Give 5 criteria needed for a diagnosis of metabolic syndrome.
Truncal obesity (waist circumference > 40-35in)
Hypertriglyceridemia (total TGs > 150)
Low HDL (<40-50)
Elevated fasting glucose (>100, presumably <126)
What else is metabolic syndrome known as?
Syndrome X (don't confuse with idiopathic angina)
Insulin resistance syndrome
Try and summarize the effects of adiposity on liver and muscle
(think physiology, not biochemical mechanisms)
Increased FFAs from adipose tissue reduces insulin sensitivity in both liver and skeletal muscle, either by deposition or proinflammatory effect.
Glucose uptake is reduce in both, and gluconeogenesis/glycogenolysis as well as VLDL synthesis in increased in the liver.
How does hypertension result from excessive adiposity?
Hyperinsulinemia (through SNS stimulation) along with increased FFAs and proinflammatory state causes hypertension.
Prothrombotic state mediated by increased hepatic fibrinogen (acute-phase reactant!) and PAI-1 from adipocytes promotes thrombosis.
In metabolic syndrome, what happens to CRP expression?
Adiponectin expression? What does this normally do?
CRP increases (acute-phase reactant in an inflammatory state)
Goes up (*Handout is ambiguous, but resistin is pro-inflammatory)
Adiponectin decreases; this is normally anti-inflammatory and mediates insulin sensitivity.
Describe the level of insulin secretion in metabolic syndrome as it progresses to T2DM.
What other hormonal resistance is seen in metabolic syndrome? (Hint: It's from adipocytes)
Increases initially to try and compensate for increased resistance but ultimately decreases
Name 2 possible mechanisms for insulin deficiency seen in muscle cells in metabolic syndrome.
1. Proinflammatory molecules (systemic or from macrophages) upregulate JNK, which in turn inhibits IRS-1 (decreased effect of insulin).
2. Free fatty acids leak from adipocytes, causing DAGs to deposit in muscle cells which activate nPKCs to block IRS-1.
What is lipotoxicity?
Deposition of fatty acids into organs such as liver, skeletal muscle, and pancreatic beta cells causes changes in post-insulin receptor functionality, mediating the insulin resistance & deficiency.
What is the most common cause of mortality in metabolic syndrome?
What can contribute to it?
Glucose intolerance (formation of AGEs, endothelial damage), dyslipidemia (atherosclerosis), hypertension, prothrombotic state.
Name 5-6 risk factors for metabolic syndrome.
Low socioeconomic status
Poor diet (high saturated fats and carbohydrates)
Use of atypical antipsychotics
Describe the epidemiology of metabolic syndrome. Pay special attention to gender and racial disparities.
Affects hispanics and asians especially.
Female preference is most pronounced in african-americans.
What factor can correct BMI to give a better estimate of risk?
Describe the 3 classes of obesity.
What is the major weight loss treatment in higher-grade obesity?
Correction with waist circumference.
I (BMI 30-34.9), II (BMI 35-39.9), III (BMI 40+)
Bariatric surgery (easily the most effective, too)
What other comorbidities are seen in metabolic syndrome?
PCOS (polycystic ovarian syndrome)
What lipid profiles indicate metabolic syndrome?
Recall how LDLs and HDLs are affected by this disease.
High LDLs, low HDLs.
Hypertriglyceridemia results in LDLs being remodeled by lipases into "dense" (more atherogenic) LDLs. HDLs gain cholesterol esters via CETP and are degraded. (ApoA is lost through renal degradation?)
Try to summarize Insulin's effect on body energy utilization in 4 points.
1. Decreased glycogenolysis
2. Decreased gluconeogenesis
3. Decreased glucagon secretion
4. Decreased lipolysis
(okay, increased glucose uptake should definitely be #1)
Review the blood glucose levels that are diagnostic for DM, Metabolic syndrome, and normalcy.
(note: Fasting and 2-hr OGTT)
Diabetes Mellitus: >126 fasting, >200 post-OGTT.
Metabolic Syndrome: 100-125 fasting, 140-199 post-OGTT.
Normal: <100 fasting, <140 post-OGTT.
Name some non-pharmacologic treaments for metabolic syndrome.
Lifestyle modifications aimed at weight loss, such as:
Improving diet (restriction, shift towards unsaturated fats)
Exercise (30min/day or 150min/week)
Bariatric surgery (it's kind of nonpharmacologic...)
What is the only drug (that we've discussed) that is indicated for weight loss?
What is its mechanism of action?
Orlistat (note: pair with diet & exercise!)
Reversibly inhibits gastric/pancreatic lipases to decrease fat digestion & absorption.
SEs: Headache, abdominal pain, gas, fecal urgency, URIs.
What are some other medications generally indicated for those with metabolic syndrome?
(it's a long list!)
ACE-I/ARBs for hypertension
Statins/Ezetimibe for LDL cholesterols
Fibrates/Niacin for HDL cholesterols & triglycerides
Metformin in select patients (young or gestational)
Maybe aspirin (assess Framingham CV risk)
How does drug regimen change when metabolic syndrome progresses to diabetes mellitus?
What are the side effects of pioglitazone?
Metformin becomes first-line for all patients. Glitazones may be indicated.
Glitazones are expensive, cause weight gain and pedal edema, may promote bladder cancer and bone loss (especially post-menopause)