Amylin is a poorly understood glucoregulatory hormone that has considerable potential to target metabolic illness. It is released by beta cells of pancreas.
2. Topic: Importance of Amylin, Cytotoxicity and
Abnormalities
Department of Zoology
Presented by: Um-e-Farwa
Roll no# UOC-BSZOL-F2020/014
BS Zoology
Session: 2020-2024
Subject: Endocrinology
Instructor Name: Dr. Syeda Nadia Ahmed
4. Introduction
Amylin is a 37-amino acid peptide hormone that is also
referred to as islet amyloid polypeptide (IAPP).
Amylin is a poorly understood glucoregulatory hormone that
has considerable potential to target metabolic illnesses.
It is released by the beta cells of the pancreas.
Because of the undesirable aggregative and solubility qualities,
which are further exacerbated by Amylin receptors, little is
known about the structure-function relationship of
amylin(Yoshimitsu Kiriyama and Hiromi Nochi, 2018).
5. Synthesis
Following 22 amino acid signal
peptide that is quickly cleaved
following translation of the 89
amino acid coding sequence ,
proIAPP is composed of 67 amino
acids.
After synthesis of protein and its
transfer to Endoplasmic reticulum,
signal peptide is eliminated.
The precursor experience further
proteolysis and post-translational
modification(Liu et al., 2023).
Figure: Synthesis of Amylin
https://images.app.goo.gl/LVfTXGQz4g7eeFuj8
6. Synthesis
Proprotein convertase 2 (PC2) extracts 11 amino acids from
N-terminus of proIAPP.
16 amino acids from C-terminus by proprotien convertase
1/3(PC1/3)
Carboxypeptidase E then eliminate last Lysine and arginine
residues at C-terminus.
This cleavage produces terminal glycine amino acid which
enables peptidoglycine alphaamidating
monooxygenase(PAM) to add an amine group.
Now transition from proIAPP precursor protein to
physiologically active IAPP is finished(Liu et al., 2023).
7. Functions of Amylin
Amylin lowers blood glucose levels and body weight
by preventing food intake and delaying stomach
emptying.
Consequently, it is believed that both Amylin and
Insulin are crucial for regulating blood glucose level.
Amylin administered peripherally decreases appetite(
Yoshimitsu kiriyama and Hiromi Nochi, 2018).
8. Role of Amylin in central nervous system
The blood brain barrier (BBB) is crossed by Amylin in order to
get its binding sites dispersed throughout CNS.
Influence the central nervous system to govern food
consumption.
Decelerate stomach emptying resulting in decrease in body
weight.
Area postrema (hindbrain) is regarded as primary site for Amylin
action.
The inhibition of amylin on food intake is lessened when AP is
abated( Yoshimitsu kiriyama and Hiromi Nochi, 2018).
9. Role of amylin in Pancreatic Islet β-cells
Amylin knock out causes β-cells to secrete more insulin in
response to glucose.
Physiological Amylin concentration upto 100pM limit this
secretion.
Amylin regulates β-cells proliferation at low glucose
concentration
Suppress proliferation at high glucose
concentration(Yoshimitsu kiriyama and Hiromi Nochi, 2018).
10. Role of amylin in increasing sensitivity to Leptin
The hormone leptin, which is generated by fat cells, promotes fat
burning and suppresses appetite.
Despite having higher leptin levels due to their increased fat cell
count, many obese individuals lack leptin-responsiveness.
An analog of amylin (metreleptin) by itself did not cause weight
loss
clinical experiment with 177 obese/overweight people; however,
when it was combined with an amylin medication (pramlintide),
considerable weight loss was observed(Yoshimitsu kiriyama and
Hiromi Nochi, 2018).
11. Cytotoxicity Of Amylin
Amyloid aggregates cause harm to pancreatic islet β-cells
and are accountable for the emergence of type 2 diabetes.
It is residues 20–29 of human amylin that cause amyloid
fibrils to develop.
In human amylin, proline substitution at positions 25
(Ala), 28 (Ser), and 29 (Ser) reduces the stability of the β-
sheet structure and pramlintide, which is used to treat
patients with type 1 and type II diabetes in clinical
settings( Yoshimitsu kiriyama and Hiromi Nochi, 2018).
