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Flashcards in adipocytes Deck (33)
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what is a major problem with using BMI to classify obesity?

muscle weighs more than fat, so highly muscular individuals could qualify as obese using this method
wasteline circumference and waist-to-hip ratio are becoming more commonly used


what is metabolic syndrome/syndrome X?

suite of conditions that often accompanies obesity
overall problem is excessive caloric intake
leads to:
1: obesity - increase in adipose tissue
2: dyslipidemia - increase in circulating FA and VLDL
3: hepatic steatosis - fatty liver (hepatocytes overloaded with TG)
4: atherosclerosis
5: insulin resistance
6: hypertension


describe a common progression to type II diabetes.

1: individual has positive energy balance = taking in more calories than needed
2: individual gains weight
3: excess fat causes insulin resistance in muscle


what are the theories as to why excess fat causes insulin resistance in muscle?

both theories converge at inhibition of the insulin receptor's ability to tyrosine phosphorylate IRS-1 during insulin signal transduction cascade
inhibition mediated by activation of particular serine/threonine protein kinases that phosphorylate IRS-1 => inhibition of its ability to be tyrosine phosphorylated by the insulin receptor

inflammation theory: increased adipose mass => cytokine release => attraction of particular type of macrophage => secretion of more inflammatory cytokines (TNF-alpha and others) => activation of insulin-responsive tissues => activation of JNK kinase => phosphorylation of IRS-1

intracellular TG theory: increased TG in cells => increase intracellular TG metabolites (esp. DAG) = agonists of serine/threonine protein kinase PKC theta => phosphorylation of IRS-1


what is the difference between early and late type II diabetes? what treatment approaches would you take in each situation?

early: hyperglycemia and hyperinsulinemia but not complete insulin resistance yet?
can try to sensitize cells to insulin as treatment

late type II diabetes: hypoinsulinemia because pancreatic beta cells either die or lose ability to produce insulin - may be genetic component in transition
now requires insulin treatment


what is the difference between glucokinase and hexokinase?

glucokinase has a much higher Km for glucose
since it's in the pancreatic beta cells, this means that the posphorilation of glucose entering the cell isn't limited by the Km of the enzyme converting it to glucose-6-phosphate, which means that the amount of glucose-6-phosphate in pancreatic beta cells is directly correlated with the amount of glucose in the blood, allowing these cells to sense the blood glucose levels


what could the effect of intracellular TG in beta cells be?

increased TG could cause impaired insulin release by up-regulating the expression of an uncoupling protein (UCP-2) => dissipation of the H+ gradient across the mitochondria => inhibited ATP production


what factors lead to hepatic steatosis (fatty liver)?

1: increased chylomicron TG from diet
2: insulin resistance in adipocytes => HSL stays active => more FA in blood
3: trascription factors SREBP-1c and ChREBP in liver up-regulate transcription of FA synthetic genes
4: increased ACC transcription => increased malonyl-CoA production => increased FA synthesis and inhibited liver FA oxidation

combined effect of increased FA synthesis and decreased FA oxidation => TG buildup as intracellular lipid droplets and secreted VLDL


how can SREBP-1c lead to hepatic steatosis?

this transcription factor is activated by insulin - the effect of insulin isn't reduced by insulin resistance, so even though diabetic patients are resistant, the insulin in their system will still act on insulin-regulated transcription factors
activation => increased synthesis of many enzymes involved in FA synthesis


how can ChREBP lead to hepatic steatosis?

transcription factor = carbohydrate response element binding protein
activated by glucose
1: increases synthesis of many of the enzymes involved in FA synthesis
2: increases synthesis of liver pyruvate kinase (L-PK) - L-PK drives glucose through Krebs cycle => citrate - needed for FA synthesis


what is orlistat and how does it work? what are the side effects?

currently the only approved drug for long-term obesity treatment
pancreatic lipase inhibitor - causes TG to stay in the gut and be secreted in the stool => reduction of fat absorption by 30%
side effects:
1: mal-absorption of fat-soluble vitamins - prevent with supplementation
2: loose, oily stools


what is rimonabant and how does it work? what are side effects?

cannabinoid receptor antagonist
acts in hypothalamus to suppress orexigenic effect of endogenous cannabinoids
has been withdrawn from the market in europe due to side effect = depression - never approved in US


what is sibutramine and how does it work? what are the side effects?

aka meridia
originally antidepressant
blocks norepi and serotonin reuptake - both NTs have anorexic effects so blocking their reuptake extends the length of the their effect and so decreases appetite
appears effective at preventing rebound after weight loss, but has been taken off the market due to cardiovascular and stroke side effects, as well as depression


how can exercise affect insulin sensitivity?

