Metabolic syndrome, obesity, diabetes, and theier implications

jan.krtil@lf1.cuni.cz

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/