A recent study explored a new drug that appears to offer promising results in treating children with hyperinsulinic hypoglycemia (HH). The study was conducted by researchers at the University of Texas Health Science Center (UTHealth) at Houston, and led by two professors in the Department of Pathology and Laboratory Medicine at the UTHealth Medical School – Robert E. Brown, M.D., and Nina Tatevian, M.D. , Ph.D., along with Sanda Alexandrescu, M.D., a former pathology resident. The effects of the drug Sirolimus were tested on four children with HH at the Great Ormund Street Hospital in London.
HH is a condition that causes serum glucose levels in patients to fall below 60 units. Overactivity of beta cells in the pancreas produce excess insulin (neonatal hyperinsulinism) due to structural, functional, or genetic abnormalities in the glucose-sensing mechanisms in the body. This causes glycogenesis in high rates in hepatic and cellular muscles, leaving very little free glucose to be utilized. As a result, there is a reduction in the amount of free fatty acids (FFA), which are an alternate source of energy for the brain. Reduction in the CNS glucose levels (20-30 mg/dL) — a condition known as neuroglycopenia — leads to severe neurologic damage, seizures, and can eventually lead to permanent brain damage if not treated properly.
Raising blood glucose levels reverses this condition. However, in very serious cases where commonly prescribed drugs such as diazoxide and octreotide fail to normalize insulin levels, surgery becomes necessary. Surgical cures for HH involve partial or complete removal of the pancreas in order to curtain the excess of produced insulin. However, having done so, partial or total removal of the pancreas still does not guarantee a complete cure of the condition, since diabetic complications and consequences soon follow.
As an alternative to surgery in HH patients where traditional treatments have failed, a study carried out in 2010 in newborns by Brown, Tatevian and Alexandrescu explored the therapeutic effects of Sirolimus. It acted as an inhibitor for the overexpressed mTORC-1 (rapamycin) pathway, which was determined to be one of the more prominent markers of HH.
The four children at the Great Ormond Street Hospital had failed to respond to all available treatment options, with pancreatectomy as the last resort, which is when researchers opted to try Sirolimus as an alternate therapy. All four children responded well to the treatment.
Speaking on the potential of this treatment option, Michael Yafi, M.D., assistant professor and director of the Division of Pediatric Endocrinology at the UTHealth Medical School, as well as a member of the medical staff of Children’s Memorial Hermann Hospital, said, “The therapy for this condition has been historically frustrating since there are not many available medications that can be used for a long time. The study’s authors have used a new medication to treat this condition with great results in maintaining euglycemia one year post therapy. Time will prove if such medication will be able to save all neonates with such a condition from the need of pancreatectomy.”
Senthil Senniappan, M.D., lead author and clinical research fellow at Great Ormond Street Hospital, reported on the follow-up on these four children, saying, “One year on, all the patients are doing well with stable blood glucose levels and no significant side effects.” Khalid Hussain, M.D., senior author and consultant in endocrinology at Great Ormond Street Hospital, was quoted as saying, “Identifying the key pathways involved in hyperinsulinemic hypoglycemia has helped us to find the most suitable treatment for these patients. We hope that in the long-term, the treatment will lessen the severity of the condition, enabling patients to be moved onto more standard drugs such as diazoxide. This new discovery could change the way patients with the disease are managed in the future.”
Further research into morphoproteomics is currently underway in order to discover the molecular and genetic aspects of this condition, so that adjunctive therapies to Sirolimus treatment can be formulated, in order to further prevent the need for pancreatectomy.