Metabolism and Insulin

Question 1

What hormone lowers blood glucose?

Answer 1

Insulin

Question 2

What hormones increase blood glucose? (x4)

Answer 2

Glucagon, catecholamines, somatotrophin, cortisol.

Question 3

What is Type 1 diabetes?

Answer 3

Elevated blood glucose from body’s inability to secrete insulin. Requires insulin to prevent ketoacidosis. Absolute insulin deficiency.

Question 4

What is ketoacidosis? What is it caused by? (x2 points) Why is it bad for patients?

Answer 4

Associated with excess ketone production. Formed by breakdown of fatty acids and aa deamination. Develops when body can’t produce insulin which helps sugar get into cells. Without enough insulin, your body uses other energy sources. In diabetes, dangerous because body unable to use blood glucose.

Question 5

What is Type 2 diabetes?

Answer 5

Insulin resistance associated with elevated blood glucose levels, hypertension and dyslipidaemia (high lipid concentration in the blood).

Question 6

What is MODY?

Answer 6

Non-insulin dependent diabetes with early onset. Diabetes caused by a single gene.

Question 7

Why has MODY knowledge been useful in other forms of diabetes?

Answer 7

Can help us to understand disease mechanisms in diabetes as it tells us what genes (and cellular processes) cause diabetes.

Question 8

How can diabetes be managed? (x4)

Answer 8

DIET. Exercise for T2DM. Insulin given physiologically (meaning tailoring insulin to meal times and eating habits). Capillary glucose monitoring.

Question 9

What do blood glucose levels in the body depend on? (x3)

Answer 9

Diet, insulin production and exercise.

Question 10

What is the cellular composition (and proportions) of pancreatic tissue?

Answer 10

98% is associated with exocrine secretions via duct to small intestines. 2% are small clumps of cells called islets of Langerhans.

Question 11

What cells are found in the Islets of Langerhans and what do each do? (x3)

Answer 11

ALPHA – secrete glucagon. BETA – secrete insulin. δ (DELTA cells) – SOMATISTATIN

Question 12

What does somatostatin do? (x3)

Answer 12

Inhibits glucagon and insulin secretion. Inhibits GHRH. It’s a NEGATIVE hormone.

Question 13

What is the role of insulin? (x3 and x3)

Answer 13

Stimulates growth and development, ovarian function, clotting – MITOGENIC effect. Decreases blood glucose, increased protein synthesis, increased fat storage – METABOLIC effect.

Question 14

Other than endocrine signalling, what other signalling is present in the Islets of Langerhans?

Answer 14

PARACRINE control of hormone secretion.

Question 15

How is there paracrine activity in the Islets of Langerhans? (x2)

Answer 15

Local hormones are sent to the cells next-door - paracrine effect. Substances are released through gap junctions and into tight junctions between cells. (remember gap are channels BETWEEN TWO CELLS, and tight junctions are areas of INTERCELLULAR SPACE between cells). Hormones held in tight junctions which allows for high concentration deposition.

Question 16

What stimulates B-cell to secrete insulin? (x5)

Answer 16

Certain amino acids. Certain gastrointestinal hormones. GLUCOSE. Parasympathetic activity. B-receptors. NEFA increase in the blood – I’m guessing because this would signify lipolysis.

Question 17

What inhibits B-cell to secrete insulin? (x3)

Answer 17

GLUCAGON. Somatostatin. Alpha receptors. Sympathetic activity.

Question 18

How does insulin (i)decrease glucose (x3), (ii)increase protein synthesis (x1), (iii)increase fat storage (x2)?

Answer 18

(i) Increased glycogenesis, increased glycolysis, increase glucose transport into cells via GLUT4. (ii) Increased amino acid transport for protein synthesis in cells. (iii) decreased lipolysis, increased lipogenesis.

Question 19

How does glucagon increase blood glucose? (x2(x2))

Answer 19

INCREASED HEPATIC GLYCOGENOLYSIS Increased gluconeogenesis – through increased amino acid transport and lipolysis.

Question 20

What stimulates and inhibits glucagon secretion from alpha cells?

Answer 20

STIMULATES: Decreased blood glucose, certain amino acids, certain gastrointestinal hormones, sympathetic activity, PARASYMPHATHETIC activity. INHIBITS: Insulin and somatostatin.

