosaminidase (6). On the other hand, the relationship between the activity of these enzymes and the presence of vascular lesions, that previously had been postulated on tenuous grounds (2), appears to be substantiated by the correlation of the higher enzyme activity observed in diabetics with disease of either the small or large blood vessels when compared with the activity in uncomplicated diabetics with similar degrees of hyperglycemia (5, 6). This relationship is also indicated by the finding that the correlation of fl-glucuronidase and N-acetyl-3-glucosaminidase with blood sugar concentration, present in uncomplicated diabetics, does not occur in diabetics with diseased blood vessels (5, 6). This shows that the presence of vascular lesions is an interfering factor that may modify serum enzyme activity. The failure of some workers (2) to demonstrate the correlation of serum 3.glucuronidase with both the blood sugar and vascular lesions may perhaps be attributed to the fact that the effect of the latter was not studied in diabetics with similar glucose concentrations, and the effect of hyperglycemia was not studied in diabetics without vascular lesions. 448

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of gly-

Concerning the correlation with sugar concentration, it must be pointed out that experiments in which j3-glucuronidase and N-acetyl-3-glucosaminidase were assayed before and after addition of glucose to serum showed that glucose per se does not affect the activity of these two enzymes (13). Since 3-glucuronidase, together with N-acetyl-3glucosaminidase and other enzymes, is able to degrade mucopolysaccharides and glycoproteins, its increased activity in the serum of diabetics has been regarded as a defense mechanism against accumulation of these compounds in the walls of blood vessels (2), as occurs in diabetics with vascular disorders. However, it has been pointed out (5) that this hypothesis can apply only for the enzyme change occurring in diabetics with lesions of large vessels, but not for those occurring in diabetics with disease of small vessels. In fact, unlike the walls of large blood vessels, the basement membrane of small blood vessels, which is the site of diabetic microangiopathic lesion, does not contain glucuronic acid, but instead glycoproteins, constituted of characteristic carbohydrate units, made up of glucose-galactose disaccharides (14). Based on the consideration that both /glucuronidase and N-acetyl-3-glucosaminidase are lysosomal enzymes (15), and that lysosomes have a rich complement of hydrolytic enzymes capable of degrading a large variety of compounds, the hypothesis has been put forward (5, 6, 13) that the increase of 9-glucuronidase and N-acetyl-flglucosaminidase in serum could be the expression of lysosome involvement in tissues, leading to activation of lysosomal hydrolases. This phenomenon probably occurs in response to the metabolic need to degrade any of these compounds that have accumulated in tissues, such as mucopolysacchanides and glycoproteins in diabetics with vascular disease (5, 6), or various constituents of cells themselves, in a context of increased tissue catabolism, as occurs in diabetics at a rate proportional to the degree of met-

abolic decompensation (13). Unpublished data from this laboratory further supports this hypothesis, for it showed that also a third lysosomal enzyme, acid phosphatase, was increased in 40 adult uncomplicated diabetics, with a mean increase of 148%, statistically significant (P 0.30.

7

Fig. 1. Behavior of four representative serum enzyme activities (lines 1-4) and of blood glucose (line 5) in a diabetic patient with severe metabolic decompensation and ketoacidosis

6 D

5. 4.

Line 1 refers to $-glucuronidase, which is representative of a group of enzymes that are increased in diabetes and correlated with glycemia; line 2 refers to alkaline phosphatase, which is representative of a group of enzymes that are moderately increased In diabetes and not correlated with glycemia; line 3 refers to phosphohexose isomerase, which Is representative of a group of enzymes that are increased in the postketotlc period; line 4 refers to aspartate aminotransferase, which is representative of a group of enzymes that may increase in diabetes with complications

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have described increased serum activity of phosphohexose isomerase, aspartate and alanine aminotransferases, and lactate dehydrogenase in diabetics with this complication. The same enzymatic changes were observed in diabetics with obesity (62). This last condition has been held responsible also for the increased serum cholinesterase activity (59, 63). The activity of this enzyme, in fact, is increased only in those diabetics who are overweight, suggesting that the elevation is associated with the accompanying obesity rather than with the diabetes itself (63).

Summary From the data reviewed above we deduce that several serum enzymes may change in diabetes mellitus. The increase of some of these enzymes (groups I and II) seems closely related to the diabetic metabolic alterations, while the change of other enzymes (groups III and IV) are only indirectly related to diabetes, being expression of either acute tissue damage caused by episodes of severe decompensation (changes of enzymes of group III), or complications that may develop during the chronic course of diabetic disease (increase of enzymes of group IV). We are greatly indebted to Saverio Signorelli, M.D., Professor and Chairman, Department of Medicine, University of Catania Medical School, and Head of the Postgraduate School of Hem atologic and Metabolic Diseases, for having supported the studies from this laboratory that have been cited in this review.

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