Insulin Flashcards
What are the two precursors to insulin?
Preproinsulin
Proinsulin
What is proinsulin cleaved to?
Insulin and C-peptide
What clinical relevance does C-peptide have?
Can be used to measure insulin production.
What happens to C-peptide?
Secreted along with insulin.
Where is insulin produced and secreted from?
Pancreatic beta cells
What are the steps in insulin secretion?
1) Glucose enters cell through GLUT2
2) GLucose met by glucokinase
3) ATP levels rise
4) ATP closes K channels (Kir6)
5) Cell depol
6) VGCC open
7) Ca allows vesicle binding and insulin release
What is the Km for glucokinase?
5mmol/l
How does the low Km for glucokinase cause problems in T2DM?
Consistently raised glucose means insulin release is constantly stimulated and makes sensing rises hard.
What is the regulatory subunit of the Kir6 channel?
SUR1
What can mutations in the SUR1 or Kir6 SU cause?
Neonatal or congenital diabetes
What are the three phases of insulin secretion?
Background
1st
2nd
How much of insulin secretion does background make up?
50%
What causes the 1st phase of insulin secretion?
Incretins and glucose sensing allowing release of prepackaged insulin.
What causes the 2nd phase of insulin secretion?
Is 1st doesn’t lower glucose levels sufficiently then more insulin is packaged and released.
What is the incretin effect?
Food ingestion stims release of GLP-1 and GIP from enteroendocrine cells in gut which enhance insulin release and inhibit glycogen release.
What does GLP-1 do?
Increase insulin release
Decrease glucagon release
What does GIP do?
Increase glucose release
What kind of receptor is the insulin receptor?
Tyrosine Kinase Receptor
What happens then insulin binds to the insulin receptor?
IRS1 or 2 is phos
Where is IRS1 found?
Periphery
Where is IRS2 found?
Hepatic cells
What two pathways can IRS activate?
MAPK
PI3K
What does the MAPK pathway regulate?
Cell growth
What happens in the PI3K pathway?
Activated PI3K converts PIP2 -> PIP3.
PIP3 activates PDK1
PDK1 activates PKC and PKB
What does PKC do in the insulin response?
Promotes GLUT channel integration into cell membrane.
What does PKB do in the insulin response?
Promotes: Glycogenesis FA + protein synthesis Proliferation NO release Inhibits: Lipolysis and gluconeogenesis
What are the two main forms of glucose transporter?
Sodium coupled glucose transporters (SGLT)
Facilitative Glucose Transporter (GLUT)
Describe SGLTs
Need 2 Na to transport 1 glucose.
Found in gut lumen.
Describe GLUTs
Found in all cells
Operate bidirectionally
What are the four Class 1 GLUTs and what are their affinities?
GLUT1- High affinity
GLUT2- Low affinity
GLUT3- High affinity
GLUT4- High affinity
Where are GLUT1s found?
Brain, RBC
Why must GLUT1s have high affinity?
To allow glucose uptake into the brain even at low glucose conc.
Where are GLUT2s found?
Kidney, liver, beta cells
Where are GLUT4s found?
Skeletal muscle
Cardiac muscle
Fat
What can stimulate glucose uptake in the absence of insulin?
Exercise
What actions do insulin stimulate?
AA uptake and protein synthesis DNA synthesis Growth Glucose uptake and glycogen storage Lipogenesis Gene expression NO synthesis
What actions do insulin inhibit?
Gene expression
Lipolysis
GLuconeogenesis
What two broad factors can cause insulin resistance?
Environmental
Genetic
Give some examples of environmental causes for insulin resistance
Alzheimer’s Disease!!!
Inflammation
What two things can be mutated giving genetic insulin resistance?
IR
SIgnalling cascade
Give two examples of mutated IRs
Donohue syndrome/Leprechaunism
Rabson Mendanhall Syndrome
What are the four broad categories of prescribed insulin?
Prandial
Basal
Ultra long lasting
Premixed/Fixed mix
What categories does prandial insulin encompass?
Ultra short acting
Short acting
Give an example of ultra short acting insulin?
Lispro
How long do ultra short acting insulins take to work?
20-40 minutes
What categories does basal insulin encompass?
Intermediate
Long lasting
Give an example of ultralong lasting insulin?
Glargine
What is premixed/fix mix insulin?
Insulin containing short and long lasting
Why is premixed/fix mix insulin good?
Fewer injections
Good for fixed lifestyle
Why is premixed/fix mix insulin bad?
Have to live fixed life and doesn’t take into account exercise and feeding etc
Give some examples of premixed/fix mix insulin
Humalog mix 25
Humalog mix 50
Why can insulin efficacy vary?
1st pass met- give 2x dose Temp Injected to muscle not fat Device inaccuracy Meal content Gastroparesis
What are the three goals of modern day insulin treatment?
Avoid hyops
Avoid hypers
Reduce chronic complications
What are some new ways of adjusting insulin levels?
Pump- give constant short for background then dial up for meals
Education on adjustment and when to take (ie. still take when ill)
Advanced carb counting
What are the targets to aim for with insulin treatment?
HbA1c <48 ideal
HbA1c <53 in reality
Who needs to check their blood glucose levels?
Those taking something such as insulin to lower their blood glucose
Should patients taking insulin check their blood glucose before driving?
Yes!!!
