Glucose Homeostasis Flashcards
What is the importance of glucose?
- Glucose is an important energy substrate
2. This is particularly true for the central nervous system
What happens if blood glucose concentration falls?
- If the blood glucose concentration falls much below normal levels of 4-5 mmol/L (hypoglycaemia), then cerebral function is increasingly impaired.
- If blood glucose concentration <2 mmol/L, unconsciousness, coma and ultimately death can result.
How is glucose broadly regulated?
- Glucose closely regulated
- Feedback system needed for this regulation
- Persistent hyperglycaemia results in diabetes mellitus
What is the most prevalent type of diabetes?
- T2DM
- T1DM
- MODY
What is the mechanism for glucose regulation?
- Increase in blood glucose
- Increase insulin production
- Decrease blood glucose use
- Then glucagon, cortisol, GH and catecholamines
What type of structure is the pancreases gland?
Retroperitonael structure
What does most of the pancreas generate?
-98% generates exocrine secretions via duct to small intestine (exocrine acinar cells secrete enzyme for digestion)
What does the other 2% of the pancreas secrete?
- Small clumps of cells within pancreatic tissue are islets of langerhans
- For glucose homeostasis
What are the different types of cells in islet of Langerhand and what does each one release?
- Alpha cells: glucagon
- Beta cells: insulin
- Delta cells: somatostatin
What type of communication is between islet cells?
Paracrine communication
What are gap junctions?
Allow small molecules to pass directly between cells
What are tight junctions?
Create small intercellular spaces
What in broad terms do pancreatic hormones do?
- Insulin stimulates growth and development and reduces blood glucose
- Glucagon increases blood glucose
- Somatostatin inhibits both insulin and glucagon (and keeps everything in check)
What it eh reaction to increase in blood glucose
-Physiological changes occur in response
to ↑ plasma glucose concentration
-These are required to ensure glucose
levels do not continue to increase beyond physiological values
1. Increase blood glucose Stimulates Beta cells to produce insulin (some aa and GI also does this and PNS activity)
2. If SNS activity switches off beta via alpha cell receptor off and and minor stimulation by beta cell receptor
What does insulin do?
- Build up of glycogen stores (increase glycogenesis)
- Breakdown of glucose (increase glycolysis)
- Uptake of glucose (increase glucose transport into cells via GLUT4)
- Increase of protein synthesis
- Breakdown of fat (increase lipogenesis and decrease lipolysis)
What is the reaction to blood glucose reduction?
- Physiological changes occur in response to reductions in glucose values
- These are required to ensure glucose levels do not continue to fall thereby compromising energy/ substrate delivery
1. Stimulates alpha cells to produce glucagon, aa also does this and some GI hormones and PNS and SNS has positive effect
How does glucagon act?
- Increase lipolysis so increasegluconeogensis
- Increase amino acid transport into liver so increase glucosneogensis
- Increase hepatic glycogenolysis
- Therefore increase blood glucose
What happens at the end of a 5000m race?
- Increase hepatic glycogenolysis
- Increase in lipolysis
- Increase aa transport into the liver
Is GLUT2 insulin sensitive?
NO
What is the main glucose sensor?
Glucokinase (hexokianse IV)
How is insulin secreted from the beta cells?
- Glucose enter beta cells through GLUT-2 transporter (not insulin dependent)
- This glucose is metabolised into glucose-6-phosphate by a rate limiting step via glucokinase enzyme (thought to be main glucose sensor) - if glucose is beyond certain threshold
- G6P converted into ATP
- ATP blocks channels in Channels at cell membrane surface
- Therefore release of K+ and then stimulates calcium voltage channels in cell
- Then Ca2+ enters cell therefore release of stored insulin and synthesis of new insulin
How is insulin stored?
- In proinsulin which is a polypeptide
- When insulin related the pro-insulin undergoes proteolytic cleavage which caused C-peptide relase and insulin which are bound together by di-sulphide bonds
- Therefore surrogate marker for insulin - so look at C-peptide
What is glucagon like peptide (GLP-1)?
•Gut hormone
•Secreted in response to nutrients in gut
•Transcription product of pro-glucagon gene, mostly from L-cell
•Stimulates insulin, suppresses glucagon
•↑ satiety (feeling of ‘fullness’)
•Short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)
•Used in treatment of diabetes mellitus
-In incretin effect
What is the insulin receptor?
- Insulin binds to the extracellular domain of the insulin receptor (can’t get through cell membrane)
- Once insulin binds to the a-subunit, there is a conformational change in the tyrosine kinase domains of the b-subunits
- So insulin can mediate its effect
