1. D. Karasek, J. Gajdova, V. Kubickova, O. Krystynik, L. Cibickova, H
D. Karasek, J. Gajdova, V. Kubickova, O. Krystynik, L. Cibickova, H. Vaverkova 3rd Department of Internal Medicine and Department of Clinical Biochemistry University Hospital Olomouc, Czech Republic
Selected adipokines in patients with type 2 diabetes: relationship to markers of endothelial dysfunction and arterial stiffness 1

2. Adiponectin
one of the most abundant peptide hormones derived from adipose tissue
plays a major role in glucose and lipid metabolism and prevents development of cardiovascular changes due to its anti-oxidative, anti-inflammatory, endothelium-protective and anti-apoptotic effects
hypoadiponectinemia is associated with obesity, diabetes, hypertension, mixed dyslipidemia, metabolic syndrome, non-alcoholic steatosis, coronary artery disease, etc.
Xu A, Vanhoutte PM. Am J Physiol Heart Circ Physiol. 2012
Fisman EZ, Tenenbaum A. Cardiovascular Diabetology 2014

3. Adipocyte Fatty Acid Binding Protein
is formed mainly in adipocytes and macrophages, partially in lymphocytes, its main function is the binding of free fatty acids
increases lipolysis and insulin resistance, reduces contractility of cardiomyocytes, promotes chronic inflammation and formation of vulnerable atherosclerotic plaques
its increased levels were found in obesity, metabolic syndrome, T2DM, NASH, CAD, ischemic stroke
is a biomarker (maybe even the main mediator) of obesity related cardiovascular diseases
Xu A, Vanhoutte PM. Am J Physiol Heart Circ Physiol. 2012
Pasterkamp G. Arterioscler Thromb Vasc Biol. 2012

4. Fibroblast Growth Factor 21
is produced by liver, pancreas, muscles and adipocytes
participates in the regulation of metabolism of sugars (increases insulin sensitivity, gluconeogenesis, glucose uptake) and fat (increases oxidation of fatty acids, ketogenesis, HDL-C levels, decreases TG and LDL-C)
stimulates thermogenesis and reduces weight (its analogs were tested as anti-obesity drugs)
its elevation is found in obesity, metabolic syndrome, non-alcoholic steatosis and coronary artery disease. (maybe due to its resistance or as a compensatory mechanism)
Woo YC, et al. Clin Endocrinol (Oxf). 2013, Li H, et al. Front Med. 2013,
Kim KH, Lee MS. Diabetes Metab J , Jin L et al. Diabetes Metab J. 2016

5. C1q/TNF-related protein 9
is the closest adiponectin paralog (↓glycemia, ↓IR, anti-steatotic effect → ↓TG accumulation)
is predominantly expressed in adipose tissue
besides its metabolic roles that overlap with those of adiponectin, has attracted a lot of attention due to its beneficial cardiovascular effects detected in animal models:
significant endothelium-dependent vasorelaxation
suppression of neointimal hyperplasia and vascular smooth muscle cells proliferation
attenuation adverse cardiac remodeling
In human:
its low levels correlated with visceral obesity, adverse metabolic profile and presence of metabolic syndrome
its circulated levels and local production protect against CAD XX
its high levels correlated with obesity and decreased after bariatric surgery and weight loss
its increased levels correlated with C-IMT in T2DM HC
CAD
Wong GW et al. FASEB J. 2009, Jung CH et al. J Clin Endocrinol Metab. 2014, Hwang YC et al. Int J Obes (Lond). 2014, Wang J et al. Biomed Res Int. 2015, Li J et al. Biochem Biophys Res Commun. 2015, Wolf RM et al. J Clin Endocrinol Metab. 2016, Asada M et al. J Diabetes Res. 2016

6. Allograft Inflammatory Factor–1
is not produced by adipocytes, but by macrophages, which belong to numerous cells presented in fat tissue
promotes macrophages, VSMCs and endothelial cells activation, proliferation and migration
correlates with clinical (BMI, waist) and biochemical (FPG, TG, HDL-C, HbA1c, uric acid) metabolic parameters and maybe associated with atherogenesis
Tian Y et al. Am J Physiol Cell Physiol. 2009, Fukui M et al. Metabolism. 2012, Zhao YY et al. Cell Immunol. 2013, Wang J et al. Cell Physiol Biochem. 2013, Fukui M et al. Diabetes Res Clin Pract. 2012

