Diabetes Lecture Notes

These are my notes, but I REALLY recommend using his from Blackboard.

Insulin Actions in diabetes
He is posting a text from which he worked as well as the lecture.
Slide3:
Structure:
note disulfide bonds. A chain, B chain , C peptide. Insulin is a highly conserved hormone among all species. See figure 9 in Johnson, page 644
Oral glucose is more effective than IV glucose for inducing insulin release.
Insulin goes from pancreas to liver (portal circulation). Diabetics can only administer insulin subcutaneously, so it is hard to recreate release of insulin into the portal circulation.
7:
Insulin is key anabolic regulator. Supports protein synthesis in muscle, inhibits gluconeogenesis in liver. Other actions are general. Production of ketone bodies is important in diabetic ketoacidosis.
Important:glucose uptake, gluconeogenesis, ketogenesis in diabetes.
Type I Diabetes:
No phenotype (symptoms) for patient until beta cells are wiped out. Metabolic symptoms: hyperglycemia. Hormone sensitive lipase is activated in diabetes- Fatty acids go to liver, ketogenesis.
Historically- Langerhans defined the islets.
Oskar Minkowski demonstrated that removing pancreas in dog caused diabetes. Tasted dog’s urine-sweet. Postulated a hormone produced by the pancreas, but was unable to purify it. Banting and Best did purify it in 1921. Administered to dogs and were able to restore blood sugar. Provided first "cure" for previously fatal type I. 1923- Nobel prize.
Energy needs met in uncontrolled diabetes:
Alanine and alpha-ketoglutarate come from muscle to liver. There is no synthesis of fatty acids in adipose tissue.
Much of damage from diabetes is due to high blood sugar. Proteins get glycosylated inappropriately. Vision, circulatory problems in periphery, kidney problems, CV trouble.
Glucose transport:
There are 7 different GLUT transporters. Liver has bidirectional non-insulin dependent transporter (GLUT 2). Glut 4 is unidirectional.Absence of insulin- less transporter in muscle.
GLUT4 – 12 membrane spanning helices. Glut 4 in muscle has insulin-responsive glucose uptake.
They are sequestered in vesicles until insulin binds receptor and triggers movement to membrane through signalling cascade.
Capacity of muscles to take up glucose is increased 30 fold in the presence of these transporters (see Johnson chapter 41).
Muscle diagram
Exercise increases insulin-independent transport.
Adipose tissue: insulin stimulates lipoprotein lipase. Brings in fats for storage. Insulin also stimulates horm-sensitive lipase. Absence of insulin- free fatty acids are released and go to liver.
Liver diagram:
amino acids come in and gluconeogenesis is strongly activated in Type I diabetes.
Fatty acids enter TCA cycle and exit as ketone bodies.
Type I:
insulin imperative. Diet and exercise help to control the damage.
Problems: kinetics of insulin release hard to replicate because treatment involves peripheral administration instead of portal release.
Exercise and diet can increase insulin sensitivity and make it easier to maintain blood sugar levels.
Pumps use only rapid insulin. Needle is in abdomen. Increase rate of infusion before meals and dial it down at night. Trying to maintain levels as close to normal as possible.
Patient comes in in coma to hospital- give fluid and glucose. If in insulin coma- will revive. Can give insulin later. Adverse reactions to insulin administration include HYPOglycemia, insulin resistance, and problems at injection site.
Type II is the most common form of diabetes. Being overweight does not mean you have type II diabetes- just a greater likelihood of developing it.
Treated with dietary and lifestyle changes first. Exercise and losing weight generally work.
With insulin resistance, B cells compensate by putting out more insulin. Increased gluconeogenesis contributes to hyperglycemia. Diabetes has decreased insulin secretion.
Graph slide- numbers don’t matter. Principle does.
McDonald’s diet, especially with children, is highly associated with Type II diabetes. High-fat, high sugar diets.
Metformin inhibits gluconeogenesis.
TZDs are calles glitazones. They improve glucose sensitivity.
Remember rosiglitazone. TZDs do not affect insulin release. They bind to DNA and express genes to improve insulin sensitivity. Drug started in clinic before they realized it was ligand for PPARgamma. Receptor is high in adipose tissue. Patients tend to gain weight.
Review:
diabetes type I II
high blood glucose Y Y
ketoacidosis Y N
obesity N Y
insulin resistance N(some) Y
pancreatic failure Y Ninitially, eventually Y
juvenile onset Y recently Y
genetic component classically no Y
Fat rats are used to model impaired insulin signalling. Remember most overweight people are not diabetic.
Insulin binds to transmembrane spanning receptor with tissue-specific effects. See slide.
How do you get from surface to every compartment of cell with a single hormone signal?
All growth-factor receptors are membrane spanning. Receptors are monomers. In case of EGF they dimerize and a tyrosine kinase allows for autophosphorylation.
Insulin binds, causing a conformational change of receptor- signal transferred to B subunit- tyrosine autophosphorylation- signal at membrane. The receptor needs an intact ATP binding domain. Tyrosines on subunits interact with other proteins. Know about the autophosphorylation of Tyrosine. Phosphorylation of Ser/Thr is inhibited.
Insulin signalling- cascade of protein-protein interaction is involved. IRS-1 is important. Kahn used a phosphotyrosine antibody within a minute of insulin admin. IRS=insulin receptor substrate.
IRS is a huge protein. 3 domains- PH (pleckstrin homology) used by many proteins. Recognizes polar lipids- keeps protein associated with membrane.
IRS gets phosphorylated by subunit.
Remember plextrin homology, PTB, and SH2 and SH3. Everything is physical interactions.
SH2/SH3 recognize phosphorylated Tyr and a short amino acid sequence in IRs (insulin receptors). protein plugs in in physical association.Advantages of IRS:
signal amplification, IRS dissociation insulin signalling from the internalization of the receptor, expansion of the number of signals possible.
IRS interacts with PI3 kinase. PI3 kinase generates PI3 inositol-> PIP3-> multiple signals.
PIP3 is important here. PI3kinase is activated by many growth factors. Insulin activates specifically through IRS.
Insulin can also activate RAS/RAF pathways, but main metabolic actions thru PKB pathways