Question 21

What are other names given to Glucokinase?

Answer 21

Hexokinase IV and the ‘glucose sensor’.

Question 22

What is glucokinase role in insulin production? How is it able to take on this role? What does it catalyse?

Answer 22

Determines at what point glucose levels are high enough to produce insulin. Glucokinase is the rate limiting step. That’s why we think it is the thermostat for glucose levels and insulin production. Glucose to glucose-6-phosphate.

Question 23

How is insulin synthesised?

Answer 23

Starts as proinsulin. Starts as three polypeptides joined end to end. Alpha and beta insulin chains are joined by a c-peptide. C-peptides are cleaved, and alpha and beta chains joined to produce insulin.

Question 24

Why is c-peptide concentration important in measuring insulin production? (x2)

Answer 24

C-peptide released in same proportion to insulin. C-peptide has no glucose lowering effect, so stays in the blood. Therefore, measuring C-peptide concentration tells us beta cell function and insulin secretion. Can help when cases of diabetes more complex. Diagnoses insulinomas (cancer).

Question 25

What is the mechanism of insulin secretion in the beta cell?

Answer 25

Glucose enters GLUT-2 and metabolised. ATP therefore increases the more glucose that enters. ATP blocks ATP sensitive K+ channel. Calcium channels therefore open and rush into the cell. This triggers insulin secretion AND insulin production.

Question 26

What does glucagon like peptide-1 do?

Answer 26

Glucagon like peptide-1 (GLP-1) – gut hormone secreted by L cell. Stimulates insulin and suppresses glucagon. Increases our feeling of fullness. Released when glucose is taken ORALLY (and not INTRAVENOUSLY) and results in high insulin production as a result. Called the incretin effect.

Question 27

How is the insulin receptor stimulated?

Answer 27

Insulin receptor. Insulin interacts with alpha subunit of receptor. Causes conformational change in Tyrosine kinase domains of the beta subunits. This has effects on the cell.

Question 28

What does the GLUT-4 channel compose of?

Answer 28

Hydrophilic core and hydrophobic outside which allows it to sit in the membrane.

Question 29

Where is the GLUT-4 found?

Answer 29

Muscle tissue. Adipose tissue.

Question 30

What does insulin do to GLUT-4 channels?

Answer 30

Causes pre made GLUT-4 channels to be inserted into the membrane so more glucose uptake.

Question 31

What stimulates and inhibits protein –> amino acids in muscles?

Answer 31

Insulin stops breakdown of proteins for energy. Cortisol enhances it. Those amino acids could be oxidised for energy. Amino acids + O2 –> Energy + CO2.

Question 32

What stimulates amino acid –> protein in muscles?

Answer 32

Insulin and growth hormone increase protein synthesis.

Question 33

What are intermediary metabolites? Order each in terms of energy concentration and time it lasts in the body?

Answer 33

Carbohydrates, proteins, fats. Goes from less energy concentration and shortest time in body and upwards in the above list.

Question 34

What is the mechanism of protein metabolism in relation to the endocrine system? (x2 cell types, x2 processes.) Hormones involved in the liver? (x3, x1)

Answer 34

Amino acids are synthesised into proteins OR proteins are broken down into amino acids – which of the two is determined by enzymes described above. This happens in muscle tissue. Some amino acids escape into the circulation. These gluconeogenic amino acids travel to the liver where they’re used to make glucose. Amino acids enter cells in the liver, and form glucose – gluconeogenesis. The amount of glucose produced and put into the blood = hepatic glucose output. This gluconeogenesis is stimulated by glucagon, cortisol and catecholamines. Inhibited by insulin.

Question 35

What other substrates can be used in the process of gluconeogenesis (and concern the same hormones)? (x3)

Answer 35

Lactate Pyruvate Glycerol (enters cell and is phosphorylated to glycerol-3-phosphate).

Question 36

What does insulin do in relation to the metabolism of triglycerides? (two sources of NEFA?)

