Flashcards in Unit 6 - Metabolic Syndrome Deck (31):
what are the hallmarks of MetS?
-visceral obesity (increased waist circumference)
-dyslipidemia (increased TG from insulin-stimulated synthesis in liver; low HDL b/c overloaded by TAG so increased clearance)
-HTN (reduced insulin-stimulated vasodilation, more atherogenic inflammation)
-insulin resistance (slow glucose disposal and hyperinsulinemia)
-hyperglycemia (increased propensity to DM2)
-increased blood clotting
what is the major risk factor that predisposes MetS, and how does it lead to the rest of the hallmarks?
1. visceral obesity (excessive adiposity) leads to cytokine (cause low grade systemic inflammation) and NEFA release
2. insulin resistance (from NEFA and cytokines)
3. hyperglycemia (directly caused by IR)
4. dyslipidemia (b/c hyperinsulinemia stimulates TG synthesis, increasing HDL clearance)
5. HTN (not fully understood, but probably caused by visceral obesity, IR, and dyslipidemia)
what percentage of US population will have MetS by the time they are 60 yo?
what causes beta-cell damage and propensity for DM2?
insulin resistance, dyslipidemia, and hyperglycemia
what is insulin resistance defined by?
-slow glucose disposal in a GTT that measures rate of glucose glearance at defined insulin levels
-high fasting insulin level
what are the effects of insulin resistance, especially on muscle, liver, and fat cells?
-in muscle: decreased glucose uptake and glycogenesis
-in liver: decreased glycogenesis; increased postprandial gluconeogenesis and glucose release
-in fat: decreased glucose uptake, LPL, TG storage, adiponectin, insulin signaling; increased lipolysis, NEFA, and cytokines
how much do muscle and fat cells account for glucose disposal? what does this mean for IR?
muscle > 90%
fat cells < 2%
this means the primary consequence of IR in muscle and lvier is elevated blood glucose
how is adipose tissue an important endocrine organ? how does it differ between fat and skinny people?
skinny: adipose releases more adiponectin (which decreases NEFA), and less leptin, NEFA, and macrophages
fatter: releases less adiponectin, and more leptin, NEFA, and macrophages (40-50% increase; release inflammatory cytokines)
what is the lipotoxicity theory and what is it caused by?
1. FA and glucose compete for access to muscle oxidation machinery
2. regulation breaks down in obesity b/c high NEFA enter muscle cells, exceeding capacity for mitochondria to oxidize them
what do adiponectin and leptin work together to do?
both adipokines stimulate beta-oxidation and lower lipolysis to reduce levels of FFA and lipotoxicity
how do macrophage levels change in obese VS nonobese?
normally 5% of all cells in adipose tissue, but in obese people it accounts for >50%
what are the 2 theories as to why insulin resistance comes about?
1. lipotoxicity theory (excessive adipose tissue and reduced adiponectin increases NEFA)
2. low-grade systemic inflammation theory (excessive adipose activates diverse range of stress-response and inflammatory signaling pathways)
what does increased DAG do to insulin signaling?
DAG accumulation inhibits insulin signaling (increases PKC and decreases P13K kinase)
-inhibits translocation of GLUT4 in muscle
-decreases glycogen synthesis in liver
what are the 5 main causes for DAG accumulation?
1. excessive caloric intake (increased lipogenesis)
2. defects in adipocyte metabolism (including lipid storage and lipolysis)
3. defects in mitochondrial function (reduced beta-oxidation)
4. gene variation in CIII (reduces LPL activity)
5. reduced AMP-activated PRO kinase signaling (decreased catabolism and increased ATP consumption)
what role does AMPK play in modulating FA oxidation?
trimeric ser/thr PRO kinase allosterically activated by AMP (low intake)
-activates catabolic pathways (glucose transport, glycolysis, FA uptake, FA oxidation, mitochondrial biogenesis and autophagy)
-inhibits anabolic pathways (lipogenesis, cholesterol and TG synthesis, glycogen synthesis, PRO synthesis)
-stimulated by adipokines
what does AMPK do to ACC and CPT1?
inhibits ACC (so no ACoA --> mCoA)
activates CPT1 (so FAcyl CoA is beta-oxidized, instead of becoming TGs)
what does metformin do? what is it used to treat?
