ENDO - Control of Glucose Flashcards
Why is glucose important and what are the ranges for hypoglycaemia, normoglycaemia and hyperglycaemia?
- 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
What do α-cells, β-cells and δ-cell
release?
- GLUCAGON - mobilisation of glucose stores
- INSULIN - glucose storage
- SOMATOSTATIN (inhibiting insulin and glucagon secretion)
What does it mean for insulin to be antagonistic with glucagon?
Insulin inhibits glucagon release
What happens to blood glucose levels throughout the day?
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
What triggers insulin release? PART 1
- 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
What triggers insulin release? PART 2
- 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.
What triggers insulin release? PART 3
- 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.
Describe MODY.
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
How do sulfonylureas work?
Block the ATP-linked K+ channel to promote cell depolarisation and subsequent insulin release
Describe incretins.
- 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
Describe the clinical use of incretins
Studied for T2DM therapy
- Analogues of GLP-1 being ivestigated - shown to lower HbA1C and fasting glucose levels as well as lower body weight
Describe the cephalic insulin response.
- Pre-absorptive
- Mediated via direct actions of ACh released from vagus nerve on beta cell
- Stimulated by anticipation of food ingestion
What are the insulin dependent organs/tissues?
Liver
Adipose tissue
Muscles
The principle energy stores of the body
Describe the mechanism of insulin at adipose tissue. PART 1
- 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
Describe the mechanism of insulin at adipose tissue. PART 2
- 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
Describe what happens to glucose in the liver.
GLYCOGENESIS
- Glycogen in muscle used as an energy source for the muscle itself
- Short-term storage of energy
Describe what happens to glucose at the liver. PART 1
- 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
Describe what happens to glucose at the liver. PART 2
- 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
What is the mechanism of action of glucagon?
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
What is the effect of glucagon on FFA?
- 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
What happens to insulin in T1DM?
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.
What can happen to patients with T1DM?
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
What is the consequences of the low insulin levels in T1DM?
- Reduced glucose transport into adipose tissue, so no lipogenesis
- Glucagon-induced mobilisation of free fatty acids to liver for ketone generation
Describe the relationship between insulin and the Na+/K+ ATPase. PART 1
- 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
Describe the relationship between insulin and the Na+/K+ ATPase. PART 2
- 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
