Pathogenesis of Diabetes: The Role of the Pancreatic Beta-Cell

Question 1

Location of pancreas

Answer 1

• below stomach
• duodenum curves around the stomach
• spleen is attached to the tail

Question 2

What are the functions of the pancreas?

Answer 2

• exocrine: secretes enzymes for digestion (digestive gland)
• endocrine: production of hormones that regulates blood sugar levels and glandular secertion

Question 3

What parts of the pancreas are the exocrine and the endocrine?

Answer 3

• 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

Question 4

How much of the exocrine and endocrine make up the pancreas?

Answer 4

• Islets (endocrine) compose only about 1% of the pancreas (along with other things)
• Aciner cells (exocrine) make up the majority composition of the pancreas

Question 5

Composition of the endocrine portion of the pancrease

Answer 5

• 70% beta cells secreting insulin
• alpha cells secreting glucagon
• delta cells secrete somatostatin
• PP is pancreatic polypeptide cells

Question 6

Insulin structure

Answer 6

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.

Question 7

Molecules that induce insulin secretion

Answer 7

• 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)

Question 8

Molecules that inhibit insulin secretion

Answer 8

• Nutrients→ Fatty acids (exposure for longer periods such as lyperlipidemia, lipotoxicity)
• Hormones → Somatostatin, Epinephrine, Norepinephrine
• SNS

Question 9

Glucose stimulated insulin secretion

Answer 9

1. 1 Glucose enters into beta cell through GLUT2
2. glucose is metabolized via glycolysis (glucokinase instead of hexokinase)
3. Acetyl CoA enters citric acid cycle in beta cell mitochondrion
4. ETC generates ATP
5. ↑ 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
6. This triggers the vesicles containing proinsulin to fuse with the beta cell membrane and be released into circulation
7. vesicle dissolves in circulation and enzymes cleave proinsulin

Question 10

What are the 2 phases of insulin secretion?

Answer 10

1. Triggering pathway: rapid release within a few seconds from the ready releasable pool which has vesicles lined up and ready to be fired
2. Amplifying pathway: Longer duration release is the reserve pool which travels a bit slower in response to the signal

Question 11

Where might FAs stimulate insulin release?

Answer 11

During the second phase from the reserve pool potentially

Question 12

Draw out insulin secretion pathway

Answer 12

Question 13

Characteristics of GLUT family members

Answer 13

MEMORIZE

Question 14

Why do beta cells have low affinity?

Answer 14

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

Question 15

Why are GLUT4 transporters hidden in cells and not always expressed?

Answer 15

• 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

Question 16

Enzymes in glycolysis regulating glucose usage

Answer 16

Question 17

Hexose kinase and the regulation of glucose usage

Answer 17

hexokinase phosphorylates glucose so it becomes trapped within a cell and efficiency of this is super high

Question 18

Why do beta cells not have hexokinase?

Answer 18

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

Question 19

What pre-exposure factors effect a persons risk of diabetes?

Answer 19

• genetics
• environmental factors
• lifestyle
• diabetes

Question 20

Diabetes progression

Answer 20

1. healthy pancreation islets
2. β cell compensation: metabolically healthy but overweight
3. β cell dysfunction: follows
4. β cell failure: obese, insulin resistant/ hyperinsulinemic, IGT

• glycemia increases over time
• circulating insulin increases with compensation and them plummets with beta cell failure

Question 21

Progressive deterioration of beta-cell mass and function in diabetes

Answer 21

• 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

Question 22

Describe graph

Answer 22

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

Question 23

Describe graphs
* Did GOTT test

Answer 23

• Lean has normal response
• obese can see compensation with more insulin
• T2D beta cells cannot respond to the glucose very well

Question 24

At what point can a person develop pre-diabetes and diabetes?

Answer 24

• pre-diabetes: 20% loss of pancreatic beta cells
• diabetes: 65% loss of pancreatic beta cells

Question 25

What are msot genes effecting diabetes associated with?

Answer 25

Basically all genes effecting diabetes are associated with beta cell genes (mass and function) * One of them regulates FA metabolism

Question 26

What are monogenic diabetes?

Answer 26

a rare condition resulting from mutations (changes) in a single gene.

Question 27

What regulates beta-cell mass?

Answer 27

Neogenesis, replication, cell death apoptosis * nutritional control: glucose, FAs, proteins * hormonal: insulin/ IGF, prolaction, GLP-1 * neuronal * other: drugs, cytokines, toxins

Question 28

Potential causes for beta cell failure

Answer 28

* 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

Question 29

How many people with IR are predicted to get diabetes?

Answer 29

Only about 30% and unknown why others may not * may be better at insulin compensation

Question 30

oxidative stress causing β cell failure

Answer 30

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

Question 31

glucolipotoxicity

Answer 31

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

Question 32

What is result of glucotoxicity?

Answer 32

* polyols-hexosamines: important regulators of cell signaling that favor tumor promotion * AGEs: Advanced glycated end products which are proteins or lipids that become glycated as a result of exposure to sugars such as HbA1c

Question 33

What is result of lipotoxicity?

Answer 33

* complex lipids * steatosis - fatty miver disease (5-10% of liver weight or more)

Question 34

Is insulin compensation a good thing?

Answer 34

In simplistic way yes so as to control blood glucose but it makes beta cells more vulnerable to toxicity

Question 35

What are potential physiological outcomes of hyperinsulinemia?

Answer 35

* dyslipidemia * hypertension * visceral adoposity * altered vascular reactivity * impaired fibrinolysis * hyperuricaemia * islet beta cell exhaustion * systemic inflammation * glucose intolerance

Question 36

What events does maintenance of normal glucose tolerance depend on?

Answer 36

1. stimulation of insulin secretion 2. insulin-mediated suppression of endogenous (primarily hepatic) glucose production by the resultant hyperinsulinemia 3. insulin-mediated stimulation of glucose uptake by peripheral tissues, primarily muscle.

Question 37

What contributes to muscle insulin resistance?

Answer 37

* Defects in insulin receptor function * insulin receptor-signal transduction pathway * glucose transport and phosphorylation * glycogen synthesisan * glucose oxidation

Question 38

What are the 2 major defects of T2D?

Answer 38

* insulin secretion * insulin action

Question 39

What is the primary cause of hyperglycaemia in T2D?

Answer 39

An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia * After a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia