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
Two ways to get diabetic cataracts
- low lens glutathione
2. aldose reductase induced osmatic stress
What happens to lipid metabolism in diabetics?
Lipid mobilization for energy. Trying to make glucose even though hyperglycemic.
Liver takes up free FA= fatty liver
Broken down to Acetyl CoA to TCA (also ketone bodies)
Ketosis- in liver
What are the 3 ketone bodies?
acetone, acetoacetate, B-hydroxybutyrate
Hypokalemia
body K is low, false hyperkalemia because nonfunctioning Sodium Potassium ATPase pump.
C peptide test
What is c peptide?
What do the c peptide levels tell you?
What is used to mark it?
C-peptide is produced in b cells of pancreas when proinsulin splits apart
C peptide levels give you an idea of how much insulin is being produced
ELISA (Enzyme-Linked Immunosorbent Assay)
- creates color precipitate
- rabbit antibody binds antigen, secondary antibody binds rabbit antibody. Metabolism causes light to be seen.
Hemoglobin A1c
Tells you the amount of blood glucose
– (N terminal glycated B-hemoglobin) reaction between hemoglobin and glucose
irreversible non-enzymatic reaction (rate dependent on blood glucose concentration)
Lasts the lifetime of erythrocyte and can tell you levels for the last 2 to 4 weeks
Advanced glycosylated end products (AGEs)
Mallard reaction( non enzyme) - glucose and amino acid
Irreversible - higher concentration lead to downstream tissue accumulations: collagen cross linking, microvascular complications.
What do the receptors for AGEs induce?
RAGEs induce ECM production, inflammatory molecules, ROS.
Also decrease in NO.
Mainly on immune, neurons, endothelial, vascular and smooth muscle cells.
Insulin binds to RTK pathway in skeletal muscle and adipose cells. What are the downstream affects?
Insulin binds Receptor Tyrosine Kinase > phosphorylates targets > downstream:
Glycogen synthesis (Akt, Gsk3)
Lipogenesis (Atp citrate lyase, Acly): citrate to aceCoA
Protein synthesis: mTOR (PI3K like kinase
Cell survival: Bad, MapK
