Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity

Abstract

Background: Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents.

Methods: Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects.

Results: ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; P<0.05). ADA activity was correlated with fasting plasma glucose (r=0.258, P<0.05), HbA1c (r=0.208, P<0.05), aspartate aminotransferase (r=0.325, P<0.05), and alanine aminotransferase (r=0.248, P<0.05). Compared with the well-controlled T2DM patients (HbA1c<7%), the poorly controlled group (HbA1c>9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; P<0.05). The effect of DPP4I on ADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; P<0.05) compared with that of those on sulfonylurea monotherapy.

Conclusion: Our results show that ADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect.

Keywords: Adenosine deaminase; Diabetes mellitus, type 2; Dipeptidyl peptidase.

Fig. 1

(A) The comparison of serum adenosine deaminase (ADA) activity levels (means±standard error) between non-diabetic control subjects (Non-DM) and patients with type 2 diabetes mellitus (T2DM). (B) Serum ADA activities show wide variations within each group. ^aP<0.05 vs. Non-DM subjects.

Fig. 2

The comparisons of serum adenosine deaminase (ADA) activity according to level of blood glucose control stratified by HbA1c (A) and fasting plasma glucose (FPG) values (B) in patients with type 2 diabetes mellitus. ^aP<0.05 vs. the group with HbA1c<7% according to one-way ANOVA test, ^bP<0.05 vs. the group with FPG <155 mg/dL according to one-way ANOVA test.

Fig. 3

The comparisons of (A) adenosine deaminase (ADA) activity and (B) ADA activity adjusted for HbA1c according to the type of antidiabetic treatment that type 2 diabetes mellitus (T2DM) patients had been receiving for at least four weeks before the laboratory tests. The comparisons of (C) ADA activity and (D) ADA activity adjusted for HbA1c between a group on DPP-4 inhibitor (DPP4I)/metformin combination therapy and a group on metformin monotherapy in patients with T2DM. Comparisons of (E) ADA activity and (F) ADA activity adjusted for HbA1c between a group on metformin monotherapy and a group on sulfonylurea monotherapy in patients with T2DM. Vildagliptin 50 mg bid or sitagliptin 50-100 mg daily. Other oral hypoglycemic agents (OHAs), monotherapy or combination therapies including sulfonylurea, metformin, acarbose, or thiazolidinedione; Insulin, any insulin therapy with or without oral antidiabetic agent(s) except for DPP4I. ^aP<0.05 vs. other OHAs, ^bP<0.05 vs. the group on metformin monotherapy.

Fig. 4

The comparisons of (A) adenosine deaminase (ADA) activity and (B) ADA activity adjusted for HbA1c from before and after the addition of DPP-4 inhibitor (DPP4I) therapy to an existing regimen of metformin monotherapy (2 g/day) in patients with type 2 diabetes mellitus. Vildagliptin 50 mg bid or sitagliptin 50-100 mg daily. ADA activity was measured before and after treatment with vildagliptin 50 mg bid or sitagliptin 50-100 mg daily for at least 8 to 12 weeks.

Fig. 5

The comparisons of (A) adenosine deaminase (ADA) activity and (B) ADA activity adjusted for HbA1c between patients with type 2 diabetes mellitus on statin therapy and those not on statin therapy. ^aP<0.05 vs. no statin.