Terence (Insulin and glucose) Flashcards
Glucose homeostasis
Blood glucose levels are maintained between narrow levels (between 4mmol/l and 9mmol/l).
There are fluctuations in BG levels- eating meals leads to a rise in BG concentrations. BG level falls overnight but don’t go below 4mmol/l.
What is the normal ranges for plasma glucose concentration
- when fasting
4.0 mmol/L to 5.4 mmol/L
Glucose ADME
The glucose concentration in the circulation is primarily dependant on the rate of adsorption into the blood and tissues. Factors which affect this are:
- Rate of digestion (glucose doesn’t need to be digested, it is just absorbed)
- Rate of gastric emptying (contents churned and released into small intestine)
- Rate of absorption/uptake in the small intestine via glucose transporters via the sodium-glucose co-transporter
- Glucose enters the hepatic portal system and enters the liver
- The liver removes excess glucose facilitated by the hormone insulin
- In the fed state, glucose is rapidly taken up into tissues/cells via glucose transporters and either metabolised or stored
- Glucose is not normally excreted (reabsorbed by kidneys)
What is the role of the liver in glucose adsorption?
The liver acts as a sink for glucose. Lots of glucose is taken up by the liver before it enters general circulation. When it leaves the concentration of glucose is relatively low. Insulin is used in the uptake of glucose.
Liver is the first organ to see insulin so sees much higher concentrations of insulin. Insulin is taken in by the liver and promotes liver to take up BG.
Insulin
Insulin is a peptide hormone that allows the uptake of glucose from blood.
51 amino acid peptide hormone.
Binds to a cell surface receptor.
Made up of two chains held together by disulphide bonds.
Secreted from pancreatic beta-cells.
Lowers blood glucose.
hormone of the fed state- see presence of hormone after eating.
Action can be considered anabolic- promote the production of larger molecules from smaller molecules.
Oral glucose tolerance test (OGTT)
A measure of glucose disposal.
Used for diabetic diagnosing.
Overnight fast followed by injection of 75h of glucose. Follow changes in blood glucose over time.
Normal: insulin rises slightly over first hour then decreases back to normal levels
Severe DMI: insulin is still high after fasting as rises for 2 hours then decreases.
The pancreas
Lies below the liver and behind stomach.
Weighs approx. 100g.
Head attached to duodenum.
Tail attached to spleen.
Made up of both exocrine and endocrine tissues.
The exocrine pancreas
Exocrine tissue- a gland that secretes outwardly through a duct or ducts.
98% of the pancreas is composed of pancreatic exocrine tissue.
the exocrine cells are arranged into grape like clusters called acini.
These cells release 1.5L of pancreatic juice per day containing digestive enzymes and bicarbonate ions into the pancreatic duct. It is released into intestines via pancreatic duct.
The endocrine pancreas
Endocrine cells- secrete internally into the systemic circulation.
Make up approx. 2% of the pancreas. (Only these 2% are hormone related).
Endocrine cells are arranged into small clusters called the Islets of Langerhans.
These cells synthesise and secrete hormones (including insulin) into the blood via the pancreatic vein.
Types of islet cells
alpha cells (20%) secrete glucagon
beta cells (70%) secrete insulin
delta cells (5%) secrete somatostatin
5% other cells
Insulin synthesis
Preproinsulin mRNA translated to preproinsulin. The signal peptide directs the mRNA into the lumen of the ER where transcription takes place. It is modified into the prohormone proinsulin. It is transported from the ER to the Golgi then to the trans Golgi network (TGN) where it is packaged into vesicles. The vesicles contain proteases and proinsulin. Condensation occurs to remove water leading to an increase in concentration of insulin inside the granules. Proinsulin is cleaved to insulin during this process (proteolytic processing via proteases turns proinsulin into insulin and a C-peptide). Granules are now mature and contain active insulin. Insulin can be released in response to a particular stimuli.
Insulin hexamer
Insulin is stored in crystalline form - 6 molecules of insulin positioned around 2 molecules of zinc. (Stored at high concentrations so it crystallises).
Increases storage capacity, reduces solubility (takes more time to dissociate and then have its action) and increases half life (less prone to degradation from enzymes)
Response driven feedback mechanism
Response driven feedback- hormone levels are regulated by their response/effect.
Initial stimulus is an increase in BG which leads to the response of an increase in insulin release. Insulin lowers BG conc which decreases the stimuli so the response is shut off.
Glucose-stimulated insulin secretion
Beta cells detect stimulus.
Glucose transporter allows glucose into the cells. Glucokinase (works more effectively at higher concentrations) converts more glucose into glucose-6-phosphate. Glucose-6-phosphate is the first step in glycolysis and can no longer leave the cell in this form.
