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Lipid Pathologies, Causes of Insulin Resistance Obesity (esp. upper body) ->excessive FFA release ->accum. fat in mm, liver too Physical inactivity ->need exercise to burn mm. fat ->exercise->inc. GLUT4 receptors on mm., adip membranes -sedentary->accum TAG in mm. ->mm. can't use glucose well Hormones -androgens->upper body obesity -cortisol->insulin resistance Aging Genetics Obesity Curvilinear BMI vs. DM-II risk inc. adiposity->inc. FFA release, TNF-a, resistin ->inhibit glu. transport, glycogen synth ->FFAs to liver->acetyl CoA for GNG ->FFAs, AAs inhibit post-receptor insulin action -->takes more insulin for homeostasis, Lipid Pathologies ???? Diabetes Mellitus, Metabolic Syndrome=multiple pathologies aka:Syndrome X, Diabesity, Insulin Resis, syn., CV Risk Factor cluster ->Risk factors that inc. CHD risk -ab. obesity -insulin resistance -HTN (dmg to endoth, drive LDL into wall) -lose weight->BP dec. -atherogenic dyslipidemia -pro-thrombolic state (high PAI-1, other coags) -pro-inflammatory state(C-reactive protein from liver) -also from lots of cytokines -->these also increase risk of: DM-II, stroke, infertiility, polycystic ovary dz Affects 40-50% American men and women over 50yo Exercise Work out and deplete mm. glycogen ->inc. insulin sensitivity in mm for 48 hr Inc. Exercise->lower systolic BP Physical training->lower plasma TGs Regular physical activity->lower PAI ->inc. fibrinolysis ->mm. mass even in elderly Diet+exercise->lose more intra-abdominal fat, Diabetes Mellitus Type I Tx: Insulin+diet counseling -insulin (long or short acting) -injections or pump diet: limit simple sugars -want lower glycemic index -unrefined carbs, fiber better ~50% kcal as carbs -balance exercise, diet, insulin, Diabetes Mellitus Type II Causes of Insulin Resistance Obesity (esp. upper body) ->excessive FFA release ->accum. fat in mm, liver too Physical inactivity ->need exercise to burn mm. fat ->exercise->inc. GLUT4 receptors on mm., adip membranes -sedentary->accum TAG in mm. ->mm. can't use glucose well Hormones -androgens->upper body obesity -cortisol->insulin resistance Aging Genetics, Diabetes Mellitus Type I If untreated: -hyperglycemia -excess fat utilization -ketogenesis, meta. acidosis -body's proteins depleted If treated but not fully controlled: -Acute:hypoglycemia w/ too excess insulin -or with extra exercise -Chronic:if blood sugar not tightly controlled: ->renal dz, periph neuropathy, retinopathy, -premature collagen, etc. aging, Diabetes Mellitus Normal Exercise-> Activate AMP-Kinase (AMPK) -regulates mm. FA metabolism -mediator of most adaptations to exercise ->up-regulate mitochondria, oxidative meta. ->inhibit Acetyl-CoA carboxylase ->raise GLUT4 activity-recruit more(like insulin) ->inc. energy expenditure via more peroxisomes ->up-regulate uncoupling proteins, Diabetes Mellitus Normal Insulin->store TGs in adip ->adip glucose uptake ->adip secrete LPLipase ->mm. glucose, AA uptake ->protein synth ->restore glycogen stores (liver too) ->liver-excess glucose->fat ->liver TG export as VLDL Glucagon->FFA release from adip ->glycerol release from adip ->mm. hydrolyze protein, AA export ->use FFAs, ketone bodies for fuel -NO direct export of glucose ->liver-GNG, glycogenolysis ->liver-FA->ketone bodies ->liver-AA catabolism->urea, Metabolic Syndrome=multiple pathologies aka:Syndrome X, Diabesity, Insulin Resis, syn., CV Risk Factor cluster ->Risk factors that inc. CHD risk -ab. obesity -insulin resistance -HTN (dmg to endoth, drive LDL into wall) -lose weight->BP dec. -atherogenic dyslipidemia -pro-thrombolic state (high PAI-1, other coags) -pro-inflammatory state(C-reactive protein from liver) -also from lots of cytokines -->these also increase risk of: DM-II, stroke, infertiility, polycystic ovary dz Affects 40-50% American men and women over 50yo Diagnosis WHO--> Central Obesity (waist circumference) +2 or more: Low HDL, HTN, high triglycerides, fasting hyperglycemia [glu], Metabolic Syndrome=multiple pathologies aka:Syndrome X, Diabesity, Insulin Resis, syn., CV Risk Factor cluster ->Risk factors that inc. CHD risk -ab. obesity -insulin resistance -HTN (dmg to endoth, drive LDL into wall) -lose weight->BP dec. -atherogenic dyslipidemia -pro-thrombolic state (high PAI-1, other coags) -pro-inflammatory state(C-reactive protein from liver) -also from lots of cytokines -->these also increase risk of: DM-II, stroke, infertiility, polycystic ovary dz Affects 40-50% American men and women over 50yo Atherogenic Dyslipidemia Lipid triad of meta syndrome -high triglycerides -small, dense LDL -Low HDL ->high TAG/HDL ratio NOT HIGH LDL, though -independent risk factor -fat in liver->inc. ApoB -obese->high LDL Insulin resistance->fatty liver ->-> Nonalcoholic Steatohepatitis (NASH)