Disorders of severe insulin resistance include lipodystrophy and pathogenic variants in the insulin receptor gene. As in other forms of diabetes, hyperglycemia develops when insulin secretion is insufficient to meet insulin demand. Due to the severe nature of insulin resistance in these patients, diabetes often develops at very young ages. Lifestyle changes including diet and exercise are key components of management. Oral and injectable drugs that improve insulin resistance can slow diabetes progression and reduce the need for insulin. However, in some patients, very high doses of exogenous insulin may be required to mitigate hyperglycemia, thereby reducing complications of diabetes. Concentrated forms of insulin may reduce injection burden and permit administrations of higher doses of insulin. Patients with generalized lipodystrophy are leptin deficient and may experience substantial improvement or even remission of diabetes with recombinant human leptin (metreleptin) treatment.