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Phase 2 3. Endocrinology > Carbohydrate metabolism and insulin synthesis > Flashcards

Carbohydrate metabolism and insulin synthesis Flashcards

1
Q

What is the pentose phosphate pathway important for?

A

> Synthesis of fatty acids through the generation of NADPH, which is critical for reductive biosynthesis

> Nucleotides through the formation of ribose 5-phosphate

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2
Q

What is the committed step of the pentose phosphate pathway?

A

Dehydrogenation of glucose 6-phosphate
G-6-P dehydrogenase

Key branch point, relevant enzymes will be switched on/off to determine which pathway the G6P goes down

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3
Q

What is glycogen?

A

A polymer of glucose synthesised from glucose

Essentially the same as starch

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4
Q

How is glycogen stored?

A

Complexed with water

Carb-deficient diets will cause depletion of glycogen stores, and loss of water mass in the first week

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5
Q

Where is glycogen stored?

A

Majority:
> The liver - storage for blood glucose maintenance
> In muscle - storage for local energy production (only used by the muscle itself)

Most tissues can store some glycogen, but it may not be physiologically relevant as it’s such a small amount

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6
Q

How is glycogen synthesised?

A

Glycogenesis

Glucose -> G6P -> G1P -> UDP glucose -> glycogen

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7
Q

What is the key enzyme in glycogen synthesis?

A

Glycogen synthase (tightly regulated)

Catalyses reaction of UDP glucose -> Glycogen

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8
Q

How is glycogen broken down?

A

Glycogenolysis

Glycogen -> G1P -> G6P -> Fructose 6P -> Glycolysis

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9
Q

What is the function of the enzyme phosphoglucomutase?

A

G6P G1P

Catalyses both reactions

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10
Q

How is glycogenesis/glycogenolysis regulated?

A

Reciprocal regulation
Glycogen synthase and glycogen phosphorylase must be regulated inversely
- you would not want both to be active at the same time

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11
Q

What does hexokinase do

A

Catalyses reaction of glucose -> G6P

irreversible

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12
Q

What is gluconeogenesis?

A

synthesis of glucose from a noncarbohydrate (nonhexose) source

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13
Q

What are the non-hexose sources used in gluconeogenesis?

A

> Lactate
Pyruvate - less commonly found in the blood than lactate
Glycerol - from fat stores
- you cannot make glucose from fatty acids, but you can from glycerol
- fatty acids are used by peripheral tissues for feul
Certain amino acids (glucogenic amino acids)
- this only happens to a certain level when muscle mass is being lost (prolonged fasting or extreme starvation)

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14
Q

Where does gluconeogenesis occur?

A

Mainly in the liver but the kidneys can contribute with prolonged starvation

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15
Q

How does gluconeogenesis occur?

A

Essentially a reversal of glycolysis, but three reactions are not reversible as they all involve ATP (use/production)

> Hexokinase/glucokinase (in liver)
PFK
Pyruvate kinase

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16
Q

How are irreversible reactions in gluconeogenesis overcome?

A

Achieved by use of other enzymes

> Hexokinase bypassed by glucose 6-phosphatase
- principally expressed in the lover
- reciprocally regulated because otherwise it would waste ATP
PFK bypassed by fructose 1,6-bisphosphatase
Pyruvate kinase bypassed by two enzymes
- pyruvate carboxylase
- PEPCK = phosphoenolpyuvate carboxykinase

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17
Q

Where is glucose 6-phosphatase found?

A

In the lumen of the endoplasmic reticulum

Needs transporters for substrates & products to get in/out
- G6P has to be transported into the ER

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18
Q

How is glucose 6-phosphatase regulated?

A

At the level of expression

Expression is stimulated by adrenaline and glucocorticoids leading to increased transcription/translation of the enzyme

Suppression is by insulin - prevents gluconeogenesis in the fed state leading to reduced transcription/translation

19
Q

What are the substrates for gluconeogenesis?

A

Lactate - pyruvate
Glycerol - dihydroxyacetone phosphate (DHAP)
Amino acids in various locations in TCA cycle and pryruvate

20
Q

Why are fatty acids unable to contribute to gluconeogenesis?

A

Fatty acids are oxidised to acetyl CoA
2 CO2 produced
lost the carbons, therefore no contribution to glucose carbons

21
Q

How is gluconeogenesis stimulated in the liver?

A

Through glucagon and adrenaline

  • decrease glucokinase
  • increases G6Pase and PEPCK activity
  • i.e. -> increases gluconeogenesis

Effect is at level of gene expression

22
Q

Which tissues are glucose dependent?

