Insulin

Insulin is a peptide hormone produced by beta cells in the islets of Langerhans of the pancreas. It plays a crucial role in regulating blood glucose levels by facilitating the uptake of glucose into cells for energy production or storage. Deficiency or resistance to insulin leads to diabetes mellitus, a condition characterized by hyperglycemia. Insulin was first isolated in 1921 and has since become a cornerstone in the management of diabetes.

Insulin
Chemical structure of human insulin
Abbreviation	INS
Molecular formula	C257H383N65O77S6
Type	Peptide
Administration	Subcutaneous injection, intravenous, intramuscular
Bioavailability	Negligible (oral)
Synonyms	Human insulin, regular insulin
Source	Beta cells of the pancreatic islets
Ray's verdict	Depends on context "Insulin is important in the regulation of blood sugar, but its importance has been exaggerated because of the diabetes/insulin industry. Insulin itself has been found to account for only about 8% of the 'insulin-like activity' of the blood, with potassium being probably the largest factor." - Ray Peat

Dosing

Dosing is individualized based on body weight, blood glucose monitoring, diet, and activity. Typical starting doses for type 1 diabetes are 0.4-1.0 units/kg/day, split between basal (long-acting) and bolus (short-acting) insulins. Regimens include basal-bolus, premixed, or insulin pump therapy.

Adjustments are made via sliding scales or carbohydrate counting. Long-acting analogs like glargine provide steady coverage, while rapid-acting like lispro cover meals.

History

Etymology

The name comes from Latin insula ("island"), referring to the islets of Langerhans in the pancreas, the clusters of cells that produce it. Jean de Meyer coined the term in 1909, before the hormone itself had been isolated.

Frederick Banting and Charles Best isolated insulin in 1921 and used it to treat diabetes for the first time in 1922; Banting shared the 1923 Nobel Prize in Physiology or Medicine for the discovery.

The term "insulin" derives from the Latin word "insula," meaning island, referring to the islets of Langerhans where it is produced. The concept of a pancreatic substance regulating glucose metabolism was hypothesized as early as 1910 by Edward Albert Sharpey-Schafer. The discovery of insulin occurred in 1921 at the University of Toronto by Frederick Banting and Charles Best, assisted by J.J.R. Macleod and James Collip. They successfully extracted insulin from dog pancreases and demonstrated its ability to lower blood sugar in diabetic dogs. The first human administration was in January 1922 to Leonard Thompson, a 14-year-old boy with type 1 diabetes. In 1923, Banting and Macleod received the Nobel Prize in Physiology or Medicine for this work. Prior to insulin's discovery, diabetes was often fatal, managed only through starvation diets.

Structure/Chemical properties

Human insulin is a small protein consisting of 51 amino acids divided into two polypeptide chains: the A chain (21 amino acids) and the B chain (30 amino acids). These chains are linked by two interchain disulfide bonds, with an additional intrachain disulfide bond in the A chain. Its molecular mass is approximately 5808 Da, and the chemical formula is C257H383N65O77S6. Insulin exists as a monomer in solution but forms dimers and hexamers in the presence of zinc ions, which stabilizes storage in the pancreas. It is soluble in water at neutral pH but precipitates at its isoelectric point around pH 5.4. Modifications to the structure have led to analog insulins with altered pharmacokinetics.

Function/Mechanism of Action

Insulin's primary function is to lower blood glucose by promoting its uptake into muscle, adipose, and liver cells via the GLUT4 transporter. It stimulates glycogenesis, lipogenesis, and protein synthesis while inhibiting gluconeogenesis, glycogenolysis, and lipolysis. At the cellular level, insulin binds to its receptor, a tyrosine kinase, triggering a cascade that phosphorylates insulin receptor substrates (IRS), activating PI3K-Akt and MAPK pathways. This leads to translocation of GLUT4 vesicles to the cell membrane and metabolic shifts favoring anabolism. Insulin inhibits lipolysis, reducing free fatty acids and supporting glucose oxidation, but its role is only about 8% of blood's insulin-like activity, with potassium being a major factor.

Medical uses/Effects

Insulin is primarily used to treat type 1 diabetes, where the body produces little to no insulin, and in advanced type 2 diabetes when oral agents fail. It is also used for gestational diabetes, diabetic ketoacidosis, and hyperosmolar hyperglycemic state.

Therapeutic effects include rapid normalization of blood glucose, prevention of long-term complications like retinopathy, nephropathy, and neuropathy, and improved energy metabolism. In non-diabetics, it has been explored for wound healing and certain metabolic disorders. According to Ray Peat, insulin can exacerbate some diabetes complications like retinal damage, and diabetes often involves normal or high insulin levels rather than deficiency.

Magnesium significantly improves insulin resistance: 382 mg of magnesium (as MgCl₂) daily decreased blood sugar by 25%, along with blood pressure, insulin, and triglycerides (down by half) in a randomized controlled trial.

Insulin resistance

Diabetes or fasting raises free fatty acids and forces cells to shift from glucose to fat oxidation, and a small amount of sugar in drinking water reversed this in animal hearts.

Insulin resistance means tissues respond poorly to insulin, so higher insulin is needed to control glucose; it tracks obesity, PUFA, and inactivity in modern research. Chronic exposure of pancreatic beta cells to elevated plasma free fatty acids impairs glucose-induced insulin secretion; estrogen and adrenaline both drive free-fatty-acid release, which in turn impairs mitochondrial energy production. Sugar with a working thyroid differs from sugar in a PUFA-heavy, sleep-deprived, under-muscled context; fix oxidation and body composition drivers rather than only blaming fruit.

