Kristina Blaslov

Relationship between Adiponectin Level, Insulin Sensitivity, and Metabolic Syndrome in Type 1 Diabetic Patients

Objective. Adiponectin is known to be decreased in insulin resistance (IR) and metabolic syndrome (MS) which can be present in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to evaluate the relationship between adiponectin level, MS, and insulin sensitivity in T1DM. Research Design and Methods. The study included 77 T1DM patients divided into two groups based on the total plasma adiponectin median value. Insulin sensitivity was calculated with the equation for eGDR, and MS was defined according to International Diabetes Federation criteria. Results. Patients with higher adiponectin level (n = 39) had significantly lower waist circumference (P < 0.002), fasting venous glucose levels (P < 0.001), higher HDL3-cholesterol (P = 0.011), and eGDR (P = 0.003) in comparison to the group with lower adiponectin who showed higher prevalence of MS (P = 0.045). eGDR increased for 1.09 mg/kg−1 min−1 by each increase of 1 µg/mL total fasting plasma adiponectin (P = 0.003). In the logistic regression model, adiponectin was inversely associated with the presence of MS (P = 0.014). Conclusion. Higher adiponectin concentration is associated with lower prevalence of MS in T1DM. Whether higher adiponectin concentration has a protective role in the development of the MS in T1DM needs to be clarified in future follow-up studies.

Incretin based therapies:A novel treatment approach for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome (MS). The current treatment of non-alcoholic fatty liver disease (NAFLD) principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment. Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion. Glucagon-like peptide-1 (GLP-1) is the most important incretin. Its receptor agonist and inhibitors of dipeptidyl peptidase-4 (DPP-4) are used in treatment of type 2 diabetes mellitus. DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases. There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment. They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes. The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear. There is growing evidence that incretin based therapies have beneficial effects on hepatocytes, however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD.

Circulating dipeptidyl peptidase-4 activity is associated with insulin resistance in type 1 diabetic patients

AIM The pathophysiology of insulin resistance (IR) comprises a complex adipokine mediated cross-talk between white adipose tissue and other organs. Dipeptidyl peptidase-4 (DPP4) is protease recently proposed as a novel adipokine linked to IR. We aimed to assess the relationship between fasting serum DPP4 activityand IR in type 1 diabetic (T1DM) patients. METHODS A cross-sectional study comprised 44 T1DM patients aged >18 and <65years. IR was esimated using the equation for insulin sensitivity derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate (eGDR). DPP4 serum activity was determined spectrophotometrically as a rate of cleavage of 7-Amino-4-Methyl Coumarin (AMC) from H-Gly-Pro-AMC. RESULTS Patients were divided according to DPP4 activity tertiles (<25.40; ≥36.54 U/L). Fasting serum DPP4 activity was related to disease duration (p=0.012), systolic (p=0.009) and diastolic (p=0.047) blood pressure, waist circumference (p=0.037), urine albumin excretion (p=0.022) and conversely related to eGDR (p=0.004). The linear regression has shown that eGDR decreases for 0.203 mgkg(-1)min(-1) by each increase of serum DPP4 activity of 1 U/L (p<0.001) after adjustment for adjusted for age, gender, disease duration, albuminuria and the use of antihypertensives and statins. CONCLUSION Serum DPP4 activity is associated with IR in T1DM patients and it might play an important role in its pathophysiology.

Circulating dipeptidyl peptidase-4 activity is associated with diabetic retinopathy in type 1 diabetic patients.

Purpose Diabetic retinopathy (DR) is the most frequent complication among patients with type 1 diabetes mellitus (T1DM). Dipeptidyl peptidase–4 (DPP4) is a protease with elevated activity in patients with T1DM. Several studies indicate that DPP4 inhibitors might have beneficial effect on nonproliferative retinopathy (NPR) development as well as on its progression to proliferative retinopathy (PR). We aimed to explore the relationship between serum DPP4 activity and DR in patients with T1DM. Methods This cross-sectional study recruited 44 patients with T1DM. The DPP4 activity was measured by colorimetric assay in a microplate reader. Photodocumented retinopathy status was made according to the EURODIAB protocol. Results A total of 28 (63.6%) patients were men, mean age 45.36 years, diabetes duration 23.71 years, glycated hemoglobin A1c (HbA1c) 7.4%. Patients were stratified into 2 groups according to retinopathy prevalence. Group 1 comprised 14 (31.85%) patients with DR absence while the second group consisted of 30 (68.15%) patients with both PR and NPR. Group 1 had lower fasting serum DPP4 activity (25.85 vs 33.84 U/L, p<0.001) when compared to the second group. In the binary logistic regression model adjusted for age, sex, diabetes duration, and HbA1c level, DPP4 activity was associated with DR prevalence (odds ratio 1.887 [1.073-3.321]). Conclusions Serum DPP4 activity may be independently associated with both DR types in patients with T1DM. Further study is warranted to elucidate whether there is an association between DPP4 activity and DR severity and/or progression.

