From lipodystrophy to subcutaneous insulin depots: Overlooked mechanisms of glycemic variability in patients with diabetes

Lipohypertrophy (LH) is the most common complication of insulin injection therapy but remains underrecognized in routine care. Repeated injections into the same area promote subcutaneous fat hypertrophy and fibrosis, which can create insulin depot behavior and lead to delayed, blunted, and highly variable insulin absorption. As a result, patients may develop unexplained glycemic instability, including persistent postprandial hyperglycemia and late, unpredictable hypoglycemia that complicates insulin titration. Clinical inspection and palpation detect only a proportion of lesions, whereas high-frequency ultrasound can improve detection and lesion mapping, particularly when lesions are subtle or deep. This review synthesizes current evidence linking injection-site tissue remodeling to altered insulin pharmacokinetics and clinically meaningful glycemic variability and provides a practical pathway for diagnosis and management. Key elements include systematic injection-site assessment, structured technique education with site rotation, and intensified glucose monitoring with individualized dose adjustment when injections are switched away from the LH, as absorption may become faster and more predictable. Recognizing LH as a modifiable driver of insulin depot-related variability shifts clinical focus from repeated dose escalation to correcting injection-site factors, thereby improving the safety and effectiveness of insulin therapy.