Outcomes of rhIGF-1 Therapy in Severe Insulin Resistance Syndromes
Overview
This single-center study reports on the long-term outcomes of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in patients with Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). While early metabolic improvements were observed, including better glycemic control and growth, the therapy showed limited long-term efficacy and did not prevent progression to diabetes mellitus in the longest-lived patients.
Background
Donohue syndrome and Rabson-Mendenhall syndrome represent severe forms of insulin resistance caused by biallelic mutations in the insulin receptor gene. These rare recessive disorders are characterized by growth restriction, dysmorphic features, and metabolic abnormalities including fasting hypoglycemia and postprandial hyperglycemia. Recombinant human IGF-1 has been used off-label to improve metabolic control by activating insulin and IGF-1 receptor pathways, but long-term benefits and optimal treatment regimens remain unclear. Previous reports have documented short-term improvements but limited data exist on sustained outcomes.
Data Highlights
Patient
Diagnosis
rhIGF-1 Duration
Metabolic Response
Outcome
4 patients (1 RMS, 3 DS)
Genetically confirmed biallelic INSR mutations
Up to 16 years
Improved fasting glucose, insulin, HbA1c, growth in early years
Two died in infancy; longest survivors progressed to diabetes mellitus
Literature cohort (12 patients)
Mostly genetically confirmed
>4 months
HbA1c improved ~1.5%; some hypoglycemia and soft tissue overgrowth reported
Variable responses; limited long-term benefit
Key Findings
rhIGF-1 therapy improved early glycemic control, fasting tolerance, and growth in DS and RMS patients.
Two patients showed poor tolerance or response to rhIGF-1 and died during infancy.
The longest surviving patients experienced progressive metabolic decompensation to diabetes mellitus despite ongoing rhIGF-1 treatment.
New clinical features associated with severe insulin receptoropathies were identified, including cataracts, liver hemangioma, and impaired hepatic protein synthesis.
Phenotypic heterogeneity exists within DS and RMS, complicating treatment response predictions.
Current high-dose rhIGF-1 regimens provide limited benefits and do not prevent disease progression.
Clinical Implications
Clinicians should recognize that while rhIGF-1 therapy can offer early metabolic improvements in patients with severe insulin resistance syndromes, it does not halt progression to diabetes mellitus and may be poorly tolerated in some cases. Monitoring for emerging comorbidities such as cataracts and liver abnormalities is warranted. There remains a critical need for alternative therapeutic strategies and individualized treatment plans for these rare disorders.
Conclusion
Long-term rhIGF-1 therapy in DS and RMS yields modest early benefits but fails to prevent eventual metabolic deterioration. Further research is essential to develop more effective treatments for extreme insulin resistance syndromes.
References
Donohue syndrome and Rabson-Mendenhall syndrome clinical features and rhIGF-1 therapy outcomes
