Pathogenesis of Diabetes: The Role of the Pancreatic Beta-Cell Flashcards
Location of pancreas
- below stomach
- duodenum curves around the stomach
- spleen is attached to the tail
What are the functions of the pancreas?
- exocrine: secretes enzymes for digestion (digestive gland)
- endocrine: production of hormones that regulates blood sugar levels and glandular secertion
What parts of the pancreas are the exocrine and the endocrine?
- exocrine: aciner cells which secrete digestive enzymes and duct cells secrete NaHCO3 solution into the pancreatic duct which goes into the duodenum
- endocrine: islets of langerhans → beta cells release insulin and glucagon into circulation
How much of the exocrine and endocrine make up the pancreas?
- Islets (endocrine) compose only about 1% of the pancreas (along with other things)
- Aciner cells (exocrine) make up the majority composition of the pancreas
Composition of the endocrine portion of the pancrease
- 70% beta cells secreting insulin
- alpha cells secreting glucagon
- delta cells secrete somatostatin
- PP is pancreatic polypeptide cells
Insulin structure
Proinsulin is the precurser to insulin and is packaged into a vesicle and released into circulation whereupon the vesicle dissolves and the proinsulin is cleaved by special enzymes into insulin and C-peptide. The insulin is made of 2 peptides, the A-chain and the B-chain connected through disulfide covalent interactions.
* Dont really know what c-peptide does
* Can measure C-peptide and insulin in diabetics and measure difference to see how much insulin is being used.
Molecules that induce insulin secretion
- Nutrients → Glucose, Fatty acids (transient), some amino acids (those that can enter krebs)
- Hormones → Glucagon (fine tuning of insulin secretion), GLP-1, GIP, CCK,
- PNS (rest and digest)
Molecules that inhibit insulin secretion
- Nutrients→ Fatty acids (exposure for longer periods such as lyperlipidemia, lipotoxicity)
- Hormones → Somatostatin, Epinephrine, Norepinephrine
- SNS
Glucose stimulated insulin secretion
- 1 Glucose enters into beta cell through GLUT2
- glucose is metabolized via glycolysis (glucokinase instead of hexokinase)
- Acetyl CoA enters citric acid cycle in beta cell mitochondrion
- ETC generates ATP
- ↑ ATP/ADP ratio on beta cell cytosol shuts down K+-ATP channel causing a depolarization and Ca2+ channels open to allow ions into the beta cell cytosol
- This triggers the vesicles containing proinsulin to fuse with the beta cell membrane and be released into circulation
- vesicle dissolves in circulation and enzymes cleave proinsulin
What are the 2 phases of insulin secretion?
- Triggering pathway: rapid release within a few seconds from the ready releasable pool which has vesicles lined up and ready to be fired
- Amplifying pathway: Longer duration release is the reserve pool which travels a bit slower in response to the signal
Where might FAs stimulate insulin release?
During the second phase from the reserve pool potentially
Draw out insulin secretion pathway
Characteristics of GLUT family members
MEMORIZE
Why do beta cells have low affinity?
Beta cells express GLUT1 and GLUT2 transporters which have a low affinity for glucose (would take a lot to become saturated and work at full capacity) which allows them to work best as a sensor
Why are GLUT4 transporters hidden in cells and not always expressed?
- GLUT4 have a high affinity for glucose so they can become saturated very easily and when we eat a meal it is about 20 mM so GLUT4 is working at full capacity. Therefore it is hidden in cells to prevent exposure to glucose and too much uptake
Enzymes in glycolysis regulating glucose usage
Hexose kinase and the regulation of glucose usage
hexokinase phosphorylates glucose so it becomes trapped within a cell and efficiency of this is super high
Why do beta cells not have hexokinase?
hexokinase immediately traps glucose inside a cell which is not ideal for beta cells as it might produce too much ATP. instead they have glucokinase which is not quite as efficient at trapping glucose and allows it to act as a sesnor and regulate ATP production
What pre-exposure factors effect a persons risk of diabetes?
- genetics
- environmental factors
- lifestyle
- diabetes
Diabetes progression
- healthy pancreation islets
- β cell compensation: metabolically healthy but overweight
- β cell dysfunction: follows
- β cell failure: obese, insulin resistant/ hyperinsulinemic, IGT
- glycemia increases over time
- circulating insulin increases with compensation and them plummets with beta cell failure
Progressive deterioration of beta-cell mass and function in diabetes
- insulin resistance the islets stretch and get bigger due to ↑ insulin production
- glucose intolerance there is development of hyperglcaemia and see deterioration of beta cell mass
- T2D beta cells not totally absent but number has decreased substantially
Describe graph
A functional link between Diabetes and beta-cell mass
* in obese can see that they can maintain normal glycemic (ND) with more beta cells.
* for both lean and obese can see that there is a threshold for beta cells at which point they can no longer compensate
Describe graphs
* Did GOTT test
- Lean has normal response
- obese can see compensation with more insulin
- T2D beta cells cannot respond to the glucose very well
What are msot genes effecting diabetes associated with?
Basically all genes effecting diabetes are associated with beta cell genes (mass and function)
* One of them regulates FA metabolism
What are monogenic diabetes?
a rare condition resulting from mutations (changes) in a single gene.
Potential causes for beta cell failure
- glucotoxicity (β cells exposed too much glucose for too long become stressed)
- lipotoxicity (β cells expose to FAs too long and deteriorate - hyperlipidemia)
- endoplasmic reticulum stress
- mitochondrial dysfunction
- oxidative stress
- inslet inflammation
- ↑ islet amyloid polypeptide
- epigenetic modifications
oxidative stress causing β cell failure
Beta cells are particularly vulnerable to stress because it is part of system that perfectly metabolizes every molecule of glucose to secrete insulin so glucose at toxic levels is deleterious. They do not have feedback mechanism to the protect cell. If they did not metabolism every molecule of glucose it will instead go into toxin pathways creating ROS and causing mito stress
induced by reactive oxygen and nitrogen species impairing beta-cell function
glucolipotoxicity
the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival
* glucose inhibits FAs from getting into mito for β-oxidation resulting in ROS development and lipotoxicity
* FAs inhibit pyruvate from going to CAC so get ROS production
* Body usually choose to oxidize one or the other but in toxicity of both are inhibited and then continue to get rise in both and go down more toxic pathways to be used up such as ceramides production (accumulation in vascular tissue promotes inflammation and cell death - CVD risk), PPP
Is insulin compensation a good thing?
In simplistic way yes so as to control blood glucose but it makes beta cells more vulnerable to toxicity
