Lecture 14 - Glucose homeostasis Flashcards
What is the endocrine system?
- Responsible for maintaining homeostasis in the body – like the nervous system
- Consists of cells, tissues and organs that secrete hormones as a primary or secondary function
- Uses chemical signalling in the form of hormones that are transported primarily by the bloodstream
- Hormones result in autocrine (affects the cells that secreted it), paracrine (affects neighbouring cells) and long-distance (other parts of the body)
The pancreas is an organ of the
Endocrine system
- Role in the body: regulation of macronutrient digestion for metabolism/energy homeostasis by releasing various digestive enzymes and hormones
- Exocrine and endocrine function
- Exocrine function: the secretion of digestive enzymes into the small intestine to aid in the digestion of carbohydrates, proteins and fats
- Endocrine function: production and secretion of hormones into the bloodstream to regulate glucose metabolism
What are the two main types of pancreatic cells?
Acinus: aids in the exocrine function
* Cluster of acinar cells
* Secretes digestive enzymes
* Produced as inactive forms and stored in zymogen granules (protects pancreatic cells from destruction)
o Amylase: breaks down carbohydrates
o Lipase: breaks down lipids
o Trypsinogen: breaks down proteins
* Stimulated by acetylcholine and cholecystokinin
Ductal cells:
* Produces an aqueous secretion containing bicarbonate
* Helps neutralise acidic stomach contents by increasing bicarbonate as needed
* Stimulated by secretin, as well as acetylcholine and cholecystokinin
What is the anatomy of the pancreas?
Acinus
>cluster of acinar cells, secrete digestive enzymes into the pancreatic duct
Islets of Langerhans
>secrete hormones into the bloodstream
>alpha cells
>beta cells
>exocrine acinus
What are the Islets of Langerhans
- The islets of Langerhans are scattered throughout the pancreas and make up only about 1-2% of its total mass. They are composed of several types of cells, including alpha cells, beta cells, delta cells, and gamma cells and epsilon cells
- Beta cells are the most abundant type of cell in the islets of Langerhans and are responsible for the production and secretion of insulin.
- Alpha cells are responsible for the production and secretion of glucagon, which is another hormone that helps to regulate blood glucose levels.
- Delta cells secrete somatostatin, which helps to regulate the release of insulin and glucagon by the alpha and beta cells.
- The islets of Langerhans are a critical component of the endocrine system and play a crucial role in regulating blood glucose levels in the body
> beta cells (65-85%): insulin
alpha cells (15-20%): glucagon
delta cells (3-10%): somatostatin
gamma cells (3-5%): pancreatic polypeptide
epsilon cells (<1%): ghrelin
What are some of the multiple fate selections that allow the development of the pancreatic islet lineages?
> Sox17 (endodermal cell)
Sox9 (can split into hepatocytes and liver duct cells, or duodenum epithelial cells and endocrine cells)
> > Pdx1 (pancreatic progenitor cells)
can split into acinar cells or duct cells
Ngn3 (islet progenitor)
beta and alpha cells
What is insulin?
- Peptide hormone that decreases blood glucose levels
- Encoded by INS gene on chromosome 11
- Initially translated as a single polypeptide chain: it consists of A chain and a B chain
- Proinsulin is cleaved to form insulin + C-peptide
- Insulin is produced and stored as a hexamer coordinated around zinc ions , monomeric form is not stable, thus stored as a hexomer, stable while inside the beta cell waiting for stimulus to be degranulated
How does glucose trigger insulin secretion from beta cells?
1) Increase in BGL
2) Uptake of glucose into Beta cells via GLUT 1/2/3 Transporters
3) Glycolysis in beta cells > produce ATP and NADH
>Increased ATP:ADP ratio
4) ATP blocks K+/ATP channels
>increased K+ in cell makes cell more positively charged
>depolarisation of cell membrane
>opens up voltage-dependent Ca2+ channels
5) Influx of Ca2+ into cell
>stimulates exocytosis of insulin granules
What are other amplification factors which promote insulin secretion?
o Hormones: glucagon, GIP and GLP-1
o All 3 can act on beta cells to amplify glucose-stimulated insulin secretion
o Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretin hormones
o Also replenishes insulin by inducing insulin transcription
o Increased fatty acid or amino acids in the blood
What are inhibitory factors for insulin secretion?
o Norepinephrine/noradrenaline:
Sympathetic nervous system
Activated during stressful situations – therefore glucose is needed
o Somatostatin:
Inhibitory hormone – produced by delta cells
Inhibits excessive release of pancreatic hormones
What is the insulin synthesis pathway?
1) Chr11 INS gene
2) Pre-pro-insulin
>signal sequence (directs PPI to ER) + Beta chain + C-peptide + Alpha chain
3)Endoplasmic reticulum (ER) processing
>cleave signal sequence
>formation of B-A disulphide bonds
>Pro-insulin
4) Shuttle to Golgi Apparatus
>C-peptide cleaved by pro-hormone convertase
>always 1:1 ratio of c-peptide to active insulin
5) Mature biological active insulin stored in insulin granules, secreted by exocytosis
What is insulin’s effects on target cells?
Insulin
>anabolic hormone
>promotes conversion of small energy molecules (glucose, fatty acids, amino acids) into large storage molecules
> > binds to cellular receptors (2 alpha 2 beta subunits-RTK) on target cells, and signals upregulation of GLUT4 transporters
What does insulin promote?
Insulin promotes *glycogenesis
>Liver
»glucose > glycogen
> > once glycogen storage in liver is full
glycolysis of glucose into pyruvate (+acetyl-coa in adipose tissue)
form fatty acids to store as fat
> Skeletal muscle
stimulates uptake of glucose and amino acids
promotes protein production and muscle growth
What does insulin inhibit?
Insulin inhibits *gluconeogenesis
>Liver
»prevent formation of glucose from lactic acid and non-carbohydrate molecules
Insulin inhibits *lipolysis
>adipose tissue
»prevent breakdown of fatty acids
What is glucagon?
Encoded by GCG gene on long arm of Chr2
>Peptide hormone that increases BGL
> stored in granules in the alpha cell where it waits to be released (monomer form)
> Preproglucagon
(leader signal peptide moves it into ER and golgi)
proglucagon
glucagon