1: more surface GLUT4 => enhanced glucose up-take into muscle
2: enhanced glucose and FA catabolism in muscle
3: longer-term enhanced transcription of several proteins including GLUT4
4: enhanced mitochondrial proliferation and FA storage


what activates AMPK? what are the effects/actions of AMPK?

activated by increase in AMP:ATP ratio
1: increases ATP generation
2: decreases ATP utilization
3: targets ACC for phosphorylation => decreased ACC activity => increased FA oxidation, decreased FA synthesis


what is metformin and when is it used? what are it's actions overall?

metformin is a diabetes drug that is used in the early stages of diabetes

overall, it activates the main glucose sink, muscle, and inhibits the main endogenous glucose source, liver by inhibiting adenylate cyclase


what are metformin's actions on the liver?

1: decreases PEPCK; decreased glucose-6-phosphatase transcription => decreased gluconeogenesis
2: decreased FA synthase; ACC; pyruvate kinase expression => decreased FA synthesis, decreased ACC activity
3: decreased ACC expression and activity => increased FA oxidation


what are metformin's actions in muscle?

increases glucose entry/catabolism


what are the advantages and disadvantages of metformin?

low risk of hypoglycemia and weight gain
orally taken

but only brings modest blood glucose lowering - so not effective in severe hyperglycemia


what are the progressive treatements for diabetes?

1: exercise and metformin
2: insulin
3: sulfonoureas
4: thiazolidinediones


what are the overall effects of insulin? (review)

1: increased muscle glucose up-take, catabolism
2: decreased liver gluconeogenesis
3: decreased FA oxidation in muscle and liver
4: increased fat storage


what are the advantages and disadvantages of insulin treatment?

can cause large decline in blood glucose

but, requires injections, high risk of hypoglycemia and weight gain
exacerbates hepatic steatosis due to selective hepatic insulin resistance


what are sulfonoureas and how do they work?

drug used to treat diabetes
inhibit K channel in pancreatic B-cell plasma membrane
action mimics effect of high blood sugar => increased ATP in B-cell cytoplasm => inhibits potassium channel => plasma membrane depolarization => activation of V-G ca channel => Ca influx => insulin secretion

therefore, increase insulin secretion from pancreus


what are the advantages and disadvantages of sulfonoureas?

orally administered

but only moderate blood glucose lowering, risk of hypoglycemia and weight gain


what are incretins and where are the secreted?

peptide hormones (GLP-1, GIP) released from small intestine


where do incretins act and what are their effects?

act on the pancreas
1: increase sensitivity of beta cells to glucose => augmented insulin release
2: decrease glucagon release from alpha cells

effects require elevated blood glucose levels


how are incretins used in therapy for diabetes?

1: DPP4 inhibitors (more detail on other card)
2: incretin analogues


what is DPP4 and how can it be targeted in the treatment of diabetes?

DPP4 is a protease that degrades incretins rapidly
inhibiting them increases incretin levels
small molecules that can be taken orally


how are incretin analogues used to treat diabetes?

example: peptide isolated from gila monster saliva
poorer substrate for DPP4 than endogenous incretins and so stays in the circulation longer
have to be injected since they're peptides


what are the advantages of incretin therapy over sulfonoureas?

1: incretin action requires elevated blood glucose, so little risk of hypoglycemia
2: lower risk of weight gain because incretins don't cause undue levels of insulin release
3: incretins don't "exhaust" the beta cell - only sensitize it to release insulin - sulfonoureas might exhaust the cells, which might lead to early demise of the cell