Metabolic syndrome, obesity, diabetes, and theier implications
Institute of Medical Biochemistry and Laboratory Diagnostics
& 1st Department of Medicine
Diabetes mellitus type 2 (T2DM) - obesity
Clinical level:
obesity T2DM vascular complications
tumours
Alzheimer disease
Cellular/biochemical levels:
glucose carbonyl stress/non-enzymatic glycationlipides (FFA) oxidation stress
Diabetes mellitus type 2 (T2DM) - obesity
Clinical level:
obesity T2DM vascular complications
tumours ↑
Alzheimer disease CHRONIC
SUBCLINICAL
(micro)INFLAMMATION
Cellular/biochemical levels:
glucose carbonyl stress/non-enzymatic glycationlipides (FFA) oxidation stress
Libby et al. Circulation 2002;106(22):2760‒2763. Jacobs et al. Diabetes Res Clin Pract. 2005;70(3):263‒269.
79 % of T2DM patients are overweight or obese63 % of T2DM patients have arterial hypertension70 % of T2DM patients have dyslipidemia
Metabolic syndrome
described by Reaven in 1988
T2DM (insulin resistance hyperglycemia + hyperinsulinaemia)
dyslipidemia ( HDL, (ox)LDL, TAG) hypertension
visceral obesity
Ravussin et al, 2002
Adipokines:
Pro-inflammatory: TNF-α, TGF β, leptin, resistinAnti-inflammatory: adiponectin
Myokines:
anti-inflammatory, pro-regenerative effects
BMI and mortality in elderly
Winter JE. Am J Clin Nutr 2014, 99: 875-90
Save your muscle!!!
Diabetes mellitus
Increasing incidence (type 2 DM) life expectancy life quality
long-term complications
Long term complication of diabetes mellitus
T2DM pathogenesis: Death octet (DeFronzo, 2009)
described by Reaven in 1988
Metabolic syndrome/T2DM/obesity
insulin resistance hyperinsulinaemia
growth factorproliferation of vessel wall, chronic inflammation, tumour cells
fixation of FA in fat tissue↑ insulin inhibits fat tissue reduction
Metabolic syndrome – consequence
eNOS activity + NO degradation + angiotensin II endothelial dysfunction - vasoconstriction
insulin resistance insulin/insulin-1 growth factor (IGF-1) vascular smooth muscle cell proliferation/vascular and cardiac fibroblast migration and proliferation vascular wall(myocard) hypertrophy
insulin/IGF-1 risk of tumour growth
plasminogen activator inhibitor-1 procoagulation status
Metabolic syndrome – consequence
abnormal accumulation of visceral fat inflammatory cytokines chronic inflammationstatus
All together tissue/organ ischemia
cardiovascular/cerebrovascular disease risk
„Toxic“ effect of hyperglycemia - mechanism
1. Polyol pathway2. Advanced Glycation End-products formation3. Protein kinase C pathway4. Hexosamine pathway
Effect of superoxide production
Polyol pathway
Polyol pathway
Consumption of reduced NADPH glutathione regeneration intracellular oxidative stress
Advanced Glycation End-products (AGEs) -formation
created by M. Kalousová
Advanced Glycation End-products (AGEs) -formation
Glucose AGEs formationimportance:• development of long-time complications• laboratory marker of diabetes compensation(HbA1)
Advanced Glycation End-products - action
Advanced Glycation End-products - action
Endothelial cell: intracellular generation of AGEs precursors (e.g. glyoxal) intracellular action intracellular proteins glycation affected gene transcriptionextracellular transport matrix proteins glycation affected cell-matrix interactionextracellular transport AGEs formation AGE-RAGE interaction nuclear NF- B pro-inflammatory cytokines and growth factors
Protein kinase C pathway
Protein kinase C pathway
Vascular/blood effect: vasoconstriction, occlusion, pro-coagulation Global effect: inflammation, protein/DNA damage INFLAMMATION
ISCHEMIA
Hexosamine pathway
Hexosamine pathway
GFAT: glutamine:fructose-6-P amidotransferaseUDP-N-acetyl glucoseamine binding to serine + threonine residues modification of transcription factors overexpession of pro-inflammatory/pro-coagulation factors
ISCHEMIA
Hyperglycaemia induces superoxide production in mitochondria
Excess of NADH+H+/FADH2 Block of complex III superoxide formation
Effect of superoxide production
Superoxide production activation of nuclear PARP /poly(ADP- ribose) polymerase/ inhibition of GAPDH accumulatin of glycolysis metabolites activation of damaging pathways
PARP inhibits GAPDH - mechanism
PARP inhibits GAPDH
Mechanism:• depletion of NAD+ (cofactor of GAPDH) • poly(ADP- ribosy)lation
Consequence:• inhibition of glycolysis, resulting excess of glycolysis metabolites• activation of damaging pathways•endothelial dysfunction, iflammation, ISCHEMIA
PARP inhibits GAPDH - consequence
Carbonyl stress – (methyl)glyoxal generation
glucose (methyl)glyoxal generation (MG)
T2DM - therapy
Change of lifestyle – body weight reduction
Pharmakotherapy:
metformin (biquanides) – 1st line therapypotential anticancer effects
gliflozins - inhibitors of SGLT-2 (sodium-glucose co-transporter type 2)
cardiovascular protection in T2DM patiens
Metabolic syndrome/T2DM - further therapy
inhibition of renin-angiotensin-aldosterone system- ACE inhibitors- AT1 receptor blockerslowering of blood pressureantiproliferative effect (fibroblasts, VSMCc, cardiomyocytes)
statins (HMG-CoA reductase inhibitors)lowering of hypercholesterolemia/improvement of dyslipidemiaantiproliferative effect (fibroblasts, VSMCc, cardiomyocytes)
Take home message/vezměte si (domů
Hyperglykémie (dlouhodobá) je nebezpečná Hypoglykémie zabíjí
Dlouhodobá hyperglykémie vede k chronickému (mikro)zánětu
Chronický (mikro)zánět poškozuje cévy
Ve vyšším věku je lepší mít mírnou nadváhu Sval si zaslouží ochranu
References:
Brownlee M /Diabetes 54, 2005/ Kanwar YS et al /Exp Biol Med 233, 2008/Porter KE, Turner NA /Pharmacol Ther 123, 2009/Duan SZ et al /Circ Res 102, 2008/Pacher P, Szabo C /Antioxid Redox Signal 7, 2005/Turk Z /Physiol Res 59, 2010/Svačina Š /výběr z prezentací/