Insulin is one of the most important hormones of the human body and at the same time a drug, a mistake with which can cost life in a matter of hours. To understand both the medical value of insulin and its dangers outside of medicine, you need to know what exactly it does in cells. The editors analyzed the path of the hormone from the beta cell of the pancreas to the muscles, liver and adipose tissue.
Where does insulin come from and how its secretion is regulated
Insulin is synthesized by the beta cells of the islets of Langerhans of the pancreas. First, preproinsulin is formed, then proinsulin, from which enzymes cut out C-peptide. The mature insulin molecule consists of two chains — A (21 amino acids) and B (30 amino acids) — connected by disulfide bridges. C-peptide is released into the blood in the same amount as insulin, so its measurement makes it possible to assess the hormone's own secretion.
The main stimulus for secretion is an increase in the level of glucose in the blood. Glucose enters the beta cell via transporters, is metabolized, ATP levels rise, ATP-dependent potassium channels close, the membrane depolarizes, calcium channels open, and insulin granules are released. It is on this chain that sulfonylurea drugs act, which close potassium channels regardless of glucose.
Secretion has two phases: a rapid peak during the first minutes after the rise in glucose and a longer second phase. In addition, during a meal, gut incretin hormones, particularly GLP-1 and GIP, enhance the beta-cell response. Therefore, glucose taken orally causes a greater release of insulin than the same amount injected intravenously - this is the so-called incretin effect.
Endogenous insulin first enters the portal vein and the liver, which retains a significant part of it. Peripheral tissues see lower concentrations than the liver. Injectable insulin given under the skin reverses this ratio, with the periphery receiving relatively more of the hormone than the liver, one reason replacement therapy never fully reproduces the physiology.
Insulin receptor and signaling cascades
Insulin acts through the insulin receptor — a transmembrane tyrosine kinase consisting of two alpha and two beta subunits. The binding of the hormone to the extracellular part changes the conformation of the receptor, and its intracellular parts phosphorylate each other and insulin receptor substrate proteins (IRS-1, IRS-2).
Then the signal diverges in two main ways. The PI3K–Akt (protein kinase B) pathway is responsible for most of the metabolic effects: moving glucose transporters GLUT4 to the membrane, glycogen synthesis, inhibition of gluconeogenesis, stimulation of protein synthesis through mTOR. The Ras–MAPK pathway is mainly associated with cell growth and division. A detailed description of these cascades is given in the classic reviews by Saltiel and Kahn and Petersen and Shulman.
Structurally, the insulin receptor is close to the insulin-like growth factor 1 (IGF-1) receptor. High concentrations of insulin can partially activate the IGF-1 receptor, and hybrid receptors combine subunits of both. This is one of the reasons why the mitogenic properties of insulin analogues are carefully studied during their registration.
The insulin signal is quickly turned off: the receptor is internalized and destroyed, phosphatases remove phosphate groups, and the hormone itself is broken down by an insulin-degrading enzyme, primarily in the liver and kidneys. The half-life of endogenous insulin from the blood is only a few minutes.
Effect on muscles, liver and adipose tissue
Insulin is the main anabolic hormone of energy metabolism. Its task after eating is to "remove" nutrients from the blood and store them. Each of the three main target tissues does this in its own way.
| Fabric | Main effects of insulin | Result for blood |
|---|---|---|
| Skeletal muscles | GLUT4 translocation, glycogen synthesis, inhibition of protein breakdown | Reduction of glucose, absorption of amino acids |
| Liver | Inhibition of gluconeogenesis and glycogenolysis, synthesis of glycogen and fatty acids | Reduction of glucose release |
| Adipose tissue | Glucose uptake, triglyceride synthesis, strong inhibition of lipolysis | Reduction of free fatty acids |
Skeletal muscles absorb most of the glucose entering the blood after a meal. Without insulin, GLUT4 mostly remains in intracellular vesicles. Interestingly, muscle contraction also translocates GLUT4 to the membrane independently of insulin — so exercise lowers glucose even in the absence of the hormone and increases the risk of hypoglycemia in people on insulin therapy.
Regarding protein metabolism, studies with infusions have shown that physiological hyperinsulinemia primarily suppresses the breakdown of muscle protein, and the stimulation of its synthesis largely depends on the availability of amino acids (Biolo et al., 1995; Greenhaff et al., 2008). That is, insulin is more of a "catabolism brake" than an independent powerful stimulator of muscle growth.