This metabolism of glucose to glucose-6-phosphate leads to a production of ATP. Channels detect a change in ATP and K+ channels close. Leads to depolarisation and opening of Ca2+ channels. Influx of calcium which stimulates pathways and leads to the release of insulin.
Exocytosis of insulin
Glucose is transported into beta cells through plasma membrane transporters GLUT1 and GLUT2.
High plasma glucose increases glucose levels within the cells.
Glucose phosphorylation in beta cells uses low affinity hexokinase called glucokinase.
The phosphorylation rate varies with intracellular glucose concentration, so in beta cells the glycolytic rate depends on the glucose concentration in arterial blood.
Most of glucose is fully oxidised leading to a rise in the ATP/ADP ratio.
ATP sensitive potassium efflux channels in beta cells are inhibited by ATP/ADP.
The channels close as ATP rises, depolarising the cells.
Depolarisation activates voltage gated Ca channels.
Rise in intracellular calcium leads to exocytosis and insulin release from stored secretory granules.
Glucose stimulated insulin secretion
Secretion occurs in a characteristic biphasic pattern
- rapid first phase release
- prolonged second phase of release
Pre diabetic people have a loss in the first phase and a reduction in the second phase. Can be an indicator they will become diabetic. They also secrete more proinsulin.
Glucose stimulated insulin secretion dose response curve is sigmoidal.
Shape governed by the activity of glucokinase as the phosphorylation of glucose by glucokinase is the rate limiting step in insulin secretion.
Small changes in glucose concentration in the physiological range lead to a large change in secretion.
The insulin receptor
Receptor Tyrosine Kinase- usually monomeric but insulin receptors are dimeric.
Insulin needs to bind to receptor to lead to a change in conformation and activation of receptor.
Recruitment and activation of signalling molecules
1. Activates and inhibits metabolic pathways by changing the activity/expression of key enzymes
2. Stimulates nutrient uptake by increasing the activity/expression of transporters
Glucose
Glucose is the preferred energy source. when energy is low other nutrients (e.g fats) are used so glucose is kept at a certain level. The brain can only use glucose so if glucose levels are too low you go into a coma. Some other tissues and cells such as RBCs also only use glucose.
Insulin is secreted by the pancreas into the blood in response to increase in blood glucose.
Insulin binds to muscle cells to stimulate uptake of glucose into muscles to be stored and used as an energy source.
REMEMBER: Insulin increases glucose uptake, utilisation and storage.
The hypoglycaemic actions of insulin in the liver
Promotes:
- glucose storage as glycogen (glycogenesis) or as fat (lipogenesis)
- glucose utilisation (glycolysis)
Inhibits:
- breakdown of glycogen (glycogenolysis) or breakdown of fat (lipolysis)
- generation of glucose (gluconeogenesis)
The hypoglycaemic actions of insulin in the muscle
Promotes:
- glucose transport (GLUT4)
- glycogenesis (glycogen cannot be released into the blood, it is only for the muscle)
- glycolysis
- lipogenesis
- protein synthesis
- amino acid transport
Inhibits:
- lipolysis
- protein catabolism
The hypoglycaemic actions of insulin in the adipose tissue (fat)
Promotes:
- glucose transport (GLUT4)
- lipogenesis (stored as fat)
Inhibits:
- lipolysis
Other hormones involved in increasing blood glucose
Glucagon (doesn’t work that well on its own so needs other hormones in conjunction- produces a synergistic effect)
Adrenaline
Cortisol (can lead to steroid induced diabetes- more common in people who are at higher risk of type 2 diabetes)
ACTH
Growth hormone
Thyroxine
Glucagon
- 29 amino acid peptide hormone
- Hyperglycaemic agent- increased blood glucose
- Secreted from pancreatic alpha cells in response to low glucose/fasting
- Acts via the glucagon receptor which is a GsPCR
- Acts on adipose and liver but not muscle (no receptors for glucagon)
- Activates glycogenolysis and gluconeogenesis in the liver
- Promotes amino acid metabolism/lipolysis for gluconeogenesis
- Effects on liver are dependant on the glucagon/liver ratio as insulin counteracts glucagon on the liver
- Effect is highly dependant on presence of other hormones e.g. cortisol
Cortisol
Cortisol is a steroid hormone secreted from the adrenal gland. It is a stress hormone.
It is released with a diurnal cycle and in response to stress and low blood glucose concentration.
Effects on glucose metabolism are delayed (30 mins to hours).
cortisol alone has no effect on glucose production. the addition of cortisol accentuates hyperglycaemia produced by glucagon and adrenaline.