Answer 36

Triglyceride broken down by lipoprotein lipase or hormone-sensitive lipase (insulin actually encourages the breakdown even though it’s supposed to reduce blood glucose). Breaking down means that glycerol and fatty acids can finally enter the cell, where triglyceride never would because it’s too large. (Fatty acids are non-esterified fatty acids (NEFA).) Glucose can enter the cell through GLUT-4 (also insulin stimulated). That glucose can be used to synthesise NEFA [MCD NOTES – FATTY ACID SYNTHESIS] – as another source. Glycerol is synthesised from glucose. Inside the cell, insulin has the opposite effect to within the blood vessel – it encourages formation of triglyceride between glycerol-3-p and NEFA. Where it is used as fat store.

Question 37

What hormones stimulate and inhibit the reverse process of triglyceride storage? (x3, x1)

Answer 37

Reverse process – Catecholamines, cortisol and GH stimulate breakdown. Insulin inhibits.

Question 38

Where is the liver positioned in circulation? Why is this important? (x2)

Answer 38

Liver is involved not in the normal systemic circulation. Blood goes through a different circulation: goes to gut, picks up nutrients, goes through liver before reaching the general circulation. IMPORTANT: means apidocytes in central circulation are different from those found in our periphery (arms and legs). Central adipocytes have the possibility of changing their metabolism more than others, so need a strong energy supply for circumstances when demands fluctuate. They are also more metabolically active.

Question 39

What energy sources can the brain use and not use? (x2, x1)

Answer 39

Can use glucose and ketone bodies (glucose is the preference). Cannot use fatty acids – not good to take enzymes that break down fat to an area that’s made of fat.

Question 40

How can fatty acids BY THEMSELVES be used as an energy source? (remember, glycerol is the only triglyceride component that can be used to synthesise glucose!) What hormones stimulate and inhibit this process? (x1, x1)

Answer 40

Broken down into 2 carbon segments (Fatty acid CoA). They can then by process to acetyl CoA –> acetoacetate –> acetone + 3-hydroxybutyrate. The last three are ketone bodies = energy source. Insulin stops this. Glucagon promotes it.

Question 41

How can insulin deficiency and diabetes be measured using these ketone bodies?

Answer 41

If you find ketones in the urine (or blood), then that patient has low insulin (because insulin is supposed to inhibit ketone body production). But ketones are normal in fasting to support the brain. Difference is – a patient with diabetes should not have elevated glucose AND ketones. Tells us insulin deficiency. C-peptide can do a similar thing.

Question 42

What hormones stimulate hepatic glycogenolysis (x2)? Where does this occur (x1), and why not the most obvious place? Why is glycogen a bad energy source?

Answer 42

Glucagon and catecholamines stimulate. Insulin inhibits. Increase HGO. Occurs mainly in the liver. Glycogen is stored in muscles but when broken down, the glucose never leaves the muscle cell – it is only used by the muscle. So, liver supports plasma glucose; muscles do not. Bad source because cannot be stored for very long compared to fats and proteins.

Question 43

How does muscle acquire energy for its metabolic processes? (x4) Hormones relevant for glucose into cell? (x1, x3)

Answer 43

Breakdown of proteins. Glucose that enters the cell from GLUT-4 protein channels. Enhanced by insulin; inhibited by GH, catecholamines and Cortisol. From glycogen (which breaks down into glucose). From fatty acids. Fatty acids and glucose is broken down into acetyl-CoA, and used in Krebs cycle for energy.

Question 44

What does blood look like in a state of fasting? (x4)

Answer 44

Low insulin to glucagon ratio. Increased concentration of NEFA. Amino acid concentrations decrease (but only when prolonged). Glucose levels relatively normal but quite low.

Question 45

How does the body respond when in a state of fasting? (x4)

Answer 45

Increased proteolysis. Increased lipolysis. Increased HGO from glycogen and gluconeogenesis (liver only obviously). Ketogenesis when prolonged increases.

Question 46

What does blood look like in a fed state? (x2)

Answer 46

Stored insulin released, then the 2nd phase. (1st phase is release of stored insulin (results in huge insulin flux); 2nd phase is release of newly synthesised insulin (slower insulin flux)). High insulin to glucagon concentration ratio.

Question 47

How does the body respond in the fed state? (x4)

Answer 47

Stop HGO. More glycogen. More protein synthesis. More lipogenesis.

Question 48

What happens when insulin is given to individuals with T1DM and T2DM?

