T2DM (Pancreas as endocrine organ and T2DM)

Question 1

T2DM is a complex interplay between

Answer 1

impaired insulin secretion
insulin resistance

Question 2

genetic factors that may contribute to T2DM

Answer 2

MODY
GLUT transporter defects
Mitochondrial defects –> abnormal fatty acid metabolism –> insulin resistance

Question 3

environmental factors that may contribute to T2DM

Answer 3

Obesity –> dysfunctional adipokine release –> insulin resistance
High fat diet
Excess nutrient intake

Question 4

increased amylin release leading to T2DM

Answer 4

increased amylin release –> amylin deposition –> beta cell damage

Question 5

inability to fully synthesize mature insulin leading to T2DM

Answer 5

inability to fully synthesize mature insulin –> release of proinsulin (immunoreactive) –> beta cell damage

Question 6

insulin receptor down regulation leading to T2DM

Answer 6

insulin receptor downregulation due to overstimulation –> further resistance

Question 7

in people without T2DM, the maximum response is released when what percent of receptors are occupied by insulin

Answer 7

5%

Question 8

obesity and endocannabinoid system

Answer 8

obesity –> increased ECS tone –> increased appetite and decreased energy expenditure –> further nutrient excess –> vicious cycle

Question 9

overactive ECS and insulin

Answer 9

Overative ECS increases insulin sensitivity in peripheral tissue independent of obesity

Question 10

ECS and dysfunction metabolism

Answer 10

ECS contributes to dysfunctional metabolism of adipose tissue, skeletal muscle, liver

Question 11

ECS and inflammation effects on beta cells

Answer 11

ECS activation inflammatory cytokines and activates macrophages –> infiltration and inflammation of beta cells –> apoptosis of beta cells

Question 12

Obesity up regulates

Answer 12

CB1 receptors and ECS expression

Question 13

CB1 receptor in the brain

Answer 13

increases food intake by modulating hypothalamic neurons
activates mesolimbic system to activate reward and reinforcement pathways –> preference for palatable food

Question 14

CB1 receptor in peripheral tissue

Answer 14

activation of anabolic pathway favoring energy storage

Question 15

CB1 receptor in adipocytes

Answer 15

increases de novo fatty acid synthesis, TG accumulation, decreases lipolysis, down regulates adiponectin

Question 16

CB1 receptor on liver

Answer 16

increases lipogenesis

Question 17

CB1 receptor on skeletal muscle

Answer 17

promotes oxidate metabolism through dysfunctional mitochondrial oxidative phosphorylation –> ROS production

Question 18

CB2 receptors

Answer 18

increase obesity associated inflammation, insulin resistance, and hepatic steatosis

Question 19

hyperglycemia and HK

Answer 19

HK is saturation and is shunted to alternative pathways

Question 20

alternative pathway complications due to HK saturation

Answer 20

over utilization of NADPH and NAD+
oxidative stress
osmotic stress
glycosylation of proteins and lipids by end products
mitochondrial dysfunction

Question 21

what does the polyol pathway require

Answer 21

NADPH and NAD+ for enzymatic activity and oxidation

Question 22

polyol pathway converts

Answer 22

glucose to fructose

Question 23

from the polyol pathway, fructose can be—

Answer 23

can be recycled into energy pathway
can increase ROS and glycation (AGEs)

Question 24

NADPH and NAD+ would normally be used for redox reactions to create

Answer 24

NO
Glutathione
Myo-inositol

Question 25

NO is needed for

Answer 25

endothelial function

Question 26

Glutathione deficiencies

Answer 26

can lead to oxidative stress and ROS

Question 27

Myo-inositol is needed for

Answer 27

normal nerve function

Question 28

overload of both HK and polyol favors

Answer 28

sorbitol production

Question 29

excess sorbitol can lead to

Answer 29

osmotic influx

Question 30

under normal conditions, 1-3% of glucose goes through what pathway

Answer 30

hexosamine pathway

Question 31

end product of hexosamine pathway

Answer 31

UDP-C1cNAc --> protein glycosylation (think about hemoglobin)

Question 32

UDP contributes to

Answer 32

increase in ROS and mitochondrial dysfunction

Question 33

Other products from hexosamine pathway (O-GlcNAcylation) causes

Answer 33

hypertrophic growth factors, particularly in myocytes --> heart failure

Question 34

hexosamine pathways and nephrons

Answer 34

flux into hexosamine pathway contributes to nephrons damage in hyperglycemic patients

Question 35

Glycation

Answer 35

process of glucose/fructose attaching to proteins or lipids

Question 36

Effect of AGE binding to RAGE

Answer 36

gene transcription alteration --> induces ROS generation and inflammatory cytokines --> dysfunctional signaling

Question 37

AGEs lead to

Answer 37

protein/collagen cross linking

Question 38

Effects of protein/collage cross linking

Answer 38

vascular stiffening and trapping of LDL in arterial walls --> stiff arteries with atherosclerosis protein degradation --> glomerular filtration barrier damaged and mesangial cells hypertrophy --> fibrosis and glomerulosclerosis

Question 39

Other pathologic effects of AGE

Answer 39

LDL oxidation (increases risk of atherosclerosis) Interferes w NO release (decreased vasodilation) Increases vascular permeability

Question 40

Protein kinase C (PKC) pathway is activated by

Answer 40

DAG

Question 41

what is DAG

Answer 41

glycerol + 2 fatty acids

Question 42

hyperglycemia and DAG

Answer 42

hyperglycemia causes overproduction of DAG --> activation of PKC

Question 43

Effects of PKC

Answer 43

collagen, fibronectin (mesangial expansion, glomerular hyperfiltration) Profibrotic gene expression Decrease fibrinolysis Increase ROS Angiogenesis

Question 44

How does polyuria occur in T2DM

Answer 44

hyperglycemia --> high renal filtered glucose > 180 ng/dL --> glucose exceeds reabsorption capacity --> glucose pulls water through osmotic pressure --> increased urinary output

Question 45

How does polydipsia occur in T2DM

Answer 45

hyperglycemia --> polyuria --> dehydration --> increased serum osmolality --> osmoreceptors in supraoptic and supra ventricular nuclei in hypothalamus recognize ---> thirst

Question 46

How does polyphasic occur in T2DM

Answer 46

impaired insulin sensitivity --> decreased glucose utilization in cells --> dysfunctional signaling that body does not have glucose for metabolism --> increased hunger

Question 47

How do cataracts occur in T2DM

Answer 47

hyperglycemia --> shunting to alternative pathways (Polyol) --> increased concentration of sorbitol --> generation of fructose and ROS AND increased concentration of sorbitol with decreased sorbitol dehydrogenase --> increased sorbitol levels --> potent osmotic factor --> increased fluid accumulation in lens