7. Aim of study, subjects Anti-diabetic medication (%) Co-morbidities (%)
To compare adipokines levels in patients with diabetes and in healthy individuals
To determine their relationship to indicators of early vascular damage
Subjects
54 patients with type 2 diabetes (32 men, 22 women) and 21 healthy controls (8 men, 13 women)
Anti-diabetic medication (%) Co-morbidities (%)

8. Methods Cross-sectional study:
adiponectin, A-FABP, FGF-21, CTRP-9, AIF-1
anthropological parameters (BMI, waist, SBP, DBP), smoking, diabetes duration
lipids: CH, TG, HDL-C, LDL-C, apoB
parameters of insulin resistance and diabetes compensation: insulin, C-peptide, FBG, HOMA, HbA1C
parameters of inflammation and CKD: hs-CRP, IL-6, ACR, eGF
markers of endothelial dysfunction: vWF, PAI-1, t-PA
markers of arterial stiffness (SfymgoCor): augmentation index (AIx=AP/ PP*100) a pulse wave velocity (PWV)

9. Markers of vascular damage
T2DM
(n=54)
nephropathy –
(n=33)
nephropathy +
(n=21)
healthy
controls
vWF
(%)
133.1 ( )**
126.0 ( )
143.5 ( )*
98.5 ( )
PAI-1
(ng/ml)
78.1 ( )***
73.6 ( )
80.0 ( )**
36.9 ( )
t-PA
2.9 ( )
2.9 ( )
2.9 ( )
2.7 ( )
AIx
(1)
22.5 ( )
18.4 ( )
27.1 ( )*
15.0 ( )
PWV
(m/s)
9.0 ( )
7.2 ( )
9.3 ( )
7.1 ( )
ANOVA (after adjustment for age, sex and BMI), * p<0.05, ** p<0.01 *** p<0.001

10. Adiponectin (μg/ml) p<0.05 p<0.001
ANOVA (after adjustment for age, sex and BMI)
Statistically significant correlations (Pearson´s correlation coefficient, p<0.05):
Negative: age (r=-0.25), BMI (r=-0.31), waist (r=-0.59), smoking (r=-0.24), TG (r=-0.39), HbA1C (r=-0.47),
C-peptide (r=-0.24)
vWF (r=-0.29), PAI-1 (r=-0.35)
Positive: HDL-C (r=0.68)

11. A-FABP (ng/ml) p<0.01 p<0.001
ANOVA (after adjustment for age, sex and BMI)
Statistically significant correlations (Pearson´s correlation coefficient, p<0.05):
Positive: age (r=0.43), BMI (r=0.56), waist (r=0.82), SBP (r=-0.29), pulse (r=0.29),
HbA1C (r=0.41), C-peptide (r=0.28), FBG (r=0.24), insulin (r=0.29)
vWF (r=0.61), PAI-1 (r=0.47), AIx (r=0.39)
Negative: HDL-C (r=-0.38)

12. FGF-21 (pg/ml)
n.s.
ANOVA (after adjustment for age, sex and BMI)
Statistically significant correlations (Pearson´s correlation coefficient, p<0.05):
Positive: hs-CRP (r=0.23), HbA1C (r=0.24), non-HDL-C (r=0.24), ACR (r=0.28)
PAI-1 (r=0.27)
Negative: HDL-C (r=-0.38)

13. CTRP-9 (pg/ml)
n.s.
ANOVA (after adjustment for age, sex and BMI)
Statistically significant correlations (Pearson´s correlation coefficient, p<0.05):
Negative: C-peptide (r=-0.26)

14. AIF-1 (pg/ml)
ANOVA (after adjustment for age, sex and BMI)
n.s.
Statistically significant correlations (Pearson´s correlation coefficient, p<0.05):
Positive: non-HDL-C (r=0.27)
Negative: HDL-C (r=-0.35)

15. Conclusion
Patients with type 2 diabetes have significantly higher levels of A-FABP and lower levels of adiponectin.
The levels of these adipokines correlate with indicators of vascular damage and could thus directly contribute to cardiovascular risk individuals with diabetes.
A-FABP could participate in direct endothelium damage.
The increase of FGF-21 could be a secondary result as an effort to increase low adiponectin (maybe also CTRP-9) levels and to protect vessels against the vascular injury.
fat tissue
endothelium
A-FABP
↑ FGF-21
liver
adiponectin, (CTRP-9 ?)