12. Cytotoxicity of Amylin
β-cells death, mitochondrial
damage, endoplasmic reticulum
stress, and disruption of cell
membranes.
Administered extracellularly at
fatal levels crosses the plasma
membrane
Processing mistake in human
proamylin linked to amyloid
formation and β-cell
death(Yoshimitsu kiriyama and
Hiromi Nochi, 2018).
Figure: Destroyed Beta cells
https://images.app.goo.gl/AxoEjjdJMedHrotu9
13. Alzheimer’s Disease
According to epidemiological
research, disruption of the insulin
and amylin pathways not only
adversely affects the body’s
homeostasis but also frequently
plays a crucial part in age-related
cognitive decline and
neurodegenerative diseases such as
AD.
Individuals with DM-II are 2-5
times more likely to have this
disease(Potenza et al., 2021).
Fig. 1.4: Alzheimer’s Disease
https://images.app.goo.gl/qaoKF1WFLr
HidzCz9
15. Causes
According to several researchers, hyperamylasemia—often
observed in people with obesity or pre-diabetic insulin
resistance—may be the mechanism underlying amylin
deposition in the brains of patients with T2DM and AD.
Cure:
There's currently no cure for Alzheimer's disease. But there is
medicine available that can temporarily reduce the symptoms.
1. Acetylcholinesterase (AChE) inhibitors
2. Memantine (Potenza et al., 2021).
16. Pharmacology
Pramlintide(symlin), was authorized in 2005
for use in patients with both type I and type II
diabetes.
Before a meal, pramlintide and insulin are
injected separately.
They collaborate to regulate the postprandial
glucose excursion.
A long-acting analog is cagrilinitide
(cagrisema)
Developed by Novo Nordisk. It treats obesity
and diabetic mellitus type II.
Fig. 1.4: Amylin analog
https://emedz.net/public/pramlintides
ymlin
17. Side Effects
Case 1: Using semaglutide and pramlintide for ten months, a 32-
year-old male patient with obstructive sleep apnea (OSA)
dropped −20.9 kg, or 16.1% of his total body weight.
Case 2: Initially treated with topiramate, 68-year-old female
patient with coronary artery disease, hypertension,
hypothyroidism, and depression lost around 8.4 kg but then
experienced a weight plateau.
She lost an additional 12.8% of her body weight after taking
dulaglutide and pramlintide, for a total weight reduction of
−21.2 kg in seven months(Wong et al., 2023).
18. Side Effects
Case 3: A 49-year-old woman on semaglutide and pramlintide
lost −14.6 kg over the course of six months. She also had
depression and hypothyroidism.
Significant adverse effects weren’t detected.
Hemoglobin A1c levels either reduced or stayed constant over
the course of treatment, and all patients reported having less
insulin requirements when using pramlintide.
In patients with obesity and type 1 diabetes, pramlintide plus
GLP1RA produced excellent weight loss(Wong et al., 2023).
19. References
Wong, G., Garner, E. M., & Srivastava, G. (2023). Combined GLP-1 Receptor
Agonist and Amylin Analogue Pharmacotherapy to Treat Obesity Comorbid With
Type 1 Diabetes. JCEM Case Reports, 1(2),luad040.
Kiriyama, Y., & Nochi, H. (2018). Role and cytotoxicity of amylin and protection of
pancreatic islet β- cells from amylin cytotoxicity. Cells, 7(8),95.
Potenza, M. A., Sgarra, L., Desantis, V., Nacci, C., & Montagnani, M. (2021).
Diabetes and Alzheimer’s disease: might mitochondrial dysfunction help deciphering
the common path?. Antioxidants, 10(8), 1257.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2496974/
Liu, Q. R., Zhu, M., Chen, Q., Mustapic, M., Kapogiannis, D., & Egan, J. M. (2023).
Novel Hominid-Specific IAPP Isoforms: Potential Biomarkers of Early Alzheimer’s
Disease and Inhibitors ofAmyloid Formation. Biomolecules, 13(1), 167.
