Małgorzata Wegner

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA(1)c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA(IR) score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA(IR), proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.

Role of epigenetic mechanisms in the development of chronic complications of diabetes

There is growing evidence that epigenetic regulation of gene expression including post-translational histone modifications (PTHMs), DNA methylation and microRNA (miRNA)-regulation of mRNA translation could play a crucial role in the development of chronic, diabetic complications. Hyperglycemia can induce an abnormal action of PTHMs and DNA methyltransferases as well as alter the levels of numerous miRNAs in endothelial cells, vascular smooth muscle cells, cardiomyocytes, retina, and renal cells. These epigenetic abnormalities result in changes in the expression of numerous genes contributing to effects such as development of chronic inflammation, impaired clearance of reactive oxygen species (ROS), endothelial cell dysfunction and/or the accumulation of extracellular matrix in the kidney, which causing the development of retinopathy, nephropathy or cardiomyopathy. Some epigenetic modifications, for example PTHMs and DNA methylation, become irreversible over time. Therefore, these processes have gained much attention in explaining the long-lasting detrimental consequences of hyperglycaemia causing the development of chronic complications even after improved glycaemic control is achieved. Our review suggests that the treatment of chronic complications should focus on erasing metabolic memory by targeting chromatin modification enzymes and by restoring miRNA levels.

Association Between IL-6 Concentration and Diabetes-Related Variables in DM1 Patients with and without Microvascular Complications

Interleukin 6 (IL-6) plays an important role in the initiation and acceleration of chronic inflammation and could contribute to development of microvascular complications in patients with type 1 diabetes (DM1). Therefore, this study was aimed to investigate the association between concentration of IL-6 in relation to glucose control, lipid profile, and body mass index (BMI) in 69 DM1 patients subdivided according to the absence or presence of microvascular complications. BMI, level of fasting plasma glucose (FPG), and concentrations of total cholesterol (TCH), LDL cholesterol (LDL-C), and IL-6 were higher in DM1 patients compared to the control group. In DM1 patients, IL-6 concentration was positively correlated with level of FPG, LDL-C, TCH concentrations, and BMI. These correlations were stronger in the subgroup of patients with microvascular complications. In addition, BMI independently influences IL-6 concentration in DM1 patients. In conclusion, elevated IL-6 concentration is associated with diabetes-related variables which could accelerate progression of microvascular complications in DM1 patients.

The evaluation of IL-12 concentration, PAF-AH, and PLA2 activity in patients with type 1 diabetes treated with intensive insulin therapy

OBJECTIVES The aim of the study was to evaluate the concentration of interleukin 12 (IL-12), the activity of phospholipase A(2) (PLA(2)), and platelet-activating factor acetylhydrolase (PAF-AH) in type 1 diabetes (DM1) patients treated with intensive insulin therapy. DESIGN AND METHODS Studied parameters were measured in 81 patients, who were subdivided according to the HbA(1)c value, hsCRP concentration, and presence or absence of late complications. RESULTS PAF-AH activity was higher in the DM1 patients versus the control group (P=0.042). IL-12 concentration was the highest in subgroup with > or =3 mg/L hsCRP (P<0.05). Negative correlations were found for the IL-12 and age of patients and for apo A-I in the subgroup with poor metabolic control. In addition, positive correlation for hsCRP and PAF-AH activity in the subgroup with > or =3 mg/L CRP (P<0.05) was also found. CONCLUSIONS PAF-AH and IL-12 appear to be implicated in the development of a chronic inflammation in DM1. In addition, our results emphasize a protective role of apo A-I against an increase in IL-12 production.

Does oxidized LDL contribute to atherosclerotic plaque formation and microvascular complications in patients with type 1 diabetes

OBJECTIVE The aim of the study was to investigate whether changes in the level of oxidized LDL (oxLDL) over 2-years contribute to the development of subclinical macroangiopathy and/or microvascular complications in patients with DM1. DESIGN AND METHODS Basic clinical and biochemical parameters and oxLDL level were measured in 70 patients at baseline and after 2 years of the study. In addition, an ultrasonographic study was performed to assess the carotid intima media thickness (IMT). RESULTS Patients did not differ according to basic clinical and biochemical parameters at the beginning and after 2 years of the study. IMT increased (p=0.000001) whereas oxLDL level decreased (p=0.00001) in DM1 patients during 2 years. Multivariate regression analysis showed that oxLDL independently influences IMT in DM1 patients (β=0.454, R2=0.35). Further, positive correlations between oxLDL value and LDL-C concentration (r=0.585, p<0.05, n=70) and between oxLDL level and apo-B concentration have been established (r=0.610, p<0.05, n=70). Moreover, patients with chronic microvascular complications showed a higher value of IMT in comparison with patients without them (p=0.003). CONCLUSION Our results provide the evidence that oxLDL accelerates atherosclerotic plaque formation and may contribute to the development of microvascular complications in DM1.

