Insulins

The insulin receptor is a heterotetramer: two extracellular α subunits bind insulin, and two transmembrane β subunits carry tyrosine kinase activity. Binding causes receptor autophosphorylation and activates the PI3K–Akt and MAPK pathways. In skeletal muscle, fat and heart, insulin moves GLUT4 transporters to the plasma membrane, so glucose enters the cells. Exercise also drives GLUT4 uptake, by an insulin-independent route. The brain is the exception: its glucose uptake is largely insulin-independent, through GLUT1 and GLUT3, which is why hypoglycemia rather than lack of insulin impairs neurons.

The effects follow the tissue. In the liver, insulin promotes glycogenesis and inhibits gluconeogenesis. In fat, it promotes lipogenesis and inhibits lipolysis by dephosphorylating hormone-sensitive lipase, and it stimulates lipoprotein lipase to clear triglyceride-rich chylomicrons. In muscle, it promotes glycogenesis and protein synthesis and inhibits protein breakdown. It also inhibits glucagon release. It moves potassium into cells by activating Na⁺/K⁺-ATPase.

Rapid analogs. Lispro reverses the proline at B28 and the lysine at B29; aspart replaces the B28 proline with aspartic acid. Lispro is equipotent to human insulin unit for unit but is absorbed more quickly, with a faster onset and a shorter duration; aspart likewise has a faster onset and shorter duration than regular insulin. (Native insulin is stored in β-cell granules as zinc-coordinated hexamers.)

NPH is human insulin precipitated with zinc in the presence of protamine, a basic polyarginine peptide. The precipitate at the injection site releases insulin slowly, and the uneven way the deposits dissolve is thought to explain NPH’s variable action. It is a cloudy suspension.

Glargine is soluble at pH 4, the pH of its solution, and insoluble at physiologic pH. After injection it forms a precipitate that releases insulin slowly over about 24 hours — which is also why it is never diluted, mixed with another insulin, or given IV or by pump. Degludec forms multi-hexamers in subcutaneous tissue, creating a depot. Its protracted action comes mainly from delayed absorption and, to a lesser extent, from binding to circulating albumin; it reaches steady state after 3–4 days. Insulin detemir is another long-acting insulin.

A rapid analog covers a meal or corrects a high glucose, so it is used with a basal insulin unless it is given by pump or IV infusion; a pump replaces long-acting insulin by delivering small amounts of short-acting insulin continuously. Regular insulin is given before meals, with food within about 30 minutes to avoid hypoglycemia. A basal–bolus regimen has given better glycemic control and fewer perioperative complications than a sliding scale alone.

Type 1 diabetes is autoimmune β-cell destruction with absolute insulin deficiency, so these patients always need insulin. In type 2 diabetes, insulin resistance comes first, followed by compensatory hyperinsulinemia and eventual β-cell exhaustion, and insulin becomes necessary in the later stages. (How the β cell secretes insulin is on the Sulfonylureas page.)

In DKA — mainly type 1 diabetes — absolute insulin deficiency plus counterregulatory hormones increase gluconeogenesis and glycogenolysis and impair glucose use. Lipolysis releases free fatty acids, which the liver oxidizes to ketone bodies, producing a high–anion gap metabolic acidosis. In HHS — mainly type 2 — the β cells still make enough insulin to suppress ketogenesis, so the picture is severe hyperglycemia and hyperosmolality (320–400 mOsm/kg is common) without significant ketosis. Cerebral edema is the most feared complication, and the risk is higher in HHS, so isotonic fluid comes first and an insulin drip is not started in the initial stage.

Continuous IV insulin is the standard of care in DKA; glargine and degludec are not recommended for it. Regular insulin is given IV only under supervision, with glucose and potassium monitored. (SGLT2-inhibitor euglycemic DKA: SGLT2 Inhibitors page.)

In DKA the serum potassium is usually high — acidosis and insulin deficiency shift potassium out of cells — but total body potassium is depleted by the osmotic diuresis. Insulin drives potassium back into cells, so it can quickly expose that deficit. Insulin is therefore started only when serum potassium is 3.5 mmol/L or higher; below that, it worsens hypokalemia and can cause arrhythmias, cardiac arrest and respiratory-muscle weakness. All insulins shift potassium this way, which is also why IV insulin treats hyperkalemia. (Potassium replacement and hyperkalemia management: Electrolyte & Fluid Replacement page.)

Hypoglycemia is the most common adverse reaction of all insulins, and the risk is highest when an insulin’s glucose-lowering effect is maximal. Neurogenic signs come from sympathoadrenal activation: adrenergic ones (tremor, palpitations, anxiety) and cholinergic ones (hunger, sweating, paresthesias); catecholaminergic signs appear first. Neuroglycopenic signs come from the brain’s own glucose deprivation: confusion, behavioral change, seizures and coma.

Symptomatic awareness is reduced in long-standing diabetes, in diabetic neuropathy, after recurrent hypoglycemia, and with drugs that block the sympathetic nervous system such as β-blockers, which can reduce or abolish the warning signs (Beta-Blockers page). β-Blockers mask catecholamine-triggered signs such as tremor and palpitations, but sweating remains unmasked and may be the only consistent sign. Symptoms typically appear at a glucose of 50–55 mg/dL or below, though the threshold varies between people.