ENDO - Control of Glucose Flashcards

1
Q

Why is glucose important and what are the ranges for hypoglycaemia, normoglycaemia and hyperglycaemia?

A
  • Accounts for a large amount of baseline energy usage
  • NORMOGLYCAEMIC - 4 to 7 mmol/litre
  • HYPOGLYCAEMIC - <4 mmol/litre - leading to seizure, confusion, dizziness and comas
  • HYPERGLYCAEMIC - >7mmol/litre - DKA and diabetic neuropathy
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2
Q

What do α-cells, β-cells and δ-cell
release?

A
  • GLUCAGON - mobilisation of glucose stores
  • INSULIN - glucose storage
  • SOMATOSTATIN (inhibiting insulin and glucagon secretion)
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3
Q

What does it mean for insulin to be antagonistic with glucagon?

A

Insulin inhibits glucagon release

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4
Q

What happens to blood glucose levels throughout the day?

A

They fluctuate - intended to be kept within a target range
- Not all needed at once - so can be stored
- Long periods of the day when not actively ingesting energy - stores utilised to maintain adequate glucose levels

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5
Q

What triggers insulin release? PART 1

A
  • Increased glucose levels in blood and outside the cells
  • Glut-2 is expressed on pancreatic B-cells and facilitates the entry of glucose down its concentration gradient
  • Glucokinase is an enzyme which phosphorylates glucose to glucose-6-phosphate, which in turn is turned into pyruvate.
  • Pyruvate enters the mitochondria and subsequently the Krebs cycle to produce ATP from ADP
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6
Q

What triggers insulin release? PART 2

A
  • On the cell surface is an ion channel called the ATP-gated K+ channel.
  • Because K+ concentration is higher inside the cell than outside, this channel facilitates K+ exit from the cell. This maintains a negative membrane potential of around -70mV
  • When ATP is produced, it closes the ATP-sensitive K+ channel. Due to the actions of the K+ influx pump, [K+]i increases leaded to cell depolarisation.
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7
Q

What triggers insulin release? PART 3

A
  • VGCC activation
  • Calcium levels higher outside cell compared to inside
  • Ca2+ enters the cell where it triggers exocytosis of insulin filled vesciles and the subsequent release of insulin into the blood stream.
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8
Q

Describe MODY.

A

Mature onset of diabetes in the young
- Genetic form of diabetes where the glucokinase enzyme is mutated, preventing the sensing and phosphorylation of glucose.
- Cause sustained and long last hyperglycaemia

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9
Q

How do sulfonylureas work?

A

Block the ATP-linked K+ channel to promote cell depolarisation and subsequent insulin release

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10
Q

Describe incretins.

A
  • Potentiate insulin secretion e.g GLP-1 and GIP
  • Secretory cells found throughout intestines - enteroendocrine cells
  • Released in response to nutrient absorption
  • Travels to pancreas and binds to GLP-1 receptors on beta cells.
  • A subsequent rise in intracellular cAMP levels causes the release of calcium from endoplasmic reticulum, which acts to stimulate insulin secretion from intracellular vesicles
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11
Q

Describe the clinical use of incretins

A

Studied for T2DM therapy
- Analogues of GLP-1 being ivestigated - shown to lower HbA1C and fasting glucose levels as well as lower body weight

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12
Q

Describe the cephalic insulin response.

A
  • Pre-absorptive
  • Mediated via direct actions of ACh released from vagus nerve on beta cell
  • Stimulated by anticipation of food ingestion
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13
Q

What are the insulin dependent organs/tissues?

A

Liver
Adipose tissue
Muscles

The principle energy stores of the body

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14
Q

Describe the mechanism of insulin at adipose tissue. PART 1

A
  • Binds to the insulin receptor, which causes autophosphorylation of the intracellular subunit, leading to phosphorylation of insulin receptor substrates
  • Translocation of the Glut-4 transporter to the cell surface, allowing the influx of glucose down its concentration gradient
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15
Q

Describe the mechanism of insulin at adipose tissue. PART 2

A
  • Glucose is metabolised to pyruvate and acetyl-CoA before entering the mitochondria and Krebs cycle to generate ATP - glycolysis
  • Glucose can also be converted to glycerol and acetyl CoA can be converted to fatty acids.
  • Together these substrates can form triglycerides, which is the main component of adipose tissue - lipogenesis which is a long-term storage of energy
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16
Q

Describe what happens to glucose in the liver.

A

GLYCOGENESIS
- Glycogen in muscle used as an energy source for the muscle itself
- Short-term storage of energy

17
Q

Describe what happens to glucose at the liver. PART 1

A
  • Enters the cell through the Glut2 channel, which is not insulin dependent
  • Insulin potentiates the inward flow of glucose by activating hepatic glucokinase, which in turn phosphorylates glucose to G6P
  • G6P then undergoes glycolysis to produce ATP
18
Q

Describe what happens to glucose at the liver. PART 2

A
  • Insulin also activates an enzyme called glycogen synthase, which stimulates glycogenesis
  • Insulin stimulates the enzymes which produce glycerol and fatty acids which ultimately result in triglyceride
19
Q

What is the mechanism of action of glucagon?

A

Glucagon binds to the glucagon receptor (a GPCR), which in turn activates intracellular glycogen phosphorylase. Glycogen phosphorylase then breaks down glycogen into glucose-1-phosphate molecules, which are further processed into glucose-6-phosphate

20
Q

What is the effect of glucagon on FFA?

A
  • Prevent FFA from becoming triglycerides and direct them to beta-oxidation where they can enter the mitochondria to form ketone bodies.
  • Ketone bodies can only be used as energy in the muscle, brain and heart
21
Q

What happens to insulin in T1DM?

A

Normally, the presence of insulin inhibits the secretion of glucagon preventing its effects such as releasing hepatic glucose stores and driving ketogenesis.
- However in Type 1 diabetes, the loss of insulin can lead to the uninhibition of glucagon.

22
Q

What can happen to patients with T1DM?

A

Ketoacidosis
- Lack of insulin prevents occurence of glycolysis, glycogenesis and lipogenesis
- Elevated glucagon levels - Activation of the glucagon receptor prevents lipogenesis and instead, the free fatty acids are diverted towards the mitochondria for conversion into ketone bodies

23
Q

What is the consequences of the low insulin levels in T1DM?

A
  • Reduced glucose transport into adipose tissue, so no lipogenesis
  • Glucagon-induced mobilisation of free fatty acids to liver for ketone generation
24
Q

Describe the relationship between insulin and the Na+/K+ ATPase. PART 1

A
  • After a meal, serum K+ levels rise. If K+ stays high it can have negative implications for muscle and neuron conductivity so K+ needs to be maintained within a tight boundary
  • Skeletal muscle is the primary reservoir for dietary potassium and stores around 70% of the bodies potassium
25
Q

Describe the relationship between insulin and the Na+/K+ ATPase. PART 2

A
  • Insulin causes upregulation of Na-K-ATPase channels
  • Na-K-ATPase uses around 30-40% of the entire bodies ATP and 75% of energy in the brains grey matter is used by this pump
  • Insulin can be used to treat hyperkalaemia if given with dextrose to prevent hypoglycaemia