Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations

Arianna Maiorana, Stefania Caviglia, Benedetta Greco, Paolo Alfieri, Francesca Cumbo, Carmen Campana, Silvia Maria Bernabei, Raffaella Cusmai, Antonella Mosca, Carlo Dionisi-Vici

Research output: Contribution to journalArticlepeer-review


Background: Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively. Results: All patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3. Conclusions: We demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Original languageEnglish
Article number424
JournalOrphanet Journal of Rare Diseases
Issue number1
Publication statusPublished - Dec 2021


  • Cognitive outcome
  • Epilepsy
  • Hyperinsulinemic hypoglycemia
  • Hypoglycemia
  • Ketogenic diet
  • Neurodevelopment

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)


Dive into the research topics of 'Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations'. Together they form a unique fingerprint.

Cite this