Glucose homeostasis Flashcards
Why is glucose important?
- it is an energy substrate (especially for the CNS)
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.
What does persistent hyperglycaemia result in?
diabetes mellitus
How is glucose regulated?
At high blood glucose: insulin will decrease blood glucose.
At low blood glucose: glucagon, cortisol, GH, catecholamines will increase blood glucose.
What % of people are affected with diabetes mellitus in the UK?
7%
What is the % risk increase risk of a person with diabetes mellitus dying relative to an age-matched control without diabetes mellitus?
34%
How much of the NHS budget is spent on diabetes mellitus?
10%
What is the most prevalent form of diabetes?
Type 2 diabetes mellitus (then Maturity onset diabetes of the young (MODY), Type 1 diabetes mellitus (T1DM))
What kind of structure is the pancreas gland?
retroperitonael structure
See diagram 12/33
What is the structure of the pancreas?
Most of pancreas (98%) generates exocrine secretions via duct to small intestine.
Small clumps of cells within pancreatic tissue (remaining 2%) are called islets of Langerhans.
Exocrine acinar cells surround the Islets of Langerhans
(See diagram 13/33)
What do alpha cells secrete?
glucagon
What do beta cells secrete?
Insulin
What do delta cells secrete?
somatostatin
What are the functions of gap junctions?
allow small molecules to pass directly between cells
What are the functions for tight junctions?
create small intercellular spaces
How do islet cells communicate with each other?
Paracrine communication between islet cells
See diagram 14/33
What is the role of insulin?
Insulin stimulates growth and development and reduces blood glucose
What is the role of glucagon?
increases blood glucose
What is the role of somatostatin?
somatostatin is a negative feedback hormone to control the concentrations of insulin and glucagon
insulin is also key in growth and development
What are the reactions 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.
increased blood glucose, some GI hormones, some amino acids, PNS activity, and SNS activity (via beta) -> gamma cells secrete somatostatin, alpha cells still secrete glucagon (to make sure of that you do not become hypoglycaemic) + beta cells produce insulin somatostatin + SNS activity (via alpha) have an inhibitory effect on the beta cells
(See diagram 16/33)
What does insulin do in response to an increase in blood glucose?
increase amino acid transport, increase protein synthesis, decrease lipolysis, increase lipogenesis, increase glycogenesis, increase glycolysis, increase glucose transport into cells via GLUT4 -> thus decrease blood glucose
- Build up of glycogen stores
- Breakdown of glucose
- Increased uptake of glucose
Additional actions of insulin include:
- Increase of protein synthesis
- Reduction in breakdown of fat
What are the reactions to decrease in blood glucose?
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.
decrease in blood glucose, some amino acids, some GI hormones, SNS activity (via alpha), PNS activity promote the secretion of glucagon by alpha cells
insulin and somatostatin have inhibitory effects on alpha cells
(See diagram 18/33)
What does glucagon do in response to a decrease in blood glucose?
increase blood plasma glucose
increase lipolysis -> increase gluconeogenesis -> increase blood glucose
increase amino acid transport into liver -> increase gluconeogenesis -> increase blood glucose
increase hepatic glycogenolysis -> increase blood glucose
What is the role of glucokinase?
(hexokinase IV) it is the main glucose sensor
it is not subject to negative feedback - therefore, you have a continual conversion of glucose
extracellular glucose = intracellular glucose = intracellular ATP
What is the difference between GLUT2 and GLUT4?
GLUT4 is insulin mediated, GLUT2 is not insulin sensitive
GLUT2 is found on beta cell membranes and has a very high affinity for glucose
How is insulin released?
- glucose passes through GLUT2 into the cell
- glucose converted to glucose-6-phospate (mediated by glucokinase)
- then converted to ATP
- closes the postassium-gated channels, preventing extracellular flux of potassium
- membrane depolarisation
- influx of Ca2+ through calcium-gated channels
- promotion of insulin secretion by beta cells
(See diagram 23/33)
What is C-peptide?
the breakdown product of proinsulin
c-peptide can give us a better indication of the levels of insulin an individual is producing
How is insulin formed?
By proteolytic cleavage of proinsulin to c-peptide and insulin
(See diagram 24/33)
A healthy person eats a Big Mac meal. What do you expect their c-peptide to be?
High
A person with Type 1 diabetes mellitus eats a Big Mac meal. What do you expect their c-peptide to be?
Low
What is glucagon like peptide-1 (GLP-1)?
gut hormone
What is a gastrointestinal ‘incretin’ effect?
The effect observed as a result of different modalities of administering glucose.
Gut hormones increase insulin secretion in response to a glucose load.
if a healthy individual is given the same amount of intravenous or oral glucose, you would expect glucose levels to rise and decrease.
mode of administeration should not matter in terms of insulin, oral glucose is associated with an enhanced insulin secreted - incretin effect
(See diagram 29/33)
When is GLP-1 secreted?
in response to nutrients in gut
What does GLP-1 do?
stimulates insulin, suppresses glucagon increases satiety
used in the treatment of diabetes
Why does GLP-1 have a short half life?
Due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)
What happens in type 2 diabetes mellitus/
response of insulin is blunted
beta cells unable to produce enough insulin
(see diagram 31/33)
What is the First Phase Insulin Response (FPIR)?
initial insulin surge/First Phase Insulin Release
What does insulin bind to?
the extracellular domain of the insulin receptor
see diagram 32/33
What happens when insulin binds to the alpha-subunit?
conformational change in the tyrosine kinase domains of the beta-subunits
therefore changes in tyrosine kinase domains
enabling of GLUT4 transport from intracellular to enable glucose uptake
