Glucose Homeostasis Flashcards
What glucose levels cause hypoglycaemia and what does this do to CNS?
Blood gluc conc falling much below normal levels of 4-5 mmol/L impairs cerebral function
If below 2mmol/L causes unconscious coma and death
What does persistent hyperglycaemia result in?
Diabetes mellitus 2
What (4) hormones does the body secrete to increase blood glucose
- Glucagon
- Cortisol
- Growth hormone
- Catecholamines e.g. adrenaline
What hormone does the body secrete to decrease blood glucose?
Insulin
What is the most prevalent form of diabetes?
- Most prevalent is type 2
- Type 1 is 11% of all diabetes
- Maturity onset diabetes of the young (MODY) is 2/3% of all diabetes
What kind of structure does the pancreas gland have?
Retroperitoneal
Which two collections of cells make up pancreas and what do they do?
- Most of pancreas (98%) are acinar cells generates exocrine secretions via duct to small intestine like amylase and protease (purple in image)
- Small clumps of cells in pancreas (2%) are islets of Langerhans (pink in image) → even tho they only make up 2%, 10-15% of pancreatic blood supply is given to them showing importance
What cells make up the islets of Langerhans and what do they each secrete?
- alpha cells that secrete glucagon
- beta cells that secrete insulin
- delta cells that secrete somatostatin
What do the gap junctions between the cells of the islets of Langerhans allow?
They allow small molecules to pass directly between cells - paracrine communication
What is the purpose of the tight junctions between the cells of the islets of langerhans?
To create small intercellular spaces
What effect does insulin have on growth and development, and blood glucose conc?
Insulin stimulates growth and development (esp in utero) and reduces blood glucose
What effect does somatostatin have on the insulin and glucagon
Inhibitory
- Somatostatin inhibits both in a negative feedback loop to keep them in balance and ensure we’re not oversecreting either of them
How does glucagon and somatostatin affect the release of insulin from beta cells when there is a rise in blood glucose?
Glucagon stimulates release of insulin
Somatostatin inhibits the release of insulin
How do the GI hormones and amino acids affect the secretion of insulin from the beta cells when there is a rise in blood glucose?
Both increase secretion of insulin
How do SNS and PNS activity affect the secretion of insulin when there is a rise in blood glucose?
SNS activity inhibits secretion of insulin via alpha cells
PNS activity stimulates the release of insulin
What effects does insulin have in the liver?
- Build up of glycogen stores (increases glycogenesis)
- Breakdown of glucose (increases glycolysis)
- Increased glucose transport into cells via GLUT4- one of a family of glucose transporters mainly found in skeletal muscle and adipocytes that moves from being intracellular to being in cell membrane to take up glucose from blood into cell
- Increases amino acid transport and therefore protein synthesis
- Decrease in lipolysis and increase in lipogenesis
What are the effects of the hormones secreted by the islets of Langerhans on the secretion of glucagon when there is a decrease in blood glucose?
Insulin inhibits release of glucagon
Somatostatin also inhibits the release of glucagon
How do the concentrations of amino acids, GI hormones and activity of SNS and PNS affect the secretion of glucagon when there is a reduction in blood glucose?
All stimulate secretion of glucagon by alpha cells
How does Glucagon increase the blood glucose level when in hypoglycaemic conditions?
Increased amino acid transport into liver → Increased gluconeogenesis
Increases lipolysis which releases more glucose and so increases gluconeogenesis occurs so more glucose in blood
Increased hepatic glycogenolysis
Is GLUT-2 insulin sensitive?
No and has a low glucose affinity (GLUT2has a low affinity for glucose with its Km of about 15–20mM glucose. GLUT2, therefore, is able to move glucose into the liver cell and the pancreatic beta cell in proportion to the plasma level of glucose. This low affinity provides a variable rate of transport (proportional to the increasing glucose concentration) so that the high level of glucose following a carbohydrate-rich meal can be accommodated)
Is GLUT-4 insulin sensitive?
Yes and has a high glucose affinity (GLUT4functions for the insulin-dependent translocation of glucose. Thus, insulin stimulates the uptake of glucose by GLUT4 in the muscle cell wherehexokinaseconverts it toglucose-6-phosphateso that the cell may utilize it for eitherglycolysisfor energy or for the formation of glycogen when glucose is abundant.)
Where is glucokinase (hexokinase IV) found in the body (give at least 2
Liver
- Pancreas, what does glucokinase serve as in beta cells?a glucose sensor
Small intestine
Hypothalamus
What is the main difference in the actions of hexokinase I and hexokinase IV?
Hexokinase IV is not subject to -ve feedback from Glucose-6-P
Describe the process by which insulin is released from the beta cells after blood glucose increases?
- Glucose transported into beta cell by GLUT-2 (which is NOT insulin sensitive and has a low glucose affinity)
- Glucose in the cell undergoes glycolysis by Glucokinase (hexokinase IV) to produce ATP (Rate-Limiting Step)
- ATP inhibits the K+ efflux pump so K+ remains intracellularly and builds up in the cell, this relative increase leads to membrane depolarisation
- This opens Ca2+ voltage gated channels leading to Ca2+ influx which promotes secretion of stored insulin in beta cellThis is a graded response as blood glucose levels will vary throughout the day so insulin secreted at different levels too
what form is insulin stored and how does that become insulin?
As proinsulin which does have some degree of activity but by proteolytic cleavage it’s split into c-peptide and insulin
Why is measuring endogenous c-peptide a good indicator for insulin?
Insulin is very unstable assay and c-peptide can be stable for up to half an hour when samples sent to lab
What is the gastrointestinal incretin effect?
GI hormones enhance insulin secretion- so when glucose is ingested orally vs IV, there’s higher plasma insulin in oral vs IV even though plasma glucose is the same
What is Glucagon like peptide-1 (GLP-1) and what is it secreted in response to?
Gut hormone
Secreted in response to nutrients in gut
(Part of the incretin effect)
- What effects does GLP-1 have on the hormones secreted by the islets of langerhans?
Stimulates insulin
Suppresses glucagon
What effect does GLP-1 have on satiety?
Increases satiety (feeling of fullness)
Delays gastric emptying
Does GLP-1 have a short or long half-life?
Short half-life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPPG-4 inhibitor)
How is it used in treatment of T2 diabetes?
Those with T2 have reduced GLP-1 reserves
Helping people with obesity feel full, can help reduce their insulin insensitivity as they eat less
What is the first phase insulin release (FPIR) in normal people vs those with T2DM
FPIR is first spike in insulin following increase in blood glucose
With normal people there’s a marked increase in insulin after IV glucose challenge and then blood gluc goes down and thus so does insulin
With T2DM this response is blunted so it’s not just that our cells are resistant to insulin, but also beta cells can’t produce enough insulin to counteract glucose load after working hard for a long time
What does the insulin receptor look like and how does it work when insulin binds (i.e. Which subunit does insulin bind to and what does this cause)?
Insulin binds to the extracellular domain of insulin receptor at the alpha subunit
This causes a conformational change in the tyrosine kinase domains of the beta-subunits
This enables GLUT4 transport from intracellular into the membrane