stimulates AMPK (phosphorylates it)
-enhances insulin sensitivity by inhibiting liver gluconeogenesis by lowering FA accumulation in mitochondria
-lowered lipid stores causes less PKC-mediated suppression of insulin receptor signaling, so more Akt, which suppresses Foxo
-commonly used to treat DM2 (less so MetS)
what does FOXO1 have to do with insulin resistance? what happens if metoformin is given?
hepatic lipid accumulation inhibits insulin receptors, which decreases the amount of P13K and Akt made
-P13K and Akt usually inactivate FOXO, so if obese, FOXO1 is active, to elevate gluconeogenesis and glucose release
-metformin lowers FA accumulation by affecting mitochondria, which decreases PKC
--the insulin receptors are now able to make P13K and Akt, which inactivate FOXO1 again, to reduce gluconeogenesis and glucose release
how do macrophages cause insulin resistance?
obese people have more macrophages, which release cytokines (TNF-alpha, IL-6, PAII) that activate stress kinases (IKK-beta, JNK1, PKC) due to inflammation
-kinases phosphorylate IRS1 on inhibitory serine residues
-these residues inhibit insulin signaling
how can severe mitochondrial dysfunction lead to FA overload and insulin resistance?
-over-nutrition and obesity causes oxidative stress to mitochondria, damaging them
-resulting decreased beta-oxidation causes increased DAGs (b/c acyl CoA have nowhere else to go), causing insulin resistance
what are two diseases that link mitochondria to diabetes?
1. MIDD syndrome - maternally inherited diabetes and deafness are due to mtDNA mutations
2. Freidreich's ataxia - mitochondrial disease where 20% of patients get DM2
what do some macronutrients, like fructose and alcohol, do to contribute to IR and MetS?
1. metabolized primarily in liver
2. metabolism is not insulin or glucose related (so continues no matter what)
3. don't have mechanism to form glycogen for storage (directly converted to lipids via lipogenesis)
-increases intrahepatic lipid deposition and steatosis
what is the difference between visceral and subcutaneous fat?
visceral: apple shaped with high waist:hip circumference ratio (upper body obesity); have smaller fat droplets so metabolically more active in lipolysis and TG synthesis for storage)
subcutaneous: pear-shaped with lower waist:hip circumference ratio (lower body obesity); one big droplet
what is different about visceral fat that causes greater risk of MetS?
1. anatomy: intra-abdominal, so direct venous drainage to liver (NEFA et al directly and uniquely affect gene regulation, liver metabolism, and hepatic insulin sensitivity)
2. distinct intrinsic properties, mainly lipolysis: high expression of beta3-adrenergic receptors on cell surface (increases lipolytic response to catecholamines) and less responsive to insulin inhibition of lipolysis (so increased NEFA)
3. more active in secreting proinflammatory molecules
what are the 3 methods to treat MetS?
1. increase AMPK
2. directly remodel lipid metabolism (decrease NEFA)
3. remodel adipogenesis (visceral --> subcutaneous fat)
4. "brown" white adipose tissue
what are PPARs (generally speaking)? what do they do? what activates them?
peroxisome proliferator-activated receptor; family of ligand-activated nuclear receptors (transcriptional activators)
-regulate genes involved in lipid metabolism
-function as heterodimers with RXR, and need coactivators (involved in chromatin modulation/histone acetylation)
-activated by Fa and their derivatives
what do fibrates do?
used to treat MetS by lowering TG and LDL, and raising HDL
what do thiazolidinediones (TZDs) do?
anti-diabetic and insulin-sensitizing drugs that mainly target PPAR-gamma
-promote insulin action, FA uptake, TG storage, and adiponectin release
although improves glycemic control and decreases NEFA circulation, there is increased caloric intake and body fat gain
-what it upregulates
-endogenous lignads and agonists
mainly expressed in liver, also muscle
-upregulation of beta-oxidation enzymes
--promotes fasting response in liver that includes gluconeogenesis and ketogenesis from glycerol released from breakdown of FFA
-endogenous ligands are unsaturated FA
-agonists are fibrate drugs
-what it upregulates
-endogenous lignads/agonists, coactivator
expressed in highest levels in fat cells, but also in liver and muscle
-no endogenous ligands, but TZD drugs are agonists
-coactivator is PGC-1 (also acts as "master regulator" of mitochondrial biogenesis)
-net effect: decreased NEFA circulation and increased insulin sensitivity
--liver: lipogenesis and lipid storage
--fat: adipogenesis, lipogenesis and lipid storage, adipokine production
--regulation of whole-body insulin sensitivity