Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes.

A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10(-11)-1.4 × 10(-23)), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10(-7)). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 "mixed" heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10(-4), n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.

Low trehalase activity is associated with abdominal symptoms caused by edible mushrooms.

BACKGROUND: The purpose of the study was to evaluate whether maldigestion of trehalose causes abdominal symptoms and which available diagnostic method best distinguishes intolerant from tolerant subjects. METHODS: A 25-g oral trehalose load test was performed in 64 subjects. The 19 experiencing clear symptoms constituted the trehalose-intolerant subjects. Changes from base-line levels of blood glucose, breath hydrogen, and methane and symptoms were recorded after the test. Trehalase activity was determined in serum and on a duodenal biopsy specimen obtained by endoscopy. RESULTS: Intolerant subjects were best differentiated from tolerant subjects by changes in breath gases (hydrogen and methane) and duodenal trehalase to sucrase ratio. The change in breath gases correlated inversely with duodenal trehalase activity, duodenal trehalase to sucrase ratio, and plasma trehalase activity. The correlation between serum and duodenal trehalase activities was on the order of 0.6. Two subjects were found to have trehalase deficiency. CONCLUSIONS: It is obvious that trehalose maldigestion can cause symptoms similar to those of lactose maldigestion and intolerance. Three factors control the genesis of symptoms: 1) the activity of small-bowel trehalase: if it is low, trehalose is maldigested and more trehalose is passed into the colon; 2) the maldigested trehalose, which causes osmotic water flow into the colon, resulting in loose stools and diarrhea; and 3) most importantly, the microflora of the colon, from which symptoms will arise if there are bacteria capable of producing gases from maldigested trehalose. If colonic bacteria cannot produce gases, then distention of the abdomen and intestinal gas expulsion as eructations and flatus will not occur.

Serum trehalase activities in controlled and uncontrolled diabetes and the impact of oral glucose, high carbohydrate and glycosuria on serum levels.

Nineteen healthy volunteers, made up of two groups were subjected to an extended oral glucose tolerance study. In one group, each had 50g glucose and in the other a high carbohydrate meal. Blood glucose and serum trehalase activities were determined on fasting blood samples and specimens collected half-hourly for 4 hours. The values obtained for both at each stage of the investigations were compared with one another. Correlation coefficient (r) between blood glucose and serum trehalase were 0.4923 for the fasting samples and 0.4762 at 1 hr. The impact of diabetes and glycosuria on serum trehalase activities in 50 diabetics consisting of treated (controlled) and untreated (uncontrolled) cases was also studied. Our study reveals a slight fall in serum trehalase values from the initial fasting level, but thereafter a gradual and progressive rise during the course of the glucose tolerance investigations. Serum trehalase values were higher in diabetics compared to normal subjects (t = 7.0168, P = 0.005). Diabetics with glycosuria had a significantly higher mean serum trehalase compared to the controlled group (t = 5.233, P = 0.005). High serum trehalase values were seen in diabetics with renal glycosuria at comparatively low levels of blood glucose. The significance of these findings is discussed in relation to the possible place of serum trehalase assay in the management of diabetes, especially when this is made difficult by renal glycosuria.

Plasma trehalase activity and diabetes mellitus.

Trehalase is an enzyme which hydrolyzes the disaccharide trehalose, yielding glucose. It is widespread in nature and found in various human tissues as well as in human plasma. The synthesis and degradation of its substrate trehalose have been considered as being implicated in carbohydrate transport mechanisms. Trehalase activity has been examined in both normal subjects and diabetic patients. In the normal subjects, the frequency histogram of the enzyme activity is bimodal, indicating the existence of genetic polymorphism. The proposed model of a single autosomal locus with two alleles has been verified, with 27% of the population tested belonging to the "low-activity" phenotype and 73% being of the "high-activity" phenotype. Males have higher mean plasma trehalase activity than females. Apparently, the reverse appears to be the case in the diabetic subjects. The mean value for all nondiabetics and that of diabetics were computed and the difference was found to be statistically significant (F = 7.02, N1 = 3, N2 = 56, P less than 0.01). An experiment showed that neither the abnormally high concentration of glucose in diabetics nor any other constituent of the diabetic plasma caused an increase in plasma trehalase activity (t = 0.0724, P greater than 0.10). A Woolf and Haldane test to determine association of diabetes mellitus and plasma trehalase phenotype indicated a highly significant association with the high-activity phenotype (chi 2 = 18.5350, P less than 0.01). Thus the inference is that people with high plasma trehalase activity are more prone to develop diabetes mellitus than people with low enzyme activity.

Trehalase activity in genetically diabetic mice (serum, kidney, and liver).

