12.5 Metabolic Syndrome & Macrovascular Complications Flashcards
What body phenotype is associated with metabolic syndrome
Apple body shape
With what is metabolic syndrome associated with?
- DM
- Gout
- Hypertension
- Insulin resistance
Define Metabolic syndrome
Slide 6 (5?)
Slide 7 very NB
Associated conditions with metabolic syndrome
not in definition but still associated
- Polycystic ovarian disease
- Fatty liver disease
- Hepatocellular carcinoma
- Hyperuricemia /gout
- Low grade inflammation with endothelial dysfunction / pro inflammatory state
- Hypercoaguability
- Chronic kidney disease
- Obsructive sleep apnoea
⬆️ risk for macro-vascular risk
Practical importance of metabolic syndrome
- 5 fold increased risk of T2DM in next 5 – 10 years
- 2 fold increased risk of CVD (MI and stroke) in next 5 – 10 years and increased associated mortality with these events
Pathophysiology of MeS
Driving force = visceral adiposity
Insulin resistance
- post receptor abnormalities in insulin signalling
- effect due to adipocyte hormones, cytokines and excess FFA release
- ⬆️glucose uptake of muscles and liver
- ✖️lipolysis and hepatic gluconeogenesis -> ⬆️ FFA’s (further ✖️ antilipolytic effects of insulin)
Neurohormonal activation
- Increased production of Ang II
Chronic inflammation
- contributes to endothelial dysfunc and vascular disease
- caused by adipocytokines
More on slide 14-18
More on slide 11
Pathophysiology process of MeS
Slide 19
Pathophysiology of Insulin resistance
- the metabolic pathway is affected and glucose homeostasis abnormal if not fully compensated
- the mitogenic pathway often continues to function normally, if metabolic abnormality compensated for with hyperinsulinaemia this may result in increased mitogenic effects on vascular smooth muscle and predispose to vascular abnormalities
- IR leads to compensatory ⬆️ in insulin secretion by pancreas to overcome deficient metabolic action
- IR in patient with normal beta-cell will be accompanied by hyperinsulinemia
Effects of IR seen in MeS the combined effect of:
- relative insulin deficiency (impaired glucose homeostasis) &
- the excess mitogenic effect of compensatory high insulin levels on insulin sensitive tissue such as vascular smooth muscle
Dysglycemia
• Result of insulin resistance and decreased signaling / decreased insulin effects along the metabolic pathway
• One of criterium for defining MeS is that of impaired fasting glucose (“pre-DM”).
• Do not have to fulfill diagnostic criteria for overt Type 2 diabetes.
• “Pre-diabetes” implies limited functional ability of -cell to
compensate for insulin resistance
• Significant risk of Type 2 diabetes mellitus in patients with MeS
Dyslipidemia
Consequence of reduced insulin effects
• Increased production of FFA by fat cells; increased production of triglycerides and VLDL by liver
• Decreased clearance of VLDL (⬇️ Lipoprotein lipase activity)
• Production of small, dense atherogenic LDL
• Increased clearance and thus reduced levels of HDL
Classic lipid abnormality in MeS and in Type 2 Diabetes Mellitus that of:
• High triglycerides
• Low HDL
• Small, dense atherogenic LDL
Hypertension
Consequence of hyperglycemia, hyperinsulinemia and IR
• Activation of the RAS system (Renin Angiotensin System) - high glucose and insulin
• Sympathetic nervous system activation induced by obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels (worsens metabolic outcome)
• Aldosterone production by adipocytes
Endothelial dysfunction & Hypercoagulable state
Endothelial dysfunction leads to accelerated atherosclerotic process
• Hyperglycemia, increased FFA, adipocytokines, reduced NO and increase in reactive oxygen species contributes to endothelial impairment
•
Pro-inflammatory state of MeS and pro-thrombotic
state metabolically interconnected; increase in fibrinogen
seen in response to high cytokine state. Increases in factor
VII & VIII ,Plasminogen Activator Inhibitor-1, abnormal platelet function ,endothelial dysfunctions contribute to tendency to thromboses
Visceral obesity
Energy intake exceeds energy expenditure
• Dietary content (high carbohydrate / processed foods…)
• Sedentary lifestyle
• Drives prevalence of MeS
• Drives Type 2 diabetes pandemic
• LIFESTYLE DISEASE!!!!!
• Significantly impacts on macrovascular disease risk
MeS significance
- Macrovascular disease is the main cause of morbidity and mortality in patients with MeS and especially in patients with overt Type 2 Diabetes Mellitus
- Atherosclerosis accounts for up to 70% of all diabetic mortality!
Risk factors for macrovascular disease in a Diabetic pt
- hypertension
- dyslipidemia
- diabetic kidney disease
- insulin resistance
- obesity