In adipose tissue, insulin is the strongest known inhibitor of lipolysis: even small concentrations of the hormone suppress the release of fatty acids. Therefore, a constantly high level of insulin contributes to the accumulation of fat, and with its deficiency, as in untreated type 1 diabetes, fat and muscles quickly break down.
Insulin, potassium and the brain: less obvious effects
Insulin stimulates the sodium-potassium ATPase and moves potassium from the blood into the cells. This effect is used in emergency medicine to treat hyperkalemia (together with glucose). The downside is that insulin can cause hypokalemia, which is dangerous for the heart rhythm, especially against the background of intensive treatment of diabetic ketoacidosis.
The brain consumes glucose constantly and has almost no reserves of its own. Most neurons absorb glucose independently of insulin, so a drop in blood sugar first affects the central nervous system: confusion, convulsions, and loss of consciousness appear. It is this dependence that makes hypoglycemia—the main risk of excess insulin—so dangerous.
- Counterregulation. In response to a decrease in glucose, the body secretes glucagon, adrenaline, cortisol, and growth hormone.
- Symptoms of adrenaline phase. Trembling, sweating, palpitations, hunger, anxiety.
- Neuroglycopenic symptoms. Disorders of thinking and speech, behavioral changes, convulsions, coma.
Insulin also affects the kidneys (sodium retention), vascular tone (endothelial nitric oxide release), hepatic lipoprotein synthesis, and appetite via the hypothalamus. These effects explain why insulin therapy is often accompanied by moderate weight gain and sometimes edema.
Insulin resistance: when the signal weakens
Insulin resistance is a condition in which the normal concentration of insulin causes a weaker than normal effect. At first, the pancreas compensates by producing more of the hormone, but over time the beta cells are depleted and type 2 diabetes develops. The main factors are excess visceral fat, hypodynamia, genetic predisposition, chronic inflammation.
The mechanism is associated with the accumulation of lipid metabolites (diacylglycerols, ceramide) in the liver and muscles, which activate protein kinases that "spoil" signal transmission at the IRS level. Exercise is one of the most effective ways to increase insulin sensitivity, in part because muscle contraction opens up an alternative pathway for GLUT4.
Importantly, resistance can be selective. In the liver, the metabolic pathway of inhibition of gluconeogenesis may be impaired, while the stimulation of fat synthesis is preserved. This "paradoxical" situation explains the combination of hyperglycemia and fatty liver disease in people with metabolic syndrome.
Exogenous insulin does not "increase sensitivity" or "improve metabolism" in a person without diabetes. On the contrary, chronic hyperinsulinemia itself can reduce the sensitivity of receptors. This is important to remember when evaluating popular myths about insulin in sports.
Editorial conclusion
Insulin is a storage hormone: it lowers blood glucose, converts nutrients into glycogen, fat and protein, inhibits the breakdown of fat and protein. Its action is realized through receptor tyrosine kinase and PI3K–Akt and MAPK cascades.
The same mechanism makes insulin dangerous: the brain depends on a constant supply of glucose, and an excess of the hormone can cause severe hypoglycemia in a short time. Additional risks include hypokalemia and effects on heart rhythm.
For muscles, insulin is primarily an anti-catabolic signal, not a magic "anabolic"; its effect on protein synthesis depends on the availability of amino acids.
Our materials "Medical use of insulin: what it was created for", "Side effects of insulin" and "Why insulin is used in sports: expectations and reality" will help to continue the topic.
References
- Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799â806.
- Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133â2223.
- Biolo G, Declan Fleming RY, Wolfe RR. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest. 1995;95(2):811â819.
- Greenhaff PL, Karagounis LG, Peirce N, et al. Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab. 2008;295(3):E595âE604.
- Cryer PE. Hypoglycemia in Diabetes: Pathophysiology, Prevalence, and Prevention. 3rd ed. Arlington: American Diabetes Association; 2016.
- Melmed S, Auchus RJ, Goldfine AB, Koenig RJ, Rosen CJ (eds). Williams Textbook of Endocrinology. 14th ed. Philadelphia: Elsevier; 2020.
