Biochemistry of Glucose and Insulin Flashcards
What are the cells found in pancreatic iselt cells in the pancreas and there function ?
- α-cells secrete glucagon
- β-cells secrete insulin
- δ- secrete somatostatin
- PP-cells secrete pancreatic polypeptide
Describe the structure of insulin
Insulin consits of 2 polypeptide chains linked by disulphide bonds
Describe insulin secretion in response to increased glucose
- Glucose enters β-cells through GLUT2 glucose transporter and is phosphorylated by glucokinase
- Increased metabolism of glucose in the β-cells leads to increased intracellular ATP concentration (remember the metabolism of a carbohydrate in this instance glucose leads to glycolysis, krebs cycle etc, its end result is ATP formation
- ATP inhibits ATP-sensitive K+ channels in the β-cell
- Results in depolarisation of the cell membrane
- Causes opening of voltage-gated Ca2+ channels
- Increase in internal Ca2+ leads to fusion of secretory vessels within the cell membrane and Release of insulin
What does insulin presence stimulate ?
- Amino acid uptake in muscle
- DNA synthesis
- Protein synthesis
- Growth responses
- Glucose uptake in muscle and adipose tissue
- Lipogenesis in adipose tissue and liver
- Glycogen synthesis in liver and muscle
What does insulin presence inhibit ?
- Lipolysis
- Gluconeogenesis
In which drug is KATP directly inhibited and how is this relevant to diabetes treatment ?
Inhibited by sulphonylurea (e.g. tolbutamide, glibenclamide, think AMIDE)
This will promote insulin secretion by acting on SUR1
In which drug is KATP directly stimulated ?
Diazoxide - this inhibts insulin secretion acting on Kir 6.2
What is MODY (maturity onset diabetes of the young)
- Monogenic diabetes with genetic defect in β-cell function
- Familial form of early-onset type II diabetes, primary defects in insulin secretion
Why does robust genetic screening to differentiate MODY from type 1 diabetes allow for better treatment ?
Because MODY is treated better on sulphonylureas rather than insulin
What type of receptors are insulin receptors ?
Receptor kinases
Describe the structure of insulin receptors
A dimetric tyrosine kinase
- Has 2 extracellular α-subunits with insulin binding domains
- Has 2 transmembrane β-subunits
Give an overview of insulin signaling
- Insuin binds to α-subunits
- Causes β-subunits to phosphorylate themselves (autophosphorylation)
- Insulin receptor substrates (IRS) are phosphorylates and result in 2 main biological effects
- Being IRS acitvation of RAS/MAPK pathway and gene expression
- Being IRS activate PIEK, PKB and glycogen synthesis
Describe what insulin resistance is
The reduced ability to respond to ‘physiological’ insulin levels is termed insulin resistance, thought to occur primarily through reduced insulin sensing and/or singalling
Give a couple examples of conditions associated with defective insulin secretion and signaling
- T2DM - associated with insulin resistance and obesity
- Monogenic diabetes - insulin resistance due to mutation in key signalling pathways
- Donohue syndrome - defects in insulin binding or insulin receptor ==> severe insulin resistance
- Rabson Mendenhall syndrome - Mutations in insulin receptor, decreased sensitivity ==> severe insulin resistance
Where are ketone bodies formed ?
Formed in liver mitochondria
How are ketone bodies formed ?
- Fatty acid oxidiation yields acetyl-CoA which enters TCA cycle if fat and carbohydrate degradation balanced
- BUT
- When glucose is not available free fatty acids are oxidised to provide energy, causing acetyl-CoA to be converted into ketone bodies
- Accumulation of ketone bodies can lead to acidosis
