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Background: Biochemical, epidemiological and experimental evidence suggests that cytosolic low molecular weight protein-tyrosine phosphatase (cLMWPTP) genetic variability may have a role in the clinical manifestations of diabetes mellitus. In this article, the authors review data from their laboratory supporting the hypothesis that high cLMWPTP activity favors severe manifestations of diabetes., Methods: In 829 type 2 diabetic patients, the authors have studied the association between clinical parameters and cLMWPTP activity. The cLMWPTP genotype was determined in all subjects., Results: In diabetic subjects, low activity cLMWPTP protects against extreme increase of glycemic level (patients studied 489). The correlation between glycemic level and glycated hemoglobin concentration is increasing with cLMWPTP activity (patients studied 270). In diabetic subjects with coronary artery disease, left ventricular ejection fraction is negatively correlated with cLMWPTP activity (patients studied 70)., Conclusions: All these observations point to a negative effect of high cLMWPTP activity on clinical manifestation of diabetes in accordance with theoretical and experimental data and suggest that pharmacological decrease of cLMWPTP activity could have beneficial effects on the clinical evolution of this disease. Moreover, in diabetic subjects with high activity ACP1 genotype, an intensive treatment could help to prevent severe clinical manifestations.

In this article, we confirm the positive association of acid phosphatase locus 1 (ACP1)*A/adenosine deaminase locus 1 (ADA1)*2 gametic type with type 1 diabetes (T1D) previously reported and show a negative correlation between the frequency of this gametic type with past malarial morbidity in Sardinia. One hundred seven adult women with T1D and 385 healthy adult women from the Caucasian population of Central Italy have been studied. Data on 1384 children from the central area of Sardinia have also been reexamined. T1D subjects show a highly significant increase of ACP1*A/ADA1*2 gametic type compared with healthy subjects from the same population (P = 0.003). The frequency of ACP1*A/ADA1*2 gametic type is decreasing with increasing past malarial morbidity. Because ADA1*2 allele decreases the activity of *A allele and since low ACP1 activity decreases Zeta-chain-associated protein kinase with molecular weight 70 kDa (Zap70) activity resulting in weak T-cell receptor signalling an epistatic interaction involving ADA1, ACP1 and Zap70 seems a likely mechanism for the associations observed.

Introduction: Previous separate studies have shown associations of coronary artery disease (CAD) with acid phosphatase locus 1 (ACP1) and adenosine deaminase locus 1 (ADA1) genetic polymorphisms. Because it is known that the 2 systems interact and have important immunologic and metabolic functions, these 2 genes were both examined in the same sets of subjects., Method: Two-hundred forty subjects with CAD, 156 subjects with cardiovascular diseases without CAD, 279 subjects with Non Insulin Dependent Diabetes Mellitus (NIDDM) without CAD and 771 consecutive healthy newborn infants have been studied., Results: The association of ACP1 and ADA1 with CAD depends on sex and diabetes. In particular, the association between ADA1 and CAD is present in nondiabetic subjects only, and it is dependent on sex (males), whereas the association of CAD with ACP1 is present in diabetic subjects only, and it is dependent on sex (females)., Conclusions: The fact that the association of ACP1 with CAD is evident only in diabetic subjects, whereas the association of ADA1 with CAD is evident only in nondiabetic subjects suggests an heterogeneity in the pathogenetic mechanisms leading to CAD. In addition, the association with sex that could be based on hormonal differences is in favor of heterogenity.

Background: We have searched for a possible association of the genetic polymorphism of Phosphoglucomutase locus 1 (PGM1), a key enzyme in carbohydrate metabolism, with body mass., Methods: Adults (n = 257) with type 2 diabetes, 74 children referred for "obesity," and 740 consecutive healthy newborn infants were studied. Body mass index, body weight, birth weight, and PGM1 phenotype were determined. Sexes were analyzed separately., Results: In type 2 diabetes, females carrying the PGM1*2 allele are less represented among subjects with extreme body mass index deviation as compared with other classes of subjects. Among children referred for "obesity," females carrying the PGM1*2 allele are less represented among children with extreme body weight deviation. Among consecutive infants, in both sexes the proportion of those showing a birth weight higher than the 3rd quartile is lower in homozygous PGM12/2 subjects than in other PGM1 phenotypes., Conclusions: The data suggest that during extrauterine life, females carrying the PGM1*2 allele are relatively protected from extreme body mass increase. During intrauterine life, PGM12/2 homozygotes show a tendency to low body mass increase. Because PGM1 enzymatic activity depends on its phosphorylation status by the kinase Pak1, both structural differences of the PGM1 allelic product and different rates of activation by Pak between sexes might be responsible for the pattern observed. At present, the effect of other genes near PGM1 and in linkage disequilibrium with it cannot be ruled out.