T2DM (Pancreas as endocrine organ and T2DM) Flashcards
T2DM is a complex interplay between
impaired insulin secretion
insulin resistance
genetic factors that may contribute to T2DM
MODY
GLUT transporter defects
Mitochondrial defects –> abnormal fatty acid metabolism –> insulin resistance
environmental factors that may contribute to T2DM
Obesity –> dysfunctional adipokine release –> insulin resistance
High fat diet
Excess nutrient intake
increased amylin release leading to T2DM
increased amylin release –> amylin deposition –> beta cell damage
inability to fully synthesize mature insulin leading to T2DM
inability to fully synthesize mature insulin –> release of proinsulin (immunoreactive) –> beta cell damage
insulin receptor down regulation leading to T2DM
insulin receptor downregulation due to overstimulation –> further resistance
in people without T2DM, the maximum response is released when what percent of receptors are occupied by insulin
5%
obesity and endocannabinoid system
obesity –> increased ECS tone –> increased appetite and decreased energy expenditure –> further nutrient excess –> vicious cycle
overactive ECS and insulin
Overative ECS increases insulin sensitivity in peripheral tissue independent of obesity
ECS and dysfunction metabolism
ECS contributes to dysfunctional metabolism of adipose tissue, skeletal muscle, liver
ECS and inflammation effects on beta cells
ECS activation inflammatory cytokines and activates macrophages –> infiltration and inflammation of beta cells –> apoptosis of beta cells
Obesity up regulates
CB1 receptors and ECS expression
CB1 receptor in the brain
increases food intake by modulating hypothalamic neurons
activates mesolimbic system to activate reward and reinforcement pathways –> preference for palatable food
CB1 receptor in peripheral tissue
activation of anabolic pathway favoring energy storage
CB1 receptor in adipocytes
increases de novo fatty acid synthesis, TG accumulation, decreases lipolysis, down regulates adiponectin
CB1 receptor on liver
increases lipogenesis
CB1 receptor on skeletal muscle
promotes oxidate metabolism through dysfunctional mitochondrial oxidative phosphorylation –> ROS production
CB2 receptors
increase obesity associated inflammation, insulin resistance, and hepatic steatosis
hyperglycemia and HK
HK is saturation and is shunted to alternative pathways
alternative pathway complications due to HK saturation
over utilization of NADPH and NAD+
oxidative stress
osmotic stress
glycosylation of proteins and lipids by end products
mitochondrial dysfunction
what does the polyol pathway require
NADPH and NAD+ for enzymatic activity and oxidation
polyol pathway converts
glucose to fructose
from the polyol pathway, fructose can be—
can be recycled into energy pathway
can increase ROS and glycation (AGEs)
NADPH and NAD+ would normally be used for redox reactions to create
NO
Glutathione
Myo-inositol
NO is needed for
endothelial function
Glutathione deficiencies
can lead to oxidative stress and ROS
Myo-inositol is needed for
normal nerve function
overload of both HK and polyol favors
sorbitol production
excess sorbitol can lead to
osmotic influx
under normal conditions, 1-3% of glucose goes through what pathway
hexosamine pathway
end product of hexosamine pathway
UDP-C1cNAc –> protein glycosylation (think about hemoglobin)
UDP contributes to
increase in ROS and mitochondrial dysfunction
Other products from hexosamine pathway (O-GlcNAcylation) causes
hypertrophic growth factors, particularly in myocytes –> heart failure
hexosamine pathways and nephrons
flux into hexosamine pathway contributes to nephrons damage in hyperglycemic patients
Glycation
process of glucose/fructose attaching to proteins or lipids
Effect of AGE binding to RAGE
gene transcription alteration –> induces ROS generation and inflammatory cytokines –> dysfunctional signaling
AGEs lead to
protein/collagen cross linking
Effects of protein/collage cross linking
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
Other pathologic effects of AGE
LDL oxidation (increases risk of atherosclerosis)
Interferes w NO release (decreased vasodilation)
Increases vascular permeability
Protein kinase C (PKC) pathway is activated by
DAG
what is DAG
glycerol + 2 fatty acids
hyperglycemia and DAG
hyperglycemia causes overproduction of DAG –> activation of PKC
Effects of PKC
collagen, fibronectin (mesangial expansion, glomerular hyperfiltration)
Profibrotic gene expression
Decrease fibrinolysis
Increase ROS
Angiogenesis
How does polyuria occur in T2DM
hyperglycemia –> high renal filtered glucose > 180 ng/dL –> glucose exceeds reabsorption capacity –> glucose pulls water through osmotic pressure –> increased urinary output
How does polydipsia occur in T2DM
hyperglycemia –> polyuria –> dehydration –> increased serum osmolality –> osmoreceptors in supraoptic and supra ventricular nuclei in hypothalamus recognize —> thirst
How does polyphasic occur in T2DM
impaired insulin sensitivity –> decreased glucose utilization in cells –> dysfunctional signaling that body does not have glucose for metabolism –> increased hunger
How do cataracts occur in T2DM
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