Obesity/ Type 2 Diabetes

Question 1

what is BMI? what are the different classifications?

Answer 1

under 24- lean
24-29.9- overweight
30-39.9- obese
over 40- morbidly obese

Question 2

metabolic syndrome

Answer 2

problems that accompany obesity d/t excess caloric intake

1 obesity
2 dyslipidemia (increase FA and VLDL)
3 hepatic steatosis (fatty liver)
4 atherosclerosis
5 insulin resistance
6 hypertension

Question 3

after a certain threshold, all excess energy is stored as what?

Answer 3

fat

this goes for carbs protein and fat

Question 4

how does excess fat cause insulin resistance?

Answer 4

insulin resistance is hyperinsulinemia but normoglycemia

this happens b/c of inhibtion at the insulin receptors ability to phosphorylate IRS-1 during signal transduction

Question 5

what is the inflammation theory of insulin resistance

Answer 5

increased adipose mass causes cytokine release that attracts inflammatory macrophages. these macrophages secrete inflammatory cytokines which activate JNK kinase, which is capable of phosphorylating IRS-1

Question 6

what is the intracellular triglyceride theory of insulin resistance

Answer 6

increased build up of TG in cells leads to increase in intracellular DAG, which acts as an agonist at PKC theta, a protein kinase that phosphorylates IRS-1

Question 7

describe the progression of diabetes 2

Answer 7

positive energy balance

weight gain

insulin resistance

early T2DM

late T2DM

Question 8

difference between early and late diabetes?

Answer 8

early- has hyperinsulinemia and hyperglycemia

late- hyperglycemia and hypoinsulinemia d/t pancreatic beta cell loss

Question 9

how are beta cells activated to secrete insulin

Answer 9

glucose enters through GLUT2 (always active and not effected by insulin)

glucokinase phosphorylates glucose that enters the cell. glucokinase hasa high Km, so phosphorylation is concentration dependent

glucose goes through the glycolytic pathway, raising ATP/ADP ratio

new ATP inhibits voltage sensitive K channel

causes depolarization that releases Ca granules- releases insulin

Question 10

mutations in beta cells linked to diabetes

Answer 10

glucokinase

potassium channel

upregulated UCP (decreases ATP generated)

Question 11

what factors lead to hepatic steatosis

Answer 11

increased TG from diet

insulin resistance in adipocytes means HSL is active and blood FA rises

upregulated FA transcription factors SREPB-1 and ChREBP

increased malonyl-CoA causes FA synthesis and decreased FA oxidation

Question 12

describe the role of SERPB-1 and ChREBP

Answer 12

SREPB-1- activated by the increased insulin, activates FA synthesis genes

ChREPB- activated by glucose- increases FA synthesis genes, activates pyruvate kinase (glycolysis), which leads to an increase in citrate, which means more FA synthesis

Question 13

how is gluconeogenesis affected by insulin resistance?

Answer 13

AKT is insulin sensitive and thus it is inhibited

Question 14

orlistat

Answer 14

pancreatic lipase inhibitor
triglyceride stays in gut and is excreted

side effects:
mal absorption of fat soluble vitamins
loose, oily stool

Question 15

rimonabant

Answer 15

cannabinoid receptor antagonist acting in hypothalamus to suppress orexigenic effects of endogenous cannabinoids

withdrawn from market d/t depression side effects

Question 16

sibutramine

Answer 16

blocks reuptake of norepeinphrine and serotonin (both suppress appetite)

prevents rebound after weight loss

removed from market d/t CV and stroke

Question 17

what is the order of treatments given to diabetics?

Answer 17

1. exercise/metformin
2. insulin
   3 sulfonoureas
   4 thiazolidinediones

Question 18

how does exercise help diabetics

Answer 18

1. enhanced GLUT4
   2 increased catabolism
2. long term transcription increase in GLUT4, mitochondria, etc.
   4 AMPK- activated by increased AMP, phosphorylates ACC to stop FA synthesis

Question 19

what does metformin do?

Answer 19

decrease hepatic gluconeogenesis

also:
decrease lipolysis
increase GLUT4
increase FA oxidation

Question 20

advantages/disadvantages of exercise/metformin

Answer 20

advantages:
low risk of hypoglycemia
low risk of weight gain
cheap
metformin is oral

Question 21

insulin effects

Answer 21

increased glucose uptake
decreased gluconeogenesis
decreased FA oxidation
increased fat storage

Question 22

benefits/risks of insulin

Answer 22

advantages- drops blood glucose

disadvantages
injection
hypoglycemia
weight gain
hepatic steatosis

Question 23

sulfonoureas effect

Answer 23

inhibit pancreatic K channel, causing increased insulin release

Question 24

sulfonoureas risk/benefit

Answer 24

advantages: oral
disadvantages: modest blood glucose lowering, hypoglycemia, weight gain

Question 25

incretin

Answer 25

GLP-1 or GIP- increase beta cell sensitivity to glucose and decrease glucagon release

require elevated blood glucose to work

Question 26

two therapies based off incretins

Answer 26

DPP4 inhibitors- DPP4 rapidly degrades incretins. taken orally

incretin analogues- must be injected, but DPP4 doesnt bind as well

Question 27

advantages of incretins

Answer 27

1. b/c need elevated blood glucose to work, hypoglycemia not a risk

2 lower risk of weight gain b/c no direct insulin release

3 incretins do not “exhaust” beta cells

Question 28

thiazolidinediones effects

Answer 28

PPAR-y agonist

1 increase adipogenesis
2 increase FA uptake into adipocytes

lowers insulin sensitivity by:
1 lowering TG in non adipocyte tissues
2. lowering adipocyte stress

Question 29

risk benefit of thiazolidinediones

Answer 29

advan- oral

disadvan- moderate blood glucose lowering, hypoglycemia, weight gain, heart attack, osteoporosis