A

> Erythrocytes - no mitochondria, therefore cannot oxidise fuels, only energy from glycolysis
Brain - fatty acids cannot cross blood-brain barrier
Retina
Testes - testes blood barrier prevents entry of fatty acids - sperm use fructose, so have high no. GLUT5

23
Q

What cell types are found in the islet of langerhans and what hormones do they produce?

A

alpha cells - secrete glucagon
beta cells - secrete insulin
delta cells - secrete somatostatin

24
Q

Describe the pathology of the islet of langerhans

A

core of beta cells with a ring of alpha cells around the edge

25
Q

How are insulin and glucagon synthesised?

A

As pro-hormones

26
Q

How is glucokinase distinguished from other hexokinases?

A

> Glucokinase has a lower affinity for glucose than the other hexokinases
- Half-saturated at glucose conc. ~8mmol/L
Glucokinase is not inhibited by its product, G6P
- Allows cont. signal output (e.g. to trigger insulin release) amid significant amounts of its product

27
Q

How does glucokinase change its activity?

A
  • Glucokinase changes conformation and/or function in parallel with rising glucose conc. in the physiologically important range of 4-10mmol/L due to lower affinity for glucose
28
Q

How is glucokinase regulated?

A

By a supply-driven metabolic pathway

The rate of reaction is driven by the supply of glucose, not by the demand for end products

29
Q

How do beta cells secrete insulin?

A

Potassium channel is inhibited by ATP causing cell depolarisation
This opens the voltage-gated L-type Ca channels causing an influx of calcium that leads to exocytosis of vesicles containing insulin

30
Q

How is insulin release regulated?

A

ATP production is a signal for glucose conc.
The more glucose enters the cell, the more ATP is made and the ATP:ADP ratio will go up
ATP will inhibit ATP-sensitive K+ channel

When glucose levels decrease, less ATP is produced, ATP:ADP ratio is decreased

31
Q

Why do beta cells not convert glucose to glycogen?

A

Because of stimulus-secretion coupling - beta cells use ATP produced as a signal for glucose conc.

Can only be converted to ATP so that the correct amount of insulin can be produced for the body’s needs

32
Q

How is insulin synthesised?

A

Preproinsulin = signal sequence - chain B - chain C - chain A

proinsulin = signal sequence cleaved

Insulin = chain C is cleaved

33
Q

What is C peptide used for?

A

In insulin overdose, C peptide levels can be used to differentiate between exogenous and endogenous cause
As C peptide is secreted along with insulin

34
Q

How is glucagon synthesised?

A

pre-proglucagon is only cleaved in a way to give glucagon in alpha cells

In cells in the GI tract, pre-proglucagon is cleaved to form glucagon-like peptide 1 and 2 and oxyntomodulin

35
Q

How is glucagon excreted?

A

Mechanism poorly understood

Secreted in response to low glucose
> May be crosstalk between glucagon and insulin secretion in human islets (unconfirmed)
> ATP-sensitive K+ channel may also be important in alpha cells, but would have to work in reverse (? possible)

36
Q

How does insulin signalling occur?

A

Insulin binds to the insulin receptor and initiates intracellular cascade

37
Q

Where is the insulin receptor primarily found?

A

Liver, striated muscle, adipocytes

38
Q

What kind of receptor is the insulin receptor?

A

Tyrosine kinase receptor

  • Autophosphorylation of tyrosine residues on cytoplasmic side upon binding
  • Initiates intracellular cascade
39
Q

Which particular kinase is activated in response to insulin?

A

Protein kinase B (akt) is activated in response to insulin and is responsible for the metabolic effects of insulin

40
Q

What are the metabolic effects of insulin?

A

Stimulation of anabolic processes

Inhibition of catabolic processes (inhibition of gluconeogenesis is one of the key roles of insulin)

41
Q

Why does T1DM cause hyperglycaemia?

A

Gluconeogenesis in the liver is never inhibited, even during the fasted state

42
Q

How does glucagon signalling occur?

A

Glucagon binds to the glucagon receptor, increasing clyclic AMP (cAMP), which stimulates cAMP-dependent protein kinases

43
Q

What type of receptor is the glucagon receptor?

A

G-protein coupled receptor

44
Q

Where is the glucagon receptor primarily found?

A

Only in hepatocytes as only the river will respond to glucagon

Phase 2 3. Endocrinology (25 decks)

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