| INS (Insulin) | |
|---|---|
| Gene | [INS](/entities/ins) |
| UniProt ID | [P01308](https://www.uniprot.org/uniprot/P01308) |
| PDB Structures | 1ZEN, 3J5Q |
| Molecular Weight | 6 kDa (processed), 51 kDa (proinsulin) |
| Subcellular Localization | Secreted, cytoplasm |
| Expression | Pancreatic β-cells, brain [neurons](/entities/neurons) |
| Function | Metabolic regulation, neurotrophic factor |
Insulin is a peptide hormone encoded by the INS gene, essential for glucose homeostasis and cellular energy metabolism. Produced by pancreatic β-cells, insulin acts as a key regulator of blood glucose levels and has critical roles in neuronal survival, synaptic plasticity, and cognitive function. The discovery of insulin signaling in the brain has revealed its importance beyond metabolic regulation, with growing evidence linking insulin dysfunction to neurodegenerative diseases, particularly Alzheimer's disease.
Insulin is synthesized as a preprohormone (110 amino acids) in pancreatic β-cells and processed to proinsulin (86 amino acids). The mature insulin hormone consists of two polypeptide chains—A chain (21 amino acids) and B chain (30 amino acids)—connected by disulfide bonds. This processed form is stored in secretory granules and released in response to elevated blood glucose. The INS gene is located on chromosome 11p15.5 and contains three exons encoding the preproinsulin peptide [1].
In the brain, insulin is produced locally by neurons and glia, and also transported across the blood-brain barrier via receptor-mediated transcytosis. Brain-derived insulin acts in an autocrine and paracrine manner, influencing neuronal function through insulin receptors (IR) expressed throughout the central nervous system, particularly in the hippocampus, cortex, and hypothalamus [2].
Neurons express both insulin receptor isoforms (IR-A and IR-B), with IR-A predominating in the brain. Insulin receptors are widely distributed in regions associated with learning and memory, including the hippocampus and prefrontal cortex. The receptor is a tyrosine kinase that autophosphorylates upon insulin binding, activating downstream signaling cascades including:
Insulin signaling modulates synaptic plasticity—the cellular basis of learning and memory—through multiple mechanisms:
Epidemiological studies have revealed a strong association between type 2 diabetes mellitus (T2DM) and increased risk of Alzheimer's disease, leading to the hypothesis that AD may represent a form of "type 3 diabetes" [3]. This hypothesis posits that brain insulin resistance contributes to:
Intranasal delivery of insulin bypasses the blood-brain barrier and has been investigated as a potential therapy for AD. Clinical trials have demonstrated:
Drugs that improve insulin sensitivity, such as thiazolidinediones (PPARγ agonists), have shown promise in preclinical models:
Metabolic and lifestyle factors that improve insulin sensitivity may reduce neurodegeneration risk:
Insulin is a crucial hormone for both peripheral metabolism and brain function. In the brain, insulin acts as a neurotrophic factor regulating synaptic plasticity, memory, and neuronal survival. Insulin resistance—common in aging and type 2 diabetes—emerges as a significant contributor to Alzheimer's disease pathogenesis. Understanding the role of insulin signaling in neurodegeneration offers therapeutic avenues for disease modification in AD and related disorders.