Morphoproteomics and biomedical analytics coincide with clinical outcomes in supporting a constant but variable role for the mTOR pathway in the biology of congenital hyperinsulinism of infancy
© The Author(s). 2017
Received: 21 July 2017
Accepted: 6 December 2017
Published: 16 December 2017
