26 - Insulin Signalling and Diabetes Flashcards
How many people have diabetes?
The number of people with diabetes has risen from 108 million in 1990 to 422 million in 2014
What is the global prevalence of diabetes in adults?
The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014
What type of countries have rising numbers of diabetes?
Diabetes prevalence has been rising more rapidly in middle- and low-income countries
What is diabetes a major cause of?
Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation
How many deaths are linked to diabetes?
In 2016, an estimated 1.6 million deaths were directly caused by diabetes
o Another 2.2 million deaths were attributed to high blood glucose in 2012
Where is diabetes ranked in the leading causes of death?
Almost half of all deaths attributable to high blood glucose occur before the age of 70 years
o WHO estimates that diabetes was the seventh leading cause of death in 2016
What ways can you avoid developing type 2 diabetes?
Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use are ways to prevent or delay the onset of type 2 diabetes
How can diabetes be treated?
Diabetes can be treated and its consequences avoided or delayed with diet, physical activity, medication and regular screening and treatment for complications
Glucose
o Many of the foods we eat are broken down during digestion to this simple sugar
o Glucose is carried to every cell in our body by the blood stream, where is is used as the source of energy for our bodies
Glycogen
o The stored form of glucose is called glycogen
o Glycogen is made up of many connected units of glucose
Insulin
o This hormone is released into the blood when blood glucose levels are high
o It enabled glucose to be transported into the cell in some tissues
What happens when glucose levels are high in the blood?
When glucose levels are high in the blood, insulin is secreted from the pancreas which enhances the normal uptake of glucose into certain cells and tissues, particularly muscle
What events does insulin switch between?
Insulin switches between anabolic and catabolic events so when insulin is released it interacts with its receptor and causes upregulation of glucose uptake into muscle and fat
What does insulin stimulate in the liver?
In the liver it stimulates glycogen synthesis, glucose is taken up by the liver and stored as a polymer
Glucagon
o This hormone is released into the blood when blood glucose levels ae low
o It enables glucose to be released from some tissues back into the blood stream
Pancreas and diabetes
Pancreas: one of the major players in glucose homeostasis, the pancreas releases the hormones, insulin and glucagon, that control blood glucose
- The cells in the pancreas that produce insulin are cells and those that produce glucagon are cells
- An endocrine organ dedicated to the fluctuation of blood glucose levels
- The beta cells are destroyed in type 1 diabetes
Liver and diabetes
o Liver: takes up glucose when levels are high and releases glucose when levels are low
- it stores glucose in chains as glycogen
- it is key for glucose regulation
- central organ for controlling levels of blood glucose in the body
Mechanism of Insulin production
- nucleus - preproinsulin (INS) –> preproinsulin mRNA
- rough ER - preproinsulin
- trans-golgi network - proinsulin
- immature secretory granules - insulin
- mature secretory granules - insulin (hexameter/crystal)
Which organ expresses insulin?
The pancreas expresses the insulin gene which produces preproinsulin mRNA which is translated into preproinsulin
What is preproinsulin?
The preproinsulin is a single peptide chain comprised of an A, B, and C chain which are linked together with a signal peptide
What does the signal peptide do?
- the signal peptide makes sure the preproinsulin is trafficked to the golgi network where it is further processed
- it is folded, disulfide bonds are formed and we have the singal peptide cleaved off in the trans-golgi network, making proinsulin
What happens as proinsulin passes into immature secretory vesicles?
As it is passaged into immature secretory vesicles, proinsulin is further modified to make insulin, involving proteolytic cleavage of the C chain, leaving the A and B chain linked together by disulphide bonds
Where does further modification of insulin take place?