Prior diet, not only acute fuel mix, sets insulin responsiveness on a dextrose load: two days of high carbohydrate left healthy young men with the best oral dextrose tolerance; two days of high fat or of fasting left them with the worst, and swapping the same men between diets kept the ranking.

Work stress tracks insulin resistance. In a cross-sectional study of workers at four Beijing companies, higher job demands and job insecurity went with higher cortisol and more insulin resistance, and cortisol predicted insulin resistance independent of waist size and other confounders.

Gut inflammation is a separate route into insulin resistance. Undigested starches can sustain intestinal inflammation, and the resulting endotoxin, nitric oxide, and serotonin drive insulin resistance from that source.

Inflammation of the intestine (which can start with an infection) can be sustained by undigested starches, and the resulting endotoxin/nitric oxide/serotonin can cause insulin resistance, so it's important to keep the small intestine relatively germ-free.

— Ray Peat

In mice fed a high-fat diet, dietary butyrate (a short-chain fatty acid made by gut bacteria fermenting fiber) prevented the development of insulin resistance and obesity, lowering fasting insulin, fasting glucose, and calculated insulin resistance (HOMA-IR) relative to untreated high-fat-fed controls, alongside increased energy expenditure; this is mouse data; human trials on oral butyrate supplementation are still limited.

Fifteen minutes of 670 nm red light before an oral glucose challenge cut the integrated 2-hour rise in blood glucose by 27.7% versus placebo in healthy adults, with a 7.5% lower peak spike; the trial measured glucose curves, not a formal insulin-sensitivity clamp. See Red light.

In healthy people, five days to two weeks on a 75% carbohydrate diet made the body markedly more responsive to insulin, even though fat cells bound less of it.

Some antipsychotic drugs cause insulin resistance directly. In a small randomized trial in healthy volunteers, nine days of olanzapine raised insulin after meals and lowered insulin sensitivity on a clamp test, with no weight gain; aripiprazole, usually considered the milder drug, also lowered insulin sensitivity. One proposed route runs through the pancreas. Insulin-making beta cells carry dopamine D2-type receptors, and dopamine acting on them holds back insulin release; this was first shown in a rat beta-cell line and in rodent and human islets in a dish. Mice bred without the D2 receptor in their beta cells released much more insulin after meals, and haloperidol, olanzapine and clozapine raised insulin release from donated human islets in the lab. These are cell, islet and mouse studies; whether lifting this brake drives the insulin resistance seen in patients has not been tested in people. See Schizophrenia for how the drugs compare.

Insulin resistance markers predicted new depression in Dutch adults with no prior mood disorder. In bipolar disorder, insulin resistance went with a chronic course and a much poorer response to lithium. Mice lacking brain insulin receptors developed higher dopamine turnover and anxious, depressive behavior.

Side/Adverse effects

Common side effects include hypoglycemia (low blood sugar), which can cause sweating, tremors, confusion, and seizures if severe. Weight gain occurs due to anabolic effects. Injection site reactions like lipodystrophy may develop.

Rare but serious effects include allergic reactions, insulin resistance from antibodies, and hypokalemia. Overdose can lead to coma. Excess insulin can cause vascular leakiness and that insulin treatment itself poses health risks, potentially worsening conditions like retinal damage.

Glucagon

Glucagon is a pancreatic hormone that raises blood glucose by breaking down glycogen and pushing gluconeogenesis. It opposes insulin in the textbook picture. Under stress it rises with adrenaline, cortisol, and growth hormone.

History (Glucagon)

Etymology (Glucagon)

The name combines Greek glukys ("sweet," referring to glucose) with agon ("fighter" or "mobilizer"), describing its role in mobilizing glucose into the blood, opposite to insulin.

Charles Kimball and John Murlin discovered glucagon in 1923 as a contaminant in early insulin extracts that raised, rather than lowered, blood sugar.

Glucagon was discovered in 1923 by Kimball and Murlin as a contaminant of early pancreatic insulin extracts that, paradoxically, raised blood sugar rather than lowering it. Its name comes from "glucose agonist," describing this glucose-raising action, the opposite of insulin's, which wasn't purified and confirmed as a distinct hormone until the 1950s.

Structure/Chemical properties (Glucagon)

Glucagon is a linear peptide of 29 amino acids (about 3.5 kDa), produced from a larger precursor, proglucagon, in the alpha cells of the pancreatic islets. Unlike insulin, it has no disulfide bonds or complex folding; it's a single unbranched chain.

Function/Mechanism of Action (Glucagon)

Glucagon binds receptors on liver cells, activating glycogen breakdown (glycogenolysis) and new glucose synthesis (gluconeogenesis), raising blood glucose. Its release from pancreatic alpha cells is inhibited by high blood glucose and by GABA, released locally from neighboring insulin-producing beta cells, so that glucagon rises exactly when glucose availability falls. Under stress it rises alongside adrenaline, cortisol, and growth hormone, part of the broader stress-hormone set that mobilizes fuel at the expense of oxidative, thyroid-supported metabolism.

Clinical significance

Chronic high glucagon with free fatty acids and low thyroid effect is a stress pattern, not a healthy default. Carbohydrate and protein with salt lower the need for constant glucagon drive.

Injectable glucagon (and, more recently, an intranasal form) is used as emergency treatment for severe hypoglycemia, particularly in insulin-treated diabetics, since it can rapidly raise blood glucose when a person is unable to eat or drink. Glucagon-based drugs are also used diagnostically to relax smooth muscle for certain imaging procedures.

Practice

Eat regular carbohydrate rather than forcing fat-and-protein-only days that keep glucagon and free fatty acids high.