Insulin secretion & intermediary metabolism Flashcards
What hormones can increase blood glucose concentration?
Glucagon
Catecholamines
Somatotrophin
Cortisol
Type 1 Diabetes
Elevated blood glucose where insulin is required to prevent ketoacidosis
Simple definition of T1D
Inability to create insulin
How many sorts of T1D are there?
10
Simple definition Type 2 Diabetes
Lack of response to insulin
How many sorts of T2D are there?
50
Proportion of diabetes mellitus cases by type
86% T2D
11% T1D
3% MODY
MODY
Mature onset diabetes of the young
What completely relies on glucose as an energy substrate in normal conditions?
CNS
What happens if blood glucose falls below 4/5 mM?
Hypoglycaemia
Brain function increasingly impaired
What happens if blood glucose falls below 2mM?
Unconsciousness
Coma
Eventually death
What hormone can decrease blood glucose concentration?
Insulin
98% pancreas is associated with
Exocrine secretions via duct to small intestine
Remaining 2% of pancreatic tissue
Islets of Langerhans
Paracrine
One cell affects cell next to it
Cells of the pancreas use
Gap junctions to allow paracrine transport effects
Alpha cells secrete
Glucagon
Glucagon action
Increases blood glucose
Beta cells secrete
Insulin
Insulin action
Stimulates growth
Decreases blood glucose
Delta cells secrete
Somatostatin
Somatostatin action
Decreases production of insulin and glucagon
Has “calming down” effect
What increases insulin secretion?
Increased blood glucose
Some GI tract hormones
Glucagon like peptide (GLP)
Neurological control of beta-cells: Sympathetic stimulation:
decreases insulin production
Neurological control of beta- cells: Parasympathetic stimulation
increases insulin production
Name 4 physiological actions of insulin
Increases glycolysis
Increases glucose transport into cells via GLUT-4
Increases glycogenesis and lipogenesis
Decreases break down of proteins and lipids
What increases glucagon secretion?
Decreased blood glucose
Certain amino acids
Certain GI hormones
Neurological control of alpha-cells:
Sympathetic stimulation
Increases glucagon production
Neurological control of alpha-cells:
Parasympathetic stimulation
Increases glucagon production
4 physiological actions of glucagon
Main effects are on the liver- increases HGO
Increased hepatic glycogenolysis
Increased amino acid transport into liver- Increased gluconeogenesis
Increased lipolysis- Increased gluconeogenesis
How does glucose enter a beta cell?
Via Glucose Transporter 2 (GLUT-2)
Not insulin regulated
What is the rate determining step in regulating insulin secretion?
Conversion of glucose to glucose-6-phosphate
by glucokinase
What is glucokinase nicknamed?
The “glucose sensor”
Important for sensing glucose concentration by beta cell
What is the precursor of insulin?
Pre-proinsulin
Describe pre-proinsulin
3 chains joined to form 1 long chain with a signal sequence
What is the final sequence in pre-proinsulin?
C Peptide
When is C-Peptide removed?
Upon release outside the cell
What is the molar ratio of insulin to C-peptide?
1:1
By measuring C peptide we can see if the beta cells are functioning
Why would it be easier to measure C peptide than insulin
C peptide has a longer half life
Why can’t insulin enter cells?
Insulin is a large protein so has to act on receptors
Mechanism for insulin secretion
- Glucose enters through GLUT-2 and is used for ATP generation using glucokinase.
- ATP blocks the ATP-sensitive K+ channels.
- This triggers opening of voltage gated Calcium ion channels
- Calcium rushes into the beta-cell & insulin is secreted via regulated secretion.
Incretin Effect
Glucose stimulates more insulin secretion when given orally rather than intravenously
Glucagon like peptide 1 (GLP-1)
Gut hormone, secreted in response to nutrients in gut
What is GLP-1 a transcription product of?
Proglucagon gene, mostly from L cell
GLP-1 actions
Stimulates insulin
Suppresses glucagon
What feeling does GLP-1 increase?
Satiety (fullness)
What is the half life of GLP-1
Short
Due to rapid degradation from enzyme: Dipeptidyl peptidase-4 (DPPG-4 inhibitor)
1st phase insulin response
Healthy person has IV glucose load that makes them produces insulin instantly
Why is 1st phase insulin needed?
To switch off liver glucose production
Do those with T2D have a 1st phase response?
No
Insulin made slower/ later
How does insulin effect cells?
Insulin bonds to alpha subunits of receptor causing a conformational change in beta subunits
Phosphorylation of beta subunits recruits substrates which have an effect on metabolic pathway
Glucose synthesis ceases
Which subunits of the insulin receptor span the membrane?
Beta subunits
Insulin resistance in T2D area of error
Post-receptor cytoplasmic effects of insulin