Waist-to-height ratio is independently associated with chronic kidney disease in overweight type 2 diabetic patients

Abstract Objective: Chronic kidney disease (CKD) is one of the most serious complications in obesity-induced type 2 diabetes mellitus (T2DM). Body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC) and waist-to-height ratio (WHtR) are recognised as sensitive obesity measures. We aimed to investigate the association of BMI, WC, WHR and WHtR with CKD prevalence in overweight T2DM patients. Design, Subjects and Methods: We obtained 125 overweight T2DM patients coming for their in-patient annual visit. Metabolic profiles and anthropometric indices were measured and calculated. Urine albumin excretion (UAE) was determined as the mean of 24-h urine from two consecutive days. Serum creatinine was measured from fasting blood sample in order to calculate the estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients were divided into two groups according to CKD prevalence. Results: Thirty-six (28.8%) patients met diagnostic criteria for CKD. The WHtR and WC were higher in the group with CKD. WHtR correlated positively with UAE (r = 0.828, p < 0.001) and negatively with eGFR (r = −0.262, p = 0.015). No significant correlation was observed with WC in relation to UAE (p = 0.335) nor eGFR (p = 0.121). WHtR yielded the significant and great OR in association with nephropathy after adjustment for all confounding risk factors. Conclusion: WHtR might be of a greater importance in association to CKD compared to other anthropometric parameters that indicate central obesity. Whether it is a best measure of central obesity and its exact role in CKD pathology is yet to be investigated.

Risk factors for development and progression of nonproliferative retinopathy in normoalbuminuric patients with type 1 diabetes

BACKGROUND The aim of this study was to evaluate risk factors for development and progression of nonproliferative retinopathy (NPR) in normoalbuminuric patients with type 1 diabetes mellitus (T1DM). METHODS A total of 223 T1DM with normal renal function and normoalbuminuria were included in this study and followed for 48 months. Photodocumented retinopathy status was made according to the EURODIAB protocol. Urinary albumin excretion rate (UAE) was measured from at least two 24-h urine samples. Possible risk factors for development or progression of NPR were examined in backward stepwise Coxs multiple regression analysis. RESULTS The majority of patients (70%) had no retinopathy while 67 (30%) had NPR at baseline. Patients with NPR were older, had longer duration of diabetes, higher systolic blood pressure, BMI, resting heart rate, UAE and lower estimated glomerular filtration rate (p ≤ 0.04 for all). After 48 months 24 patients (10.7%) developed NPR or progressed to proliferative retinopathy. Systolic blood pressure (HR 1.03, CI 1.01-1.05, p=0.02), UAE (HR 1.14, CI 1.07-1.21, p<0.001), and resting heart rate (HR 1.05, CI 1.01-1.09, p=0.006) were significantly associated with development or progression of NPR. CONCLUSIONS Our results suggest that retinopathy is present and may progress in T1DM even when coexisting renal disease is excluded. Normoalbuminuric T1DM requires close monitoring for the early detection of retinopathy, especially if they have a higher UAE, systolic blood pressure and resting heart rate.

Dipeptidyl peptidase-4 activity is associated with urine albumin excretion in type 1 diabetes

AIMS The inability of kidneys to prevent urinary protein leakage represents the earliest sign of renal damage in diabetic kidney disease (DKD). Recent data suggest the possible nephroprotective role of the dipeptidyl peptidase-4 (DPP-4) inhibitors. We aimed to investigate whether serum DPP-4 activity is associated with urine albumin excretion (UAE) in patients with type 1 diabetes (type 1 DM). METHODS DPP-4 activity and UAE measurement were performed in 113 patients with type 1 DM and glomerular filtration rate (GFR) within normal range. They were divided into three groups according to UAE tertiles. RESULTS Worse lipid profile and higher waist circumference were observed in the group with highest DPP-4 activity. Patients within lowest UAE tertile group had lowest DPP-4 activity value (p<0.001) compared to group within second and third tertile of UAE. DPP-4 activity correlated with systolic blood pressure (ρ=0.142; p=0.001), HbA1c (ρ=0.133; p=0.013) and UAE (ρ=0.349; p<0.001). In the linear regression analysis when DPP-4 activity was adjusted for age, gender, disease duration, HbA1c, waist circumference, the use of ACEI and hypolipemic agents the association remained significant; UAE increased for 8.136mg/24h by each increase of DPP-4 activity of 1U/L (p<0.008). CONCLUSION Our results indicate that serum DPP-4 activity is associated with albuminuria in type 1 diabetes. This arises the question whether the use of DPP-4 inhibitors might serve as an additional therapeutic strategy to prevent proteinuria in patients with DKD.

Fasting serum dipeptidyl peptidase-4 activity is independently associated with alanine aminotransferase in type 1 diabetic patients.

