Anti-diabetic treatment regulates pro-fibrotic TGF-β serum levels in type 2 diabetics

Abstract

Background: The single-center, open-label, four-arm, exploratory study investigates the relation of different anti-diabetics to serum levels of active TGF-β, a known pro-fibrotic stimulus, before and after a defined test meal.

Findings: We investigated sera of patients with type 2 diabetes mellitus (T2DM) treated with metformin and sulfonylurea, insulin glargine or a DPP-4 inhibitor (DPP4i). Patients' sera were analyzed before and 5 h after a defined test meal at intervals of 30 min.The sulfonylurea/metformin group exhibited the highest basal levels of active TGF-β (31.50 ± 3.58 ng/ml). The glargine/metformin group had active TGF-β levels (24.98 ± 1.90 ng/ml) that were comparable to those of the healthy participants (22.12 ± 2.34 ng/ml). The lowest basal levels of active TGF-β were detected in the DPP-4i/metformin group (12.28 ± 0.84 ng/ml). Following the intake of a standardized meal, active TGF-β levels decreased (approx. 30%) in healthy subjects as well as in the sulfonylurea/metformin group and in the glargine/metformin group. After 5 h, the active TGF-β levels were normalized to basal levels. Active TGF-β levels in the DPP-4i/metformin group did not change significantly after the test meal. Overall plasma levels of insulin and proinsulin were comparable between healthy participants, and T2DM patients in the glargin/metformin group and in the DPP4i/metformin group. However, no correlation between active TGF-β levels, glucose, insulin or pro-insulin levels was detected.

Conclusions: T2DM patients often exhibit elevated levels of pro-fibrotic active TGF-β. Our results suggest that glargine/metformin and DPP4i/metformin treatment may more effectively reduce active TGF-β serum levels than the sulfonylurea/metformin treatment.

Figure 1

Blood glucose, insulin and proinsulin levels after a test meal. T2DM patients treated with metformin and sulfonylurea (S+M), insulin glargine (G+M) or a DPP-4 inhibitor (D+M) as well as non-diabetic controls (C) received a standardized test meal. Over the course of 5 h, (a) blood glucose, (b) insulin, and (c) proinsulin levels were determined at intervals of 30 min. Each group consisted of 20 individuals on average. All three serum parameters increased after the test meal reaching their peak between 60 and 90 min after the test meal. “ p < 0.05, * p < 0.01 and ° p < 0.001 as compared to C.

Figure 2

Active TGF-β serum levels before and after a test meal. T2DM patients treated with metformin and sulfonylurea (S+M), insulin glargine (G+M) or a DPP-4 inhibitor (D+M) as well as non-diabetic controls (C) received a standardized test meal. Over the course of 5 h, active TGF-β serum levels were measured at 30 min intervals. Each group consisted of 20 individuals on average. (a) Basal active TGF-β serum levels strongly depend on the pharmaceutical strategy. * p < 0.05, ** p < 0.01 and *** p < 0.001. (b) After the test meal, active TGF-β serum levels dropped after having reached their peak about 60 min after the test meal and then normalized to baseline levels. “ p < 0.05 as compared to C.

Figure 3

Correlation analysis between basal active TGF-β serum levels and fasting blood glucose, insulin and proinsulin levels. Basal active TGF-β serum levels of T2DM patients treated with metformin and sulfonylurea (S+M), insulin glargine (G+M) or a DPP-4 inhibitor (D+M) as well as of non-diabetic controls (C) were correlated with basal (a) blood glucose levels, (b) insulin levels, and (c) proinsulin levels.