Glucose Homeostasis by Rachel Reiser

3 Main Energy Sources for Tissues

rachel_e_reiser — 2017-08-17 05:27:16 UTC

Carbohydrates
- Glucose <--> Glycogen
Lipids
- Fatty acids <--> Triacylglyceride
Proteins
- Amino acids <--> Proteins

CARBOHYDRATES

rachel_e_reiser — 2017-08-17 05:28:39 UTC

The most important energy source for all cells.
Only form of energy for brain - essential for normal CNS function

Glucose homeostasis

rachel_e_reiser — 2017-08-17 05:30:25 UTC

Necessary for maintaining brain function
Provides energy for cells

Persistent HYPERGLYCAEMIA - high blood glucose (>30-40 mM) leads to osmotic diuresis and signs of diabetes mellitus

HYPOGLYCAEMIA - low blood glucose (<2-3 mM) leads to confusion, seizures, coma

Maintaining blood glucose

rachel_e_reiser — 2017-08-17 05:33:47 UTC

Following a meal the blood glucose is increased -> glucose is taken up via facilitated diffusion by GLUT transporters.

Glucagon

rachel_e_reiser — 2017-08-17 05:44:13 UTC

During fasting state (low blood glucose - hypoglycaemia) gluconeogenesis occurs which stimulates the alpha cells to produce glucagon

Stimulated by high blood amino acids and low fatty acid levels
Infection and exercise also stimulates
As does cortisol
Somatostatin inhibits
Glucagon acts as a catabolic hormone to mobilise glucose, fatty acids and amino acids from stores to blood
Impaired glucagon secretion can be compensated (no disease state)
Acts as a functional antagonist to insulin
Major site of action is the liver and adipose tissue

Glucagon secretion is also stimulated/inhibited by the autonomic nervous system:

Sympathetic nervous system stimulates via adrenaline and the beta-adrenoceptor to conserve energy.

Mechanism of Action

Glucagon receptor a GPCR predominantly found in hepatocytes
Glucagon binds to it's receptor and causes a conformational change
The G-alpha stimulatory subunit breaks away and stimulates adenylate cyclase
This forms cAMP from ATP
cAMP activates protein kinase a (PKA)
PKA phosphorylates key enzymes in gluconeogenesis

Insulin

rachel_e_reiser — 2017-08-17 06:11:00 UTC

High levels of glucose, amino acids and fatty acids in the bloodstream stimulate the insulin receptor on beta cells and insulin is released

Insulin acts as anabolic hormone on liver, skeletal muscle & adipose tissue
This increases the storage of glucose, fatty acids and amino acids
Impaired insulin secretion = diabetes mellitus

Insulin secretion is also stimulated/inhibited by the autonomic nervous system:

Parasympathetic nervous system stimulates via the vagal nerve.
- At the beginning of a meal the vagal nerve stimulates the GI tract and uses a feedforward response that stimulates insulin release so that insulin is readily available when food arrives to the stomach.
Sympathetic nervous system inhibits in a fight or flight response.
- It promotes breakdown of glycogen in order to provide energy for 'flight'
Gastrointestinal hormones stimulate including gastrin, secretin, gastric inhibitory peptide

Mechanism of action

Insulin binds to the tyrosine kinase receptor
This causes autophosphorylation
Activates tyrosine kinase
Phosphorylates proteins such as IRS family
Activates downstream pathways e.g. MAP kinase
Leads to activation/deactivation of enzymes and induce/suppression of gene expression
Stimulates glucose uptake by GLUT4 in skeletal muscle as well as adipose tissue and by enzymes in liver

GLUT4 in Skeletal Muscle/Adipocytes

rachel_e_reiser — 2017-08-17 06:28:42 UTC

Stimulated by insulin binding to receptor and activating downstream pathways
Cytoplasmic vesicles containing GLUT4 undergo exocytosis positioning GLUT4 on the cell membrane

Glucose uptake in liver

rachel_e_reiser — 2017-08-17 06:32:29 UTC

Insulin stimulates enzymes - glucokinase, glycogen synthase activity
- Glucokinase facilitates phosphorylation of glucose to glucose-6-phosphate --> leads to glycogen formation and storage of glucose
- Glycogen synthase aids in this conversion and storage
Insulin also inhibits glucose-6-phosphate, glycogen phosphorylase
- Glucose-6-phosphate is the transition-state between glucose and glycogen synthesis and glucose and glycolysis
- Glycogen phosphorylase is a key enzyme in glycogenolysis (breakdown of glycogen stores)
Maintains a concentration gradient and promotes further entry of glucose into the hepatocyte
Insulin promotes lipid storage and protein synthesis as well as inhibits gluconeogenesis

Glucose uptake in skeletal muscle

rachel_e_reiser — 2017-08-17 23:36:55 UTC

Insulin promotes:

Glucose uptake via GLUT4
Glycogen synthesis through hexokinase expression and glycogen synthase activity
- Hexokinase phosphorylates glucose to form glucose-6-phosphate
- Glycogen synthase is a key enzyme is glycogen formation
Glycolysis and oxidation via phosphofructokinase activity and pyruvate dehydrogenase
- Oxidation occurs when pyruvate is oxidised to CO2
- Phosphofructokinase is a key enzyme in the glycolysis pathway
- Pyruvate dehydrogenase is part of the pyruvate dehydrogenase complex (PDC) and contributes to transforming pyruvate to acetyl CoA
Protein synthesis

Glucose uptake in adipocytes

rachel_e_reiser — 2017-08-17 23:49:30 UTC

Insulin promotes:

Glucose uptake via GLUT4
Glycolysis to give precursors for lipogenesis
- Lipogenesis is the formation of fat
Synthesis of lipoprotein lipase
- Lipoprotein lipase is a water-soluble protein that hydrolyses triglycerides in lipoproteins
- It is responsible for the processing and absorption of fats
Inhibits hormone-sensitive triglyceride lipase
- This enzyme is responsible for mobilising stored fats

Very good Rachel!

h_sidjabat — 2017-08-18 18:16:47 UTC

You have done really well!

Summary of insulin effects

rachel_e_reiser — 2017-08-23 03:00:51 UTC

Summary of glucagon effects

rachel_e_reiser — 2017-08-23 04:03:36 UTC

Effect of glucagon on liver

rachel_e_reiser — 2017-08-23 04:12:49 UTC

Glucagon promotes the breakdown of glycogen -
By inhibiting:

Glucokinase expression
Glycogen synthase activity

By activating:

Glycogen phosphorylase
G6Pase

Glucagon promotes gluconeogensis -
By inhibiting:

Glucokinase
Phosphofructokinase activity
Pyruvate kinase
PEPCK
FBPase

-- all key enzymes in promoting the storage glucose to glycogen

Glucagon also promotes lipid oxidation.

Varying secretion concentrations of glucagon and insulin according to glucose amount

rachel_e_reiser — 2017-08-23 04:25:43 UTC

During exercise...

rachel_e_reiser — 2017-08-23 04:27:03 UTC

Lower amounts of glucose in the blood inhibit insulin and stimulate glucagon secretion:

Leads to the breakdown of glycogen stores in order to increase blood glucose levels

The sympathetic nervous system also plays a role in the control of secretion:

Noradrenaline inhibits insulin release
Adrenaline stimulates glucagon release

Glucose enters the muscle due to acute muscle contractions stimulating GLUT4 translocation to the membrane.
Chronic exercise increases GLUT4 expression and thus the ability to take up glucose by the cells.