The relationship between concentrations of magnesium and oxidized low density lipoprotein and the activity of platelet activating factor acetylhydrolase in the serum of patients with type 1 diabetes

The study was aimed at comparing the concentration of metabolic parameters, the serum concentration of oxidized low density lipoproteins (oxLDL) and the activity of platelet activating factor acetylhydrolase (PAF-AH) in the relation to the serum concentration of magnesium (Mg) in patients with type 1 diabetes (DM1). DM1 patients (n=78) were divided into 2 groups: patients with low serum Mg concentration (<0.7 mmol/L, group 1, n=34) and patients with reference levels of Mg (>or=0.7 mmol/L, group 2, n=44). A control group (n=24) of healthy subjects was also recruited. Our results showed that DM1 patients had lower serum Mg concentrations than the control group. It was found that parameters of poor metabolic control and lipid profile are not related to the serum Mg concentration in DM1 patients. However, both the Mg concentration and the PAF-AH activity are independently related to the serum oxLDL concentration. In group 1 the oxLDL concentration and the PAF-AH activity were higher than in group 2, and the control group. Two groups of DM1 patients did not show any differences with regard to the metabolic control. Therefore, the oxidative modification of LDL and the higher activity of PAF-AH are related with the low Mg status; however, no relation has been observed between these parameters and the poor metabolic control in DM1 patients.

Does serum cystatin C level reflect insulin resistance in patients with type 1 diabetes

OBJECTIVES The aim of study was to evaluate the relationship between serum cystatin C and insulin resistance (IR) in type 1 diabetic patients being the participants of Poznan Prospective Study. DESIGN AND METHODS The study was performed on 71 Caucasian patients (46 men); with type 1 diabetes, who were recruited into the Poznan Prospective Study, at the age of 39±6.1 meanly, and treated with intensive insulin therapy since the onset of the disease. The follow-up period and diabetes duration were 15±1.6 years. Insulin resistance (IR) was assessed by estimated glucose disposal rate (eGDR) calculation with cut-off point 7.5 mg/kg/min. Patients were divided into two groups, according to the presence or absence of IR. RESULTS From among 71 patients, 31 patients (43.7%) presented decreased sensitive to insulin with eGDR below 7.5 mg/kg/min. Patients who had eGDR <7.5 mg/kg/min (insulin resistant), compared with subjects with eGDR >7.5 mg/kg/min (insulin sensitive), had higher level of serum cystatin C [0.59 (IQR:0.44-0.84) vs 0.46 (IQR:0.37-0.55) mg/L, p=0.009]. A significant negative correlation between cystatin C and eGDR was revealed (Rs=-0.39, p=0.001). In regression model cystatin C was related to insulin resistance, adjusted for sex, BMI, eGFR and duration of diabetes [OR 0.03 (0.001-0.56), p=0.01]. CONCLUSIONS Higher level of serum cystatin C is related to decreased insulin sensitivity in patients with type 1 diabetes. This relationship seems to have an important clinical implication.

Higher concentrations of osteoprotegerin in type 1 diabetic patients are related to retinopathy: Results from the Poznań Prospective Study

BACKGROUND Osteoprotegerin (OPG) is an arterial calcification marker which has been associated with vascular damage. Elevated OPG concentrations associated with low-grade inflammatory processes are found in diabetic subjects. OBJECTIVES The aim of the study was to assess concentrations of OPG in relation to the presence of diabetic complications in patients with diabetes type 1 (DM 1) participating in the Poznań Prospective Study (PoProStu). MATERIAL AND METHODS The study included 74 patients with DM1 (48 men) with a median age of 39 years (interquartile range [IQR]: 34-43) and a median 15-year history (IQR: 14-16) of diabetes, who were participants in the PoProStu. Serum OPG concentration was measured using the ELISA method, and serum concentration of C-reactive protein was measured with a high sensitivity test (hsCRP). The visceral adipose index (VAI) was used to determine indirect markers of insulin resistance (IR). The prevalence of microangiopathic diabetes complications was assessed. RESULTS Retinopathy was diagnosed in 28 patients (38%), diabetic kidney disease (DKD) in 28 (38%) patients, and neuropathy in 17 (23%) patients. The median OPG level was 43.8 (28.0-74.0) pg/mL. Patients with retinopathy had higher levels of OPG than those without retinopathy: 47.5 (35.0-88.0) vs 35.4 (24.7-69.4) pg/mL (p = 0.04). Positive correlations were observed between OPG concentration and hsCRP (Rs = 0.53; p < 0.001), HbA1c level (Rs = 0.36; p = 0.002), VAI (Rs = 0.23; p = 0.04) and waist circumference (Rs = 0.24; p = 0.04). CONCLUSIONS Higher concentrations of osteoprotegerin in DM1 patients are related to the presence of retinopathy. The study results indicate that OPG might play a role in the pathogenesis of vascular complications in association with hyperglycemia and low-grade inflammatory processes.