Further modification takes place in the mature secretory granules where we have formation of insulin hexamer crystals whereby six insulin molecules form a crystal coordinated by zinc ion
What happens when mature secretory granules are stores in the beta cells until glucose levels rise? (step 1)
o When his happens glucose enters the cell, and enters metabolism and is broken down to make pyruvate which enters the TCA cycle
o We get production of ATP as a consequence
What happens when ATP levels rise ? (step 2)
ATP is serving as a signalling molecule, so as ATP levels rise this blocks the action of a potassium channel and this change is membrane polarisation-reduction of transmembrane charge difference, depolarisation- triggers the insulin release
o Does this by triggering the activation of voltage dependent calcium channels, calcium is able to enter the cell via these channels triggering exocytosis of insulin containing vesicles
o These dock with microtubules, travel along the microtubules and interact with the cortical actin and dock with the SNARE protein complexes at the surface and this triggers the exocytotic where the insulin is released
What happens when the insulin is further modified by ion channels and receptors?
They will then enhance the amount of insulin secretion in response to glucose
Certain responses cause calcium to be released from intracellular stores
o one example is a hormone called glucose like peptide which is an incretin hormone, these ae released by the gut, and these can interact with G-protein coupled receptors
- they elevate cAMP, activating phospholipase C epsilon, produce IP3 which will caus calcium release and that will enhance the insulin exocytosis so GLP will act on its receptor which will elevate cAMP and that will cooperate with glucose to elevate the amount of insulin secreted
- so GLP is secreted when the gut Is full
What types of cells are in the pancreas?
- there is a number of different cell types in the pancreas
- islets which secrete insulin, we have the beta cells and alpha cells, and we also have delta cells which secrete somatostatin
- all of these cooperate to regulate glucose levels in the body and we have insulin secretion into the blood supply to the liver
Muscles
Muscles: our muscles are able to take up and store lots of glucose when insulin is present
- More muscle mass means more of a reservoir for glucose
- The striated muscle cells cover the body, like an exoskeleton
Fat cells (adipocytes)
Fat cells (adipocytes): adipocytes take up glucose when insulin is present and use glucose to make more fat
Brain
Brain: the brain takes up glucose whenever it needs energy, and doesn’t require insulin
- Glucose is the fuel the brain normally uses
Journey of insulin in the body
START: pancreas (BIOSYNTHESIS) –[portal vein]–> liver (CLEARANCE) –[venous circulation]–> heart (DELIVERY) –[arterial circulation–> liver (LOOP BACK TO HEART) OR adipose/skeletal muscle (GLUCOSE UPTAKE) —-> kidney (DEGRADATION) END
Where does insulin enter and where does it cycle through?
It is cycles through the liver so it can travel through the venous circulation and return via the heart to the liver
o As long as glucose levels are high, insulin will be supplying the liver and stimulating the liver to take up glucose and store it as glycogen
o This is called CLEARANCE
What happens when insulin as it passes from the liver and through the heart?
Insulin as it passes from the liver and through the heart will enter the arterial circulation through the arteries and will interact with receptors on the adipose tissues (fat cells) and on skeletal muscle
o It will stimulate glucose intake into the fat cells and the smooth muscle cells
o Insulin will be stored as glycogen in the smooth muscle cells and transformed into fat in the adipose tissues
Where is insulin degraded?
As insulin has done its job it will pass through the kidney and be degraded there
Signalling in adipocytes and myocytes
The signalling is similar in both adipocytes and myocytes with a few differences- there are different molecular players involved
Net effect of signalling in muscle and adipose cells
The net effect is that insulin docks with its effector which exist as a preformed dimer leading to the recruitment of glucose transporters, GLUT4, to the cell surface
How does GLUT4 exist (pt. 1)?
GLUT4 exists as vesicles inside the cell, these vesicles will travel along the cytoskeletal scaffold, helped by adaptor proteins, including small G proteins called Rab
What happens when glucose transported vesicles arrive at the cell surface (pt. 2)?
When the glucose transported vesicles arrive at the cell surface, they are labelled with particular proteins which are recognised by receptors at the cell surface called SNAPs
What happens when SNAP receptors dock together (pt. 3)?