Answer 48

Insulin controls blood glucose in T1DM. Insulin fails to control blood glucose in T2DM. Called insulin resistance, where the pathways of insulin are affected – IT’S NOT A RECEPTOR PROBLEM! (as explained above).

Question 49

What metabolic changes occur when an individual is insulin deficient?

Answer 49

Proteolysis continues (so muscle bulk lost). Breakdown of fat to glycerol and fatty acids uncontrolled. High HGO and high ketone production. Therefore, sugar and ketones found in urine.

Question 50

How does T1DM present? (x4(x1))

Answer 50

Before management, patients would be very thin from muscle wasting and lipolysis. Glycosuria (glucose in urine) – when glucose levels are too high, the body responds by secreting it in the urine (which it never would usually) This causes polyuria (frequent urination) because as glucose flows into urine, water follows with the glucose concentration passively. Ketonuria. Hyperglycaemia.

Question 51

What is the concern with injecting insulin?

Answer 51

Insulin induced hypoglycaemia where insulin still present in blood when glucose levels normal, and glucagon (and other hormones) not high enough concentration to counter-act its affects. Insulin can’t be switched off in diabetics. It remains in high levels.

Question 52

What are the METABOLIC effects of insulin resistance?

Answer 52

• Usually with insulin resistance, there’s usually enough to stop proteolysis and ketogenesis. However, not enough to stop its affects in other metabolites: i.e. insulin resistance = not losing weight (which is associated with proteolysis), and body does not produce inappropriate ketone levels. This is why T2DM differs in symptoms from T1DM. In T1, no cells respond to insulin because there isn’t any; in T2, there’s insulin resistance which affects only certain metabolic actions. • Associated with high triglyceride concentration and low HDL concentration. • Slightly high blood glucose even when not diabetic. • Higher waist circumference (fat!) • Hypertension.

Question 53

What happens to levels of insulin in cases of insulin resistance?

Answer 53

Insulin has affects in the metabolic and mitogenic pathway – growth and proliferation (also known as MAPK (mitogen activated protein kinase) pathway). Insulin resistance has an affect in ONLY the metabolic pathway of insulin (i.e. does not affect MAPK pathway). Insulin resistance means hyperinsulinemia to compensate for the high glucose levels. This corrects high glucose levels but puts MAPK pathway into overstimulation. This can affect people who don’t have diabetes but still have insulin resistance.

Question 54

What happens when mitogenic pathway is overstimulated? (x5 and x1 major)

Answer 54

Dyslipidaemia – Low HDL and high LDL. Contributing to damage of arteries. Hypertension – caused by smooth muscle hypertrophy (increased cell size). Ovarian function – contributes to polycystic ovary syndrome. Abnormal affects on clotting. Abnormal affects on energy expenditure. For both increased blood pressure AND dyslipidaemia, insulin resistance can therefore cause ischaemic heart disease, even when blood glucose levels are managed (because insulin resistance affects the mitogenic pathway).

Question 55

How does T2DM present?

Answer 55

CAN HAVE VERY SUBTLE SYMPTOMS. BECAUSE PROBLEMS WITH GLUCOSE LEVELS ARE VERY SUBTLE, PATIENTS PRESENT WITH THE DISEASE VERY LATE AND THEREFORE USUALLY HAVE COMPLICATIONS. Insulin resistance. Usually obese (insulin not working well enough to keep glucose down, but is working well enough to stop ketone production and lipolysis). Dyslipidaemia (abnormal levels of individual types of lipid in the blood). Later, there is insulin deficiency. Hyperglycaemia. No ketones in urine as insulin is still produced in the body – the same can be said about other metabolic processes.

Question 56

What is the mechanism of glucagon synthesis and secretion in alpha cells?

Answer 56

Glucose too low to produce enough ATP to close K+ channels. Membrane depolarises which affects different protein channels: Sodium channels open and there’s sodium influx in the cell. This stimulates L-type and N-type Ca2+ channels to open which results in influx of calcium inside the cell. This results in glucagon secretion and synthesis.

Question 57

What are the macro and micro complications of diabetes? (x3 and x3)

Answer 57

MACRO: Strokes, cardiovascular disease, PVD (peripheral vascular disease). MICRO: Neuropathy, retinopathy, nephropathy (damage to capillaries).