Insulin

Insulin is a peptide hormone central to the regulation of metabolism and energy storage in the human body. Produced by the beta cells of the pancreatic islets, it is encoded by the INS gene and represents the primary anabolic hormone in human physiology. Its main functions involve controlling the levels of glucose, fats, and proteins in the bloodstream and promoting their uptake, storage, and utilisation by target tissues. Insulin plays a crucial role in maintaining metabolic balance, and disturbances in its secretion or action result in metabolic disorders, most notably diabetes mellitus. Its evolutionary history, complex biochemical regulation, and central role in clinical medicine make insulin one of the most extensively studied molecules in biology.

Physiological Role and Metabolic Functions

Insulin exerts its effects chiefly by regulating carbohydrate, fat, and protein metabolism. In the presence of high blood glucose levels, beta cells release insulin to promote glucose uptake into skeletal muscle, adipose tissue, and the liver. Within these tissues, glucose is converted into glycogen through glycogenesis or processed via glycolysis into intermediates used for the synthesis of fatty acids and triglycerides.

• In the liver, insulin enhances the formation of glycogen and promotes lipogenesis.
• In adipose tissue, it stimulates triglyceride synthesis.
• In skeletal muscle, it assists in glycogen formation and protein synthesis.

High circulating insulin concentrations suppress hepatic glucose output by inhibiting gluconeogenesis and glycogenolysis. As an anabolic hormone, insulin fosters the conversion of small molecules into larger, energy-rich compounds. Conversely, low insulin levels encourage catabolic processes, increasing the breakdown of stored fats and proteins.
Insulin secretion is tightly regulated by blood glucose concentration. When glucose levels rise, beta cells respond by increasing insulin release; when levels fall, secretion decreases. Alpha cells in the pancreatic islets work synergistically with beta cells by secreting glucagon, a hormone that increases blood glucose during periods of low availability. Together, insulin and glucagon form the core regulatory mechanism of blood glucose homeostasis.

Diabetes and Insulin Dysregulation

A deficiency in insulin secretion or responsiveness results in diabetes mellitus, characterised by chronic hyperglycaemia. Two principal forms of the disease are recognised:

• Type 1 diabetes: An autoimmune condition in which beta cells are destroyed, leading to an absolute inability to produce insulin. Individuals require lifelong insulin replacement therapy.
• Type 2 diabetes: Involves a combination of reduced beta-cell mass, impaired insulin secretion, amyloid accumulation in pancreatic islets, and peripheral insulin resistance. Insulin is still secreted, often at high levels initially, but the tissues fail to respond effectively. Increased glucagon secretion, which becomes largely independent of blood glucose concentration, further contributes to elevated glucose levels.

In both types, insufficient insulin action results in harmful metabolic consequences, including increased fatty acid breakdown, impaired protein synthesis, and progressive tissue damage.

Structure and Species Variations

The human insulin molecule comprises 51 amino acids and has a molecular mass of approximately 5808 Daltons. It consists of two polypeptide chains, termed the A-chain and B-chain, linked by disulfide bonds. Although insulin is conserved across animal species, slight variations exist in sequence and structure, influencing its metabolic effects when used therapeutically. Porcine insulin, nearly identical to the human form, was historically employed in diabetes treatment before the advent of recombinant DNA technologies allowed the large-scale production of synthetic human insulin.
Insulin holds special significance in the history of biochemistry. It was the first peptide hormone discovered, the first protein ever sequenced, and one of the earliest proteins to have its crystal structure determined. It was also the first protein to be synthesised chemically and later produced using recombinant DNA technology. Today, synthetic human insulin and its analogues remain essential medicines globally.

Evolution and Biological Distribution

The evolutionary origins of insulin are ancient, extending back more than a billion years. Insulin-like molecules have been identified not only in animals but also in fungi and protists, suggesting early and conserved roles in cellular signalling. Most vertebrates produce insulin in pancreatic islets, whereas certain teleost fish synthesise it in a specialised organ known as the Brockmann body.
Some venomous organisms have also adapted insulin for predatory purposes. Cone snails such as Conus geographus and Conus tulipa use modified insulin molecules in their venom to induce rapid hypoglycaemia in prey fish, slowing them down and enabling capture. These insulin variants resemble fish insulin more closely than snail insulin, demonstrating remarkable evolutionary adaptation.

Genetic Regulation of Insulin Production

Human insulin production is governed by the INS gene located on chromosome 11. In rodents, two functional insulin genes exist: Ins2, homologous to most mammalian insulin genes, and Ins1, a retroposed copy lacking one intron. Expression of the insulin gene increases in response to rising blood glucose and is mediated by several transcription factors acting on enhancer regions upstream of the promoter.
Key regulators include:

• PDX1: A transcription factor central to pancreatic development and insulin gene activation. At low glucose levels, it is held at the nuclear periphery; high glucose causes its phosphorylation, nuclear entry, and binding to the A3 promoter element.
• NeuroD1 (β2): Influences insulin exocytosis and gene expression. It translocates to the nucleus upon glucose-stimulated phosphorylation and binds the E1 element, recruiting coactivators such as EP300.
• MafA: A glucose-sensitive transcription factor that binds the C1 promoter element. Its activity rises under high glucose and falls during low-glucose states due to proteasomal degradation.

These factors operate synergistically, and their dysfunction—sometimes provoked by oxidative stress—can diminish insulin output and contribute to diabetes. Promoter regions contain specialised binding motifs such as A-boxes for PDX1, E-boxes for NeuroD1, C-boxes for MafA, and cAMP response elements for CREB, as well as silencers that reduce transcription.

Synthesis and Processing of Insulin

Insulin biosynthesis begins with the formation of preproinsulin, a 110-amino-acid precursor translated directly into the rough endoplasmic reticulum. The signal peptide is removed to form proinsulin, which undergoes folding and disulfide bond formation before being transported to the Golgi apparatus. In secretory granules, specific proteolytic enzymes cleave proinsulin to yield mature insulin and C-peptide, both released in equimolar amounts during secretion.
The final hormone is stored in granules within the beta cells and released through regulated exocytosis when glucose levels rise. This sophisticated processing ensures precise and timely release of insulin in response to metabolic needs.
Insulin remains indispensable to medicine, physiology, and evolutionary biology. Its interplay with glucagon, its tightly regulated gene expression, and its critical role in nutrient metabolism underscore its importance in maintaining the body’s internal energy balance.