When these receptors dock together, the energy between the plasma membrane and in the intracellular vesicle is reduced, so they fuse forming an exocytotic invagination
What happens to the transmembrane proteins (pt. 4)?
These glucose transporters which are transmembrane proteins will ow be expressed at the cell surface and will enhance glucose uptake into adipocytes and muscle cells
What are the signalling steps that are the same for both adipocytes and muscle cells? (1-4)
- When the receptor is activated it causes transphosphorylation of the intracellular domain
- Recruitment of IRS1 (insulin substrate receptor 1) which is a protein that has a phosphotyrosine binding domain- this docks with the phosphorylated receptor
- Recruitment and activation of PI3K
- Phosphorylation of phosphatidylinositol-4, 5 bisphosphate on three positions to make PIP3
What are the continued signalling steps for adipocytes? (5-8)
- PIP3 production allows activation of PKB or Akt through PDK1 recruitment
- Recruitment of Rab, which is a small G protein, to the GLUT4 vesicles
- Allows assembly of vesicles onto the microtubular cytoskeleton
- Vesicles can travel along these and fuse with the cell membrane, expressing glucose transporters
What are the continued signalling steps for muscle cells? (5-7)
- Activation of Rac1 which is a GTPase- greater assembly of actin tubules
- Enhanced docking of GLUT4 containing vesicles
- Trafficking along the actin tubules to the cell membrane where there is expression of GLUT4 allowing glucose uptake
What is missing in cell signalling in diabetes?
In diabetes we don’t get recruitment of GLUT4 to the cell surface
Why is there a cardiovascular element in diabetes?
In diabetes there is also a cardiovascular element, so people with diabetes are more likely to develop cardiovascular disease
o This is because insulin receptors are also found on endothelial cells that line the bloodstream/vasculature
How does diabetes put stress on the heart?
Insulin promotes vascular relaxation, so if we no longer get proper insulin signalling, we get a block in this pathway and the blood vessels will narrow, and put stress on the heart
Role of insulin in endothelial cells
In the endothelial cells that line the blood vessels, insulin interacts with receptors causing activation of IRS2, activation of PI3K, production of PIP3 and PIP2, activation of Akt
o Akt phosphorylates and activates nitric oxide synthase
What does nitric oxide do in smooth muscle cells?
Nitric oxide synthase diffuses rapidly into the vascular smooth muscle cells and activates guanylate cyclase which causes the formation fo cyclic GNP
o This activates its protein kinase G, causing a reduction in calcium levels
o The smooth muscle cells relax and blood vessels open
What is the classic way to detect diabetes?
The classic way to detect diabetes is through the oral glucose tolerance test (OGTT)
* The patient is instructed to fast, then they are given a glucose solution to drink and the levels of glucose in the blood after a period of time is measured
Normal range of blood glucose vs diabetic
The normal range is in the region of 140 mg/dl blood
* If clearance is not so efficient and levels are detected between 140 and 200 mg/dl after a meal, the patient is pre-diabetic
* If levels are greater than 200mg/dl, this is known as type II diabetes
Blood glucose levels in Type II diabetes
Blood glucose levels are always high because of high insulin resistance and/or low insulin levels
Blood glucose levels in pre-diabetes
At this stage, blood glucose levels are higher than normal after a meal and at a resting state but not high enough to be classified as full-blown diabetes
People with pre-diabetes are at increased risk for type 2 diabetes
Blood glucose levels - normal
Blood glucose levels are well regulated
Correlation of insulin sensitivity and blood glucose levels in type 2 diabetes
- Insulin sensitivity is directly correlated with the development of diabetes
- When someone is highly sensitive to insulin, i.e., receptors are responding properly, the blood glucose concentration is in the region of about 5mM
- As insulin sensitivity drops, we enter a more resistant stage where blood glucose levels start to rise between 8 and 10 mM
- In the full diabetic stage, the insulin sensitivity is very low and blood glucose levels are higher than 12mM
