12- Diabetes Case Study Flashcards
Type II diabetes is multifactoral and encompasses many genes. What do those genes do?
B cell formation B cell function insulin secretion Regulate fasting glucose levels BMI regulation Adipocyte differentiation insulin pathway regulation
Many different polymorphisms inheritted collectively
What kinds of pancreas glands are present?
What do they do?
Exocrine- duct, secrete enzymes that digest food
Endocrine- secretes hormones. Glucagon and insulin
— islets of langerhans: regulate hormone secretion
Transcription factors related to glucagon and insulin
Foxo1- Bind to IRE (insulin response element), regulate downstream of insulin signaling.
– ex. negatively regulate adipogenesis. When stimulated by insulin, Foxo1 is excluded from the nucleus and unable to prevent transcription of PPAR y
Pdx1- glucose dependent insulin production
– insulin promoter, critical for pancreatic development
Insulin biosynthesis pathway
- pre proinsulin, cleaved amino terminal
- proinsulin, cleavage of internal 31 aa residue = C peptide, A chain, B chain (B and A connected by disulfide bond)
- – C peptide is marker of insulin. - All three pieces are secreted together.
Secretion of insulin pathway
What are the phases?
Glucose enters through GLUT2 > Glycolysis > Increase in ATP : ADP > Closes K+ channel > depolarization opens up Ca2+ channels > Ca rushes in moves vesicles to surface > Rlease insulin
1st phase- 10-15 min after meal, stored insulin secreted
2nd phase- genes turned on, 2-3 hours.
What is the key regulator of insulin secretion?
What is the level glucose plasma needs to go above to stimulate insulin synthesis?
Glucose, >3.9mmol/L
What comprises the insulin receptors?
two alpha (extra membrane) and two beta (trans/intra)
Where do you find GLUT2? GLUT4
GLUT2- liver, pancreas
GLUT4- skeletal muscle and adipose (insulin dependent)
– Insulin releases GLUT4 from stored vesicles.
Glucagon stimulates gycogenolysis and gluconeogenesis where?
liver and renal medulla
Where does glycolysis happen in the body when insulin is produced?
Liver, via PFK II enzyme.
What happens in the glucagon world?
gluconeogenesis, glycogenolysis, ketogenesis ( for brain
What happens to glycolysis in diabetes?
Reduced phosphorylation in liver (glucokinase is insulin dependant)
Glucagon modifies enzymes
Reduced activity of PFK I and PFK II
Reduced rate of glycolysis
What happens to gluconeogenesis in people with diabetes?
Increased rate due to:
Increased availability of substrates
Increased activity and concentration of enzymes
What happens to glycogenesis and glycogenolysis in people with diabetes?
Glycogenesis- Inhibited due to reduced activity of glycogen synthase
Glycogenolysis- stimulated due to increased activity of phosphorylase
Sorbitol pathway
How is it related to diabetic cataracts?
Increase in glucose > Aldose Reductase > sorbitol
Sorbitol increases cell osmolality, generates reactive oxygen species, leads to other types of cell dysfunction
Diabetic cataracts is the result of osmolysis by sorbitol accumulation.
2nd option leads to neuropathy, nephropathy, retinopathy, vascular complications