Diabetes Mellitus Flashcards
What are the actions of insulin in the fed state?
Decreases hepatic glucose output, increase glucose uptake into skeletal muscles, decreases proteolysis, decreases lipolysis, decreases ketogenesis
Which glucose transporter does insulin act on?
Where is this type of glucose transporter found?
How does it work?
What is its structure?
GLUT-4
Myocytes (skeletal muscle cells) and adipocytes (fat cells)
The GLUT-4s are highly insulin responsive, when there are high BGLs, insulin is released, which causes the recruitment of the GLUT-4s in vesicles that are then placed along the membrane, aiding glucose uptake
Outer hydrophobic chain, inner hydrophillic chain
How does insulin effect myocytes (muscle cells) after the fed state?
What happens if you are fasting and your BGL is low?
Other than insulin, what 2 other hormones also stimulate protein synthesis?
Insulin inhibits proteolysis, instead stimulates conversion of amino acids to proteins Iincrases protein synthesis)
Other hormones e.g. cortisol is released - can cause proteolysis and release amino acids that are then taken up by the liver for hepatic gluconeogenesis
GH (growth hormone) and IGF-1 (insulin-like growth factor-1)
How does gluconeogenesis take place in the liver?
Which hormones increase gluconeogenesis?
What happens to the amino acids in the fed state?
What is gluconeogenesis?
Amino acids (AAs) taken up by the liver with the help of glucagon, AAs undergo gluconeogenesis to produce glucose
Glucagon and cortisol
Insulin is released, which increases protein synthesis so the AAs taken up in the liver are stored as proteins, inhibits gluconeogenesis
Production of glucose from other energy sources e.g. amino acids - when fasting, other hormones are released to increase this
Out of carbohydrates, proteins and fats, which are the temporary energy stores lasting for the shortest time, and which last much longer?
How long do each of these energy stores last?
How much energy (kJ/kg) is released from each of these stores?
Carbohydrates = shortest-lasting, energy stores, these deplete first and quite quickly (around 16hrs)
Proteins = second go-to fuel source, makes up about 20% pf energy storage, lasts around 15 days
Fat = biggest energy source, makes up about 30-40% of energy storage, using fats to create energy lasts about a month
Carbohydrates and proteins release around the same kJ/kg, fats release 2x as many
How are fats stored after a meal?
And broken down to use as a metabolite when required?
Which hormones stimulate the process of lipogenesis and lipolysis?
Requires insulin to stimulate this function: after a meal, triglyceride levels in the blood increase, (lipoprotein lipase) LPL is used to break down triglycerides into free fatty acids and glycerol so they can leave circulation and enter adipocytes. Insulin then stimulates the glycerol and free fatty acids to combine and be rebuilt into triglyceride molecules for storage
In a fasting state, BGL drops, cortisol and GH stimulate the break down of triglycerides into glycerol and free fatty acids which are released from the fat cell
Lipogenesis = insulin
Lipolysis = cortisol and GH
What is the hepatic portal circulation?
Into which circulation system is insulin released?
Blood goes directly from the heart to the gastrointestinal system, and on the way back picks up nutrients from the digestive tract, which are the proccessed in the liver, before the blood returns to the heart
Into the hepatic portal ciculation system - therefore insulin = fast acting
How is glycerol taken up the liver, and what happens to it e.g. fed VS fasting state ?
What energy substrates can the cerebral hemisphere (i.e. the brain) use?
Glycerol is taken up to the liver by a transporter, when fasting the glycerol converted into glucose (gluconeogenesis), in the fed state it is stored as triglycerides
Brain = only utilise glucose (preferred source) and ketone bodies if they are available, but not free / non-esterified fatty acids (NEFAs)
How are fatty acids taken up by the liver, and what happens to it e.g. fed VS fasting state?
How can ketone bodies be used to determine insulin deficiency?
NEFAs are taken up into the liver via transporters, and can be converted into fatty acyl CoA. In the fed state, insulin prevents the breakdown of this fatty acyl CoA to ketone bodies. In the fasting state, glucagon can stimulate the breakdown of fatty acyl CoA to produce keotne bodies
After a meal, when there are high BGLs, if there is still ketone body production, it suggests insulin levels are too low to prevent this, indicating insulin dificiency
How is glucose taken up by the liver, and what happens to it e.g. fed state VS fasting state ? What is hepatic glycogenolysis?
