The Effectiveness of Sirolimus Treatment in Two Rare Disorders with Nonketotic Hypoinsulinemic Hypoglycemia: The Role of mTOR Pathway

• Main Authors: Zeynep Şıklar, Tugba Çetin, Nilgün Çakar, Merih Berberoğlu
• Format: Article
• Language: English
• Published: Galenos Yayincilik 2020-12-01
• Series: JCRPE
• Subjects: akt2; pten; sirolimus; hypoglycemia; treatment
• Online Access: http://www.jcrpe.org/archives/archive-detail/article-preview/the-effectiveness-of-sirolimus-treatment-in-two-ra/36223
• ISSN: 1308-5727; 1308-5735

Nonketotic-hypoinsulinemic hypoglycemia (NkHH) is a very rare problem charcterized by increase in glucose consumption without hyperinsulinism. This disorder has mainly been reported in cases with <i>AKT2</i> mutation and rarely in cases with <i>PTEN</i> mutation. In cases with <i>PTEN</i> or <i>AKT2</i> mutation, there is no effective therapy other than frequent feeding to counter hypoglycemia. The mammalian target of rapamicin (mTOR) inhibitor, sirolimus, has been used in hyperinsulinemic hypoglycemia that was unresponsive to other medical treatment. In the insulin signaling pathway, both <i>AKT2</i> and PTEN function upstream of mTOR. However, the role of Sirolimus on hypoglycemia in <i>AKT2</i> and <i>PTEN</i> mutations is unknown. Case 1: Six month-old female with <i>AKT2</i> mutation [c.49G>A (p.E17K)] and evidence of NkHH. Frequent feeding was unsuccesful in correcting hypoglycemia and her proptosis continued to worsen. Sirolimus treatment was started at three years of age. Subsequently, blood glucose (BG) levels increased to normal levels. Case 2: In a male with PTEN mutation (p.G132V (c.395G>T), persistent NkHH started at 16 years of age (fasting BG: 27 mg/dL, fasting insulin 1.5 mmol/L, while ketone negative). Sirolimus treatment was started and hypoglycemia was succesfully controlled. NkHH is a very rare and serious disorder which is challenging, both for diagnosis and treatment. Additionally, <i>AKT2</i> and <i>PTEN</i> mutations may result in NkHH. Sirolimus treatment, through mTOR inhibition, appeared to be effectively controlling the peristent hypoglycemia and may be a life-saving therapy in this NkHH due to <i>AKT2</i> and <i>PTEN</i> mutations.