IAPP 37 aminoacid peptide hormone co-secreted with insulin and forms amyloid fibrils in t2dm

1. Presented by:
L.Bala krishna
18PCM2790
Dept. of Pharmacology and
Toxicology
1NIPER SAS Nagar

2. Flow of presentation
 Background of islet amyloid, IAPP and type 2 diabetes
 Role of iapp
 Processing and secretion of IAPP
 Possible mechanisms for amyloid formation
 Islet amyloid and β-cell toxicity
 Techniques used to monitor aggregation
 Therapeutic approaches
2

3. Islet amyloid
 Eugene Opie (1900’s) described the occurrence of
‘hyaline degeneration of the islets of Langerhans’ in
patients with hyperglycemia
 In 1987, Westermark and Cooper with separate
groups identified peptide aggregates in β-cells of
pancreas in type 2 diabetes and named it as IAPP &
AMYLIN
 IAPP is 37 AA’ peptide hormone co-secreted with
insulin and forms amyloid fibrils in type 2 diabetes that
disrupts the cell membrane and is responsible for β-
cells death
 Present in ≥90% of type 2 diabetic subjects
3

4. Type 2 diabetes
 Non-insulin dependant diabetes mellitus
 Long term metabolic disorder characterized by high
blood glucose levels, decreased insulin sensitivity
 Body’s inability to utilize the insulin present
 complications: CVD, blindness, kidney failure,
cognitive dysfunction
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5. Comparison of β-cell, normal vs. diabetic
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6. Figure. Sequence of aminoacids in IAPP and the amyloidogenic region from 20-29
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7. IAPP or AMYLIN
 Amylin, or islet amyloid polypeptide (IAPP), is a
37-residue peptide hormone
 Disulfide bond between 2nd & 7th position between
two Cysteine aminoacids
 It is cosecreted with insulin from the pancreatic β-cells
in the ratio of approximately 100:1 (insulin:amylin)
 contributes to glycemic control
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8. Role of IAPP
8
Debbie L et al., Amylin: Pharmacology, Physiology, and Clinical Potential
Pharmacological Reviews July 2015, 67 (3) 564-600

9. Processing and secretion of IAPP
 derived from larger molecule proIAPP and processed
by two enzymes called prohormone convertases
(PC) – PC 1/3 and PC2
9https://en.wikipedia.org/wiki/Amylin

10. 10
Jing Wang et al., The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid
Polypeptide at the NH2-Terminal Cleavage Site. Diabetes 2001 Mar; 50(3): 534-539

11. 11
Figure. Alignment of sequence of IAPP in different species
•Rodent IAPP is non amyloidogenic, proline in the
region of 24-29 prevents fibrillization
•8-20; 20-29; 30-37 regions have tendency to form β-
sheets can form fibrils
Hye Rin Jeong et al., 2015 Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes
mellitus, Clinical Interventions in Aging

12. Possible mechanisms for amyloid
formation
 Mutations in pro IAPP gene leads to misfolding of
IAPP, misfolded IAPP form fibrils and tend to attract
other IAPP monomer
 Increased production of IAPP with increased demand
for insulin (hyperglycemia & hyperlipidemia)
 Impaired precursor IAPP processing NH2 terminus
elimination
 Unprocessed IAPP binding with heparan sulfate
proteoglycans
 Presence of fibril seeds
12

13. 13
Figure. List of genetic mutations of IAPP determined from in silico studies,
and naturally occurring (eg, S20G) mutations.
Karen Pillay et al., 2013 amylin
uncovered. biomed research
international.

14. Figure. proposed mechanism of N-terminal of pro-Amylin binding with
perlecan heparan sulfate proteoglycan at basement membrane of β-cell.
Marzban l et al., 2013 Islet amyloid polypeptide and type 2 diabetes 2, experimental
gerontology 14

15. β-cell toxicity by Islet amyloid
 Cell membrane disruption and disrupts the
intracellular homeostasis
 Causes oxidative stress by ROS generation
 Deposits of IAPP in β-cell causes apoptotic cell death
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16. Figure. Apoptosis in β-cell by islet amyloid aggregation
16
Karen Pillay et al., 2013 amylin uncovered. biomed research international.

17. Techniques used to monitor
aggregation and toxicity
 Dyes : Congo red, Thioflavin T
 Microscopic techniques:
Transmission electron microscopy
Atomic force microscopy
 Spectroscopic techniques:
Circular dichromism
FT-IR spectroscopy
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18. Drugs reported
 NSAIDS have shown to decrease the association between β-
sheets
 EPIGALLOCATECHIN decreases many peptides aggregation
 polyphenol RESVERATROL has been shown to inhibit
amyloid formation
 ASCORBIC ACID, LIPOIC ACID have shown to interact with
amylin and inhibit early stages of aggregation process
 Tannic acid, curcumin, myricetin have also been reported
for their activity in inhibiting aggregation
 Rifampicin invivo studies has shown to inhibit the
aggregation and preformed aggregates
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19. Therapeutic approaches
Target or intended effect Drug therapy or approach
1. Direct inhibition of gene
transcription
Drugs inhibiting the activity
of the IAPP gene promoter
2. Direct inhibition of
translation of mRNA
3. Reduction in the demand
for endogenous insulin
Insulin therapy in T2DM
4. Reduction in hepatic
glucose production &
increase in insulin sensitivity
conventional antidiabetic
drugs like metformin,
sulfonyl ureas etc..
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A. Production of hIAPP

20. Target or intended effect Drug therapy or approach
1. Inhibition of fibril
formation, stabilization,
protection.
Drugs that inhibit binding of
serum amyloid p with
developing fibril
2. Inhibition of fibril
formation
Drugs inhibiting the
interaction between perlecan
and fibril forming protein.
3. Removal of deposits invivo Phagocytosis or increase
solubility of fibril
4. Inhibition of fibril
formation and dissociation
with existing fibrils
Disrupt the aggregation of β-
pleated sheets
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B. Fibrillization

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