The present study confirms the low grade systemic inflammation status in T2D patients which is related to features of the metabolic syndrome. However, the main and novel findings are related to increased levels of TGF-β1 concentration in patients with LDL phenotype B, compared to those with phenotype A, and its reduction after a marked improvement of glycemic control. These findings suggest that TGF-β1 may be a link to glycemic control and atherogenic dyslipidemia with the development of diabetic nephropathy.
Systemic inflammation status in T2D subjects
The analysis of inflammatory parameters showed that plasma concentrations of CRP and MCP1 were higher and that of adiponectin was lower in T2D patients than in control subjects. This observation indicates a greater global systemic inflammation status in diabetic patients, which has been previously suggested that may reflect the activity of the underlying atherosclerotic process , and it is concordant with several cross-sectional studies which have shown an increase of CRP levels in patients with diabetes [25–27]. Although the results reported in the literature on the association between IL-6 and T2D are contradictory [26, 28, 29], the absence of statistical differences in IL-6 and other inflammatory parameters could be related to the fact that most patients were treated with medications such as metformin, antihypertensive agents and lipid-lowering drugs, which have demonstrated a beneficial effect on inflammation [12–14]. In addition, the available information about the relationship between inflammatory biomarkers and the characteristics of the diabetes is limited. Some studies have demonstrated significant correlation between CRP levels with features of the metabolic syndrome, including adiposity, hyperinsulinemia, insulin resistance, hypertriglyceridemia and low HDLc [9, 30]. The preponderance of small LDL particles (LDL phenotype B) is a component of atherogenic dyslipidemia. In accordance, we have observed that obese T2D subjects have higher CRP concentrations and inflammatory status was more unfavorable in patients with LDL phenotype B, who had higher concentration of TGF-β1 and lower of adiponectin than patients with phenotype A. To our knowledge, no other studies have examined this association, but there are some publications agreeing that serum levels of TGF-β1 are higher in patients with metabolic syndrome than those without it  and that oxidized low-density lipoprotein, which is increased in subjects with LDL phenotype B, is associated with TGF-β1 in T2D subjects . Finally, TGFβ family members have been involved in vascular remodeling defects in experimental models , which could contribute to explain the worse prognostic of atherosclerotic cardiovascular disease in diabetic patients.
The effect of improving glycemic control on markers of inflammation in T2D
It has been shown that in the individuals with impaired glucose tolerance  the low-grade chronic inflammation is related to glucose metabolic disturbance and a growing body of evidence supports the hypothesis that chronic systemic inflammation contributes to decrease insulin sensitivity . Moreover, hyperglycemia is a significant stressor that has also been shown to cause chronic inflammation . However, the relationship between inflammatory markers and glycemic control is still not fully understood. In our study, no inflammation marker correlated with HbA1c levels. These results are consistent with the findings of previous cross-sectional studies which have found an inconsistent association between inflammation and blood glucose levels [16–18], possibly due to previous treatment with metformin, statins and antihypertensive agents, which may limit the power to detect an association between HbA1c and inflammatory markers. In the longitudinal study, we demonstrated for the first time that improvement of glycemic control by different therapeutic strategies can lower TGF-β1 concentrations. These results are consistent with the findings in diabetic rats treated with insulin and with the increased expression of TGF-β1 receptor in the diabetic kidney and in mesangial cells cultured in high glucose [37, 38]. The lack of significant correlation between the magnitude of the reductions in HbA1c and TGF-β1 after glycemic optimization may reflect differences in the relative importance of the local versus systemic blood glucose levels, and it does not preclude an underlying relationship between these two parameters. The lack of change in CRP and other inflammatory markers in our study cannot be attributed to weight gain or pharmacological therapy, and confirms the results in the few studies which have evaluated the effect of improving glycemic control on markers of inflammation in type 1 diabetes (DCCT) and T2D [19, 20]. In the DCCT study, intensive glycemic control was not associated with changes in levels of CRP and among intensively treated subjects who gained the most weight, there was a significant rise. In T2D, in a study of 18 patients who had been hospitalized to initiate insulin therapy because of poor diabetes control, CRP values, but not MCP1 and fibrinogen levels, were decreased 2 weeks after initiation of insulin therapy. This effect could result from anti-inflammatory effects of insulin , although these findings were not confirmed in the study of Pradhan et al. . They found that, in patients with recent-onset T2D, treatment during 14 weeks with insulin glargine or metformin compared with placebo did not reduce CRP, IL-6 and soluble tumor necrosis factor receptor 2, despite improving glucose control. In the present study, the duration of the study was sufficient on the basis of assessment of glycemic control by HbA1c, and a marked improvement of glycemic control was obtained, being nearly normal in most of the patients without changes in body weight. Furthermore, lipid-lowering and antihypertensive therapy was unchanged and in most patients insulin therapy was the strategy used to improve glycemic control.
The possible role of TGF-β1 in diabetic nephropathy
The critical role of hyperglycemia in the genesis of diabetic nephropathy has been established by cell culture studies, experimental animal models, and clinical trials. Certain cytokines have been identified as likely mediators of the effects of high ambient glucose on the kidney. TGF-β1, a known pro-fibrotic factor, activates the production of extracellular matrix by mesangial cells and interstitial fibroblasts in the kidneys, and thus contributes to the manifestation of diabetic kidney disease through a number of key pathological events leading to reduced glomerular filtration and impaired renal function [39, 40]. In mesangial cells, it has been demonstrated that the expression and activity of TGF-β1 are directly influenced by glucose levels . Moreover, atherogenic dyslipidemia is associated with the onset and progression of nephropathy in T2D subjects, by a mechanism not fully understood [41, 42]. Therefore, the finding of a higher concentration of TGF-β1 in patients with atherogenic dyslipidemia provides a potential explanation.
In conclusion, the present study confirms that low-grade chronic inflammation in T2D is related to LDL phenotype B and obesity. In addition, our data demonstrates that improvement of glycemic control reduces TGF-β1 levels, through an unknown mechanism. These findings might support the role of TGF-β1 as a likely mediator of the effects of high ambient glucose on the kidney and the beneficial effects of strict glucose control on the development of diabetic nephropathy. However, future studies in larger groups of patients should be performed to confirm these findings.