adiponectin its emerging role in atherosclerosis, metabolic syndrome and insulin resistance rt...
TRANSCRIPT
ADIPONECTINIts emerging role in Atherosclerosis,
Metabolic Syndrome and Insulin Resistance
RT ERASMUS
Chemical Pathology, Tygerberg Hospital,
NHLS &University of Stellenbosch
Discovery and Structure (1)
● Discovered by 4 independent researchers in 1996● More than 1000 papers published mostly from
Japan ● Specific and most abundant in adipocytes● Part of adipokine family (TNFalpha, leptin)● 30 kDa protein; 247 amino acids coded by apM1
gene● Member of collagen family, shares homology with
collagen VIII & X and complement C1q
Copyright ©2005 The Endocrine Society
Kadowaki, T. et al. Endocr Rev 2005;26:439-451
FIG. 1. Structure and domains of adiponectin
Physiology(1)● Expressed and secreted only in adipose tissue
● Endogenous adiponectin post translationally modified into 8 isoforms
● Globular portion as efficient as full length adiponectin at lowering glucose & FFA
● Pulsatile & diurnal secretion similar to other hormones
● Secretion hormone regulated: ↓levels with insulin& glucocorticoids
● TNFα decreases adiponectin transcription
● Elisa &RIA methods available : 5-10 ug/ml
Physiology (2)
● Correlates negatively with BMI & more –vely with visceral than subcut fat
● High levels in plasma (3 x normal conc of other hormones)
● Low levels seen in obesity, type 2 DM, IHD● Levels correlate with insulin sensitivity
Biological Effects (1)
● Insulin- sensitizing actions
● Adiponectin reduces tissue TG content and up regulates insulin signaling through ↑CD36, ↑combustion of fatty acids →↑GLUT4 ( Rx of obese diabetic mice with adiponectin →↑phosphorylation of IRS-1 & insulin receptor)
● Activation of PPARα leading to ↑ fatty acid combustion → ↓tissue FA → ↑ insulin sensitivity (C2C12 myocytes with adiponectin)
Biological effects (2)
● No adiponectin found in normal vessels but in balloon injured vascular walls
● Inhibits adhesion molecules eg E selectin, vascular adhesion mol 1, intracellular adhesion 1
● Inhibits SR-A class of macrophages – decreases uptake of oxidised LDL & thus inhibiting foam cell formation
Polymorphisms in Gene ass with hypoadiponectinaemia, Type 2 DM and Insulin Resistance
● Adiponectin gene, chrom 3, spans 17kb, 3 exons & 2 introns
● Several SNP polymorphisms in Japanese, German and Americans have been identified and ass with Type 2 DM and IR eg SNP 276 and SNP 45(many ass with abnormal forms of adiponectin or low levels)
● This strongly suggests pivotal role of Adiponectin in dev of type DM
Adiponectin Receptors● 2003 : 2 receptors identified:Adipo R1 & R2● Expressed in skeletal muscle and liver● 7 transmembrane proteins● Receptors for both full length & globular
adiponectin● Recently receptors also found in pancreas β
cells● Receptors mediate ↑AMP kinase & PPARγ
activity→ FA oxidation & ↑glucose uptake
Regulation of Adiponectin Receptors● Fasting upregulates expression and refeeding
restores them● Insulin negative regulator – low levels in
insulin resistance● Decreased expression in obesity leading to
decreased adiponectin sensitivity and adiponectin resistance and subsequent insulin resistance setting up a “vicious cycle”
Obesity, adiponectin and insulin resistance
Adiponectin and atherosclerosis
● In cultured cells, human recombinant adiponectin suppresses endothelial expression of adhesion molecules, proliferation of vascular smooth muscle cells & transformation of macrophages to foam cells: adiponectin may thus protect vascular wall against atherogenic changes
● In mice overexpression of adiponectin reduced atherosclerotic plaques
Adiponectin and Insulin Resistance
● Low adiponectin levels seen in obese humans, cardiovascular diseases, hypertension or metablocs syndrome – all of which are ass with IR
● Whether there is cause and effect relationship not known
● Several exp in mice have clearly established the insulin sensitizing effects of adiponectin (along with leptin) as well as the reversal of IRS with recombinant adiponectin – could this be used to treat IR and type 2 DM ?
Adiponectin Hypothesis
● Reduced levels may occur due to genetic(polymorphisms, SNP 276) or environmental factors(obesity,HF diet) and or reduced actions due to down regulation of receptors (obesity)
● These reduced levels may play a causal role in dev IR, MS & progress to atherosclerosis
Conclusion
● Adiponectin specific adipokine produced by adipocytes in large amounts
● Has potent antinflammatory and atheroprotective properties
● Has insulin sensitizing effect influencing glucose and lipid metabolism
● Is associated with insulin resistance and the metabolic syndrome