Structure and Biosynthesis

• Amylin or Islet Amyloid Polypeptide (IAPP) is a hormone composed of 37 amino acids released by pancreatic beta cells along with insulin.
• Synthesized as an 89-amino acid preprohormone, undergoing several processing steps to produce the mature peptide.
• Key features:
• Highly conserved across species
• Contains a disulfide bridge between residues 2 and 7
• Amidated C-terminus
• Intrinsically disordered in its monomeric state
• Biosynthesis process:
• Translation of pre-proIAPP
• Signal peptide cleavage
• Prohormone convertase processing
• C-terminal amidation
• Storage in secretory granules

Physiological Functions

• Complements insulin's actions in maintaining glucose homeostasis:
• Metabolic Regulation:
• Suppression of glucagon secretion
• Delayed gastric emptying
• Reduced food intake
• Enhanced satiety signalling
• Central Nervous System Effects:
• Appetite regulation
• Energy expenditure modulation
• Mood and cognitive function
• Pain perception
• Interaction with Other Hormones:
• Synergistic action with insulin
• Counter-regulatory effects to glucagon
• Integration with incretin hormones
• Calcium homeostasis
• Helps maintain blood glucose levels, energy balance, nutrient utilization, and body weight regulation.

Role in Disease Pathogenesis

• Tendency to form amyloid deposits plays a central role in various pathological conditions, particularly type 2 diabetes (T2DM):
• Amyloid Formation:
• Misfolding of IAPP monomers
• Formation of toxic oligomers
• Development of fibrillar structures
• Accumulation in pancreatic islets
• Pathological Effects:
• β-cell dysfunction
• Cellular stress and inflammation
• Reduced insulin secretion
• Progressive islet destruction
• Contributing Factors to IAPP Aggregation:
• Aging
• Obesity
• Genetic predisposition
• Environmental stressors
• Associated with decreased β-cell mass, impaired insulin secretion, increased oxidative stress, and progressive diabetes development.

Therapeutic Applications and Future Directions

• Various therapeutic strategies:
• Pramlintide (synthetic IAPP analog):
• Treatment of type 1 and type 2 diabetes
• Weight management
• Glycemic control improvement
• Reduced postprandial glucose excursions
• Anti-amyloid Strategies:
• Small molecule inhibitors
• Peptide-based interventions
• Immunotherapy approaches
• Stabilization of native IAPP
• Emerging Research Areas:
• Novel IAPP analogs development
• Targeting amyloid formation
• Biomarker identification
• Combination therapies
• Future therapeutic directions:
• Development of long-acting IAPP analogs
• Novel drug delivery systems
• Prevention of amyloid formation
• Early intervention strategies
• Continued study holds promise for:
• Improved diabetes treatments
• Better understanding of amyloid diseases
• Novel therapeutic approaches
• Prevention strategies