Trehalase activity was determined in serum, liver, and kidney in alloxan treated Swiss mice and in homozygous (Ob/Ob, Db/Db) and heterozygous (Ob/+, Db/m+) diabetic mice. Both alloxan and genetic diabetic mice exhibited a large increase in serum and liver trehalase activity with no change in kidney trehalase activity. The heterozygotes (Ob/+, Db/m+) showed only a slight increase of enzyme activity. Further quantitative differences were noticed between the genetic and alloxan diabetic animals. The liver enzyme activity increased from 10- to more than 20-fold in the liver of the homozygous Ob/Ob and Db/Db strains and only 3-fold (not significant compared to controls) in the alloxan treated animals. The above results suggest a regulatory relationship between the genes coding for trehalase and the enzymes of glucose metabolism activity involved in the development of the metabolic anomalies of diabetes. The structural gene for trehalase may well have survived elimination of selective pressure during phylogenesis and remained part of a co-regulated group of glucose metabolising enzymes. This could explain its sensitivity to mutations affecting glucose metabolism and its sensitivity to insulin directed regulatory mechanisms.

Two forms of trehalase activity in mice.

Trehalase activities from mouse serum and kidney have been compared on ion exchange chromatography (DEAE-cellulose and SP-Sephadex). The two activities showed a distinct behaviour. This was confirmed by polyacrylamide gel electrophoresis and thermal lability, suggesting the presence of at least two forms of the hydrolytic enzyme trehalase in mice.

Cell membrane enzymes: L-gamma-glutamyl transpeptidase, leucine aminopeptidase, maltase and trehalase in normal and leukaemic lymphocytes.

Several cell-membrane enzymes, which serve functions in amino acid and sugar transport, were measured in peripheral blood lymphocytes from chronic B and T lymphocytic disorders, blast cells in acute leukaemias, and in normal lymphocytes from cord blood, peripheral blood of adults, tonsils and bone-marrow plasma cells in myelomatosis. The specific activities of L-gamma-glutamyl transpeptidase, maltase and trehalase were low, as compared with those measured in normal blood lymphocytes, in the acute leukaemias and in the chronic B-cell disorders. In myelomatosis and in the chronic T-cell disorders, the specific activity of these three enzymes was in the normal range or above normal. The specific activity of leucine aminopeptidase was low in all the chronic B-cell disorders and in some of the lymphoblastic leukaemias. It was elevated in Sézary syndrome cells but low in T-chronic lymphocytic leukaemia. All four enzymes were lower than normal in cord blood lymphocytes and higher than normal in tonsils. These findings are discussed in relation to the patterns of lymphoid cell differentiation and maturation in normal tissues and in leukaemic states.

Trehalase activity in diabetes mellitus and in cirrhosis of the liver.

Trehalase (an enzyme decomposing the disaccharide trehalose) activity was studied in 29 healthy subjects, 25 patients with cirrhosis and 112 diabetics. Mean trehalase activity was 176 +/- 11 units in the control group, 647 +/- 421 units in the patients with cirrhosis and 467 +/- 239 units in diabetics. The differences between the control group on the one hand and the groups with cirrhosis and diabetes on the other were statistically significant. The results show that the organism, under pathological conditions, makes far greater use of its enzymatic apparatus to assure its basic requirements, but the scatter of the values is so great that the determination of trehalase has no discriminative value in individual cases.

[L-alanyl-L-proline-dipeptidase and glycyl-L-valine-depeptidase in malabsorption syndrome]. / L-Alanyl-L-Prolin-Dipeptidase und Glyzyl-L-Valin Dipeptidase beim Malabsorptionssyndrom

On the basis of comparative determinations of the activities of dipeptidases and disaccharidases of the mucous membrane of the small intestine (proximal jejunum) clear correspondences between the morphological findings and the biochemical parameters were the result. L-alanyl-L-prolin-dipeptidase and glycyl-L-valin-dipeptidase as well as lactase, saccharase, maltase and trehalase were determined in altogether 45 children with various malabsorption syndromes of different age in different stages of disease. Diminutions of the activity of the dipeptidases were to be proved analogously to maltase, saccharase and lactase, too, in most cases of subtotal or total villous atrophy. From the results conclusions may be derived to the restricted ability of protein absorption in chronic disease of the small intestine.

[Influence of parenterally injected trehalose in mammals having trehalase activity at different sites]. / Influence de l'injection parentérale de tréhalose chez des mammifères possédant une activité tréhalasique diversement localisée

When trehalose is injected via parenteral pathway into animals lacking kidney trehalase (rat), more than 75 per cent of this disaccharide is eliminated in urine. When the injected animals possess an active kidney trehalase (guinea-pig, rabbit), there is only a low urinary trehalose excretion. Moreover, in rabbit, a marked hyperglycaemia is observed which is due to the rapid hydrolysis of trehalose by kidney trehalase.