OBJECTIVES Dipeptidyl peptidase-4 (DPP4) was recently proposed as a novel adipokine linked to insulin resistance (IR). As IR represents a cluster of disorders in hepatic and muscle cell insulin signalisation, we aimed to assess the possible correlation between fasting serum DPP4 activity, IR and liver enzymes in order to elucidate the question of hepatic contribution to serum DPP4 activity. DESIGN AND METHODS This cross-sectional study comprised 44 T1DM patients aged 18 to 65years. IR was estimated using the equation derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate (eGDR). DPP4 serum activity was determined spectrophotometrically as a rate of cleavage of 7-amino-4-methyl coumarin (AMC) from H-Gly-Pro-AMC. The patients were divided into two groups according to the mean value of fasting serum DPP4 activity (31.42U/L). RESULTS The group with lower fasting serum DPP4 activity had lower mean rate of liver biomarkers alanine aminotransferase (ALT) (p=0.001) and aspartate aminotransferase (AST) (p=0.002) while higher eGDR (p=0.003) compared to group with higher DPP4 activity. DPP4 activity showed positive correlation with AST (r=0.358, p=0.017) and ALT (r=0.364, p=0.015) while negative correlation with eGDR (r=-0.612, p<0.001). ALT remained positively associated with fasting serum DPP4 activity after controlling for age, gender, diabetes duration, the use of statins and antihypertensives (p=0.025). CONCLUSIONS Fasting serum DPP4 activity might be associated with hepatic IR in T1DM patients and a part of soluble DPP4 activity might be of a hepatic origin. Further study investigation is warranted to elucidate this topic.

Difference in glucagon-like peptide-1 concentrations between C-peptide negative type 1 diabetes mellitus patients and healthy controls.

Background The role of glucagon-like peptide-1 (GLP-1) has become a new scientific interest in the field of pathophysiology of type 1 diabetes mellitus (T1DM), but the results of the published studies were contradictory. The aim of our study was therefore to measure fasting and postprandial GLP-1 concentrations in T1DM patients and in healthy controls and to examine the difference in those concentrations between the two groups of subjects. Methods The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20–59), with disease duration 22 years (3–45), and 10 healthy controls, median age 30 years (27–47). Fasting and postprandial total and active GLP-1 concentrations were measured by ELISA (ALPCO, USA). The data were statistically analysed by SPSS, and significance level was accepted at P < 0.05. Results Both fasting total and active GLP-1 concentrations were significantly lower in T1DM patients (total 0.4 pmol/L, 0–6.4 and active 0.2 pmol/L, 0–1.9) compared with healthy controls (total 3.23 pmol/L, 0.2–5.5 and active 0.8 pmol/L, 0.2–3.6), P = 0.008 for total GLP-1 and P = 0.001 for active GLP-1. After adjustment for age, sex and body mass index, binary logistic regression showed that both fasting total and active GLP-1 remained significantly independently lower in T1DM patients (total GLP-1: OR 2.43, 95% CI 1.203–4.909 and active GLP-1: OR 8.73, 95% CI 1.472–51.787). Conclusions T1DM patients had independently lower total and active GLP-1 fasting concentrations in comparison with healthy people, which supports the potential therapeutic role of incretin therapy, along with insulin therapy, in T1DM patients.

Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes

AIMS We aimed to determine serum dipeptidyl peptidase-4 (DPP-4) activity in a group of persons with latent autoimmune diabetes in adults (LADA) and to compare it with persons with type 1, type 2 diabetes and healthy controls. METHODS DPP-4 activity measurement was performed in 67 persons (21 with type 1, 26 type 2 and 19 with LADA) and 13 healthy age and gender matched controls. RESULTS Persons with LADA showed highest DPP-4 activity among the study groups (32.71±3.55 vs 25.37±2.84 vs 18.57±2.54 vs 18.57±2.61U/L p<0.001). Mean glutamic acid autoantibody in persons with LADA was 164.32±86.28IU/mL. It correlated with DPP-4 activity (r=0.484, p=0.013). Furthermore, DPP-4 activity correlated with waist circumference (r=0.279, p=0.034) and glycated haemoglobin A1c (r=0.483, p<0.001), as well as with LDL cholesterol (r=0.854, p<0.001) and total daily insulin dose (r=0.397, p=0.001). In the multinomial regression analysis DPP-4 activity remained associated with both LADA (prevalence ratio 1.058 (1.012-1.287), p=0.001) and type 1 diabetes (prevalence ratio 1.506 (1.335-1.765), p<0.001) while it did not show an association with type 2 diabetes (prevalence ratio 0.942 (0.713-1.988), p=0.564). CONCLUSIONS Persons with LADA express higher DPP-4 activity compared to persons with both type 1 and type 2 diabetes. The possible pathophysiological role of DPP-4 in the LADA pathogenesis needs to be further evaluated.