Commercially available insulin preparations span a range from ultra-rapid analogs designed to mimic mealtime secretion to near-peakless basal analogs that provide 24 to 42 hours of background coverage. Each reflects specific amino acid substitutions or formulation changes that alter the speed of subcutaneous absorption.

Regular insulin (human insulin) forms hexamers in the vial and must dissociate to monomers before absorption, producing an onset of 30 to 60 minutes and duration of 5 to 8 hours. It must be injected 30 minutes before meals. Regular insulin is the only preparation safe for intravenous use and remains important for intravenous infusions in the intensive care unit and perioperative setting.

Rapid-acting analogs (lispro, aspart, glulisine) carry amino acid substitutions that disrupt hexamer formation, yielding onset within 10 to 15 minutes, peak at 1 to 2 hours, and duration of 3 to 5 hours. They can be injected immediately before or at the start of a meal, substantially improving postprandial glucose control and convenience compared with regular insulin.

Neutral protamine Hagedorn insulin is an intermediate-acting preparation with onset 1 to 2 hours, peak 4 to 8 hours, and duration 12 to 18 hours. Its pronounced peak causes nocturnal hypoglycemia when injected at bedtime and produces significant day-to-day variability. It remains widely used where cost is a concern.

Long-acting basal analogs are designed to provide a flat, peakless background insulin level. Glargine (precipitates at subcutaneous pH, dissolving slowly) provides approximately 20 to 24 hours of coverage with the standard formulation and approximately 36 hours with the concentrated formulation. Detemir (fatty acid chain causes albumin binding in subcutaneous tissue) provides 18 to 22 hours, often requiring twice-daily dosing. Degludec forms multi-hexamer complexes that dissociate slowly, providing more than 42 hours of coverage with the least day-to-day variability of any basal analog.

Hypoglycemia is the most clinically consequential adverse effect of insulin and the primary barrier to achieving optimal glycemic control. The adverse effect profile also includes weight gain and injection site complications. Insulin is the only antihyperglycemic agent with an established safety record in pregnancy.

Hypoglycemia is defined by the Whipple triad: symptoms consistent with hypoglycemia, a low measured glucose (below 70 mg/dL for level 1, below 54 mg/dL for clinically significant level 2), and relief with glucose administration. Neurogenic symptoms (sweating, tremor, palpitations, hunger) appear at approximately 65 to 70 mg/dL. Neuroglycopenic symptoms (confusion, visual changes, seizure) appear at approximately 55 to 60 mg/dL and reflect direct neuronal glucose deprivation. Common precipitants include excess dose, missed meals, unplanned exercise, and alcohol (which suppresses hepatic gluconeogenesis).

Hypoglycemia unawareness develops in some patients with longstanding type 1 diabetes mellitus: repeated hypoglycemic episodes lower the glucose threshold at which counter-regulatory responses are triggered, so the first sign of hypoglycemia may be loss of consciousness without any warning symptoms. Continuous glucose monitoring with low-glucose alerts is recommended for these patients.

Treatment of mild hypoglycemia follows the rule of 15: 15 grams of fast-acting glucose orally, recheck in 15 minutes, repeat if still below 70 mg/dL. For severe hypoglycemia with inability to take oral glucose, glucagon (intramuscular or intranasal) is the standard out-of-hospital treatment; intravenous dextrose is given in hospital. Glucagon mobilizes hepatic glycogen and is ineffective in patients with depleted stores (prolonged fasting, alcoholism, hepatic failure).

Weight gain of 2 to 6 kg is predictable with insulin initiation, driven by reversal of glycosuria, enhanced lipogenesis, and increased appetite from hypoglycemia episodes. Adding a glucagon-like peptide-1 receptor agonist or sodium-glucose cotransporter-2 inhibitor to insulin attenuates weight gain and provides cardiovascular benefit in type 2 diabetes mellitus.

Insulin is the standard of care for both type 1 diabetes mellitus and gestational diabetes mellitus in pregnancy. Insulin does not cross the placenta in clinically significant amounts. Requirements typically double by the third trimester due to placental hormone-driven insulin resistance, then fall abruptly after delivery. Lispro and aspart are the preferred rapid-acting analogs in pregnancy. Regular insulin, neutral protamine Hagedorn, and glargine are also used with established safety records.