In the fed state, BGL is high, glucose is taken up via the GLUT-2 receptors in the liver. Insulin stimulates the conversion of the glucose to glycogen for storage, in the fasting state, glucagon stimulates hypatic glycogenolysis - break down of liver glycogen stores to release glucose
In the fed state, what are the effects of high BGL and insulin release on the muscle cells?
What is the difference between the glycogen stores in the muscles compared to the liver?
When BGL is low, which hormones stop glucose uptake into the muscle cells?
Insulin acts on GLUT-4 receptors and causes: Glucose taken up by muscle cells, can be stored as glycogen if glucose is not needed immediately. In the fed state, NEFAs can also be taken up by muscle cells
Muscle = use internally only, glucose cannot be released; liver = release into bloodstream for body to use
Glucagon, GH
What happens in the body during the fasting state (fill in diagram)?
Increased proteolysis to use amino acids for gluconeogenesis / as an energy substrate, but prolonged fasting = amino acids used up so amino acids conc. drops
Breakdown of fat and proteins = products used for gluconeogenesis
Increase hepatic glucose output
Increased ketogenesis so ketone bodies can be used by the brain
What happens in the body after eating a meal?
High glucose levels detected by the pancreas (contains GLUT-2 receptors), insulin and C-peptide is released in equal quantities. Insulin acts on liver, muscle and fat.
Liver = decrease glycogenolysis, gluconeogenesis; increase glycogenesis
Muscle (GLUT-4) = increases glucose uptake and glycogenesis
Fat (GLUT-4) = inhibits lipolysis, increases glucose uptake, increases triglyceride uptake
GLP-1 released - signals to your brain = feel full
Hypoglycaemia medically is a good stressor, can be used tp stress many hormones. e.g. small child not growing, give them insulin to stress their body, but if GH levels dont increase in response to that, they have GH deficiency
c-peptide = more stable, insulin degrades more quickly, so c-peptide is measured to look at how much insulin the person themselves are producing
What is the body’s response to fasting?
Less insulin release
More proteolysis and lipolysis so products can be used for gluconeogenesis (increases hepatic glucose output)
Depletion of glycogen stores eventually leads to ketone body production (for the brain to use)
What is the body’s response during the fed state?
2 phases of insulin release - 1st = stored insulin release, 2nd = insulin synthesised and being released at the same time
Everything is stored, HGO reduces as there is already sufficient glucose in the blood to use as an energy substrate
Describe this flow chart of what happens to the body during the fed state:
AAs not required for gluconeogenesis, therefore stored as proteins (increased protein synthesis)
Same with fats - lipogenesis
Little / No HGO
What is the counterregulatory response to hypoglycaemia?
Are these still present in people with T1DM?
Increase in glucagon, catecholamoines, cortisol, GH - increases glycogenolysis / gluneogenesis and lipolysis to help increase BGL
Yes
How does insulin resistance arise?
Where is insulin resistance found?
In T2DM is there a lot of ketogenesis and proteolysis?
Pancreas can still produce insulin, which can still bind to the GLUT-4 receptors. Insulin resistance pathway resides from when there is insulin resistance, so there is more glucose in the blood, so more insulin is produced (hyperinsulinemia) to counterract that. Eventually, the resistance to insulin has greater impacts on BGL, and leads to a diagnosis of T2DM
All metabolic sites e.g. liver, muscle and adipose tissues
No, unlike in T1DM where there is a lot of ketogenesis and peoteolysis, in T2DM, there is usually enough insulin to suppress these functions
What happens if there is insulin resistance but not diabetes? Is it still important?
Yes, still important because when insulin binds to the insulin receptor, it activates the MAPK pathway that is responsible for growth and proliferation. This pathway does not have insulin so is not compromised, therefore the hyperinsulinemia can cause e.g. increased smooth muscle growth in the blood vessels, leading to hypertension, etc.
What is the management of both types of DM?
BOTH: Controlled diet; monitoring complications e.g. retinopathy, neuropathy, nephropathy, cardiovascular, etc.
T1DM: Try to replicate normal insulin physiology with insulin injections and finger prick testing (4-7 times a day); long acting insulin once a day, plus fast-acting insulin before meals. Techonology = insulin pumps, flash glucose monitoring devices
T2DM: Diet is first line management; oral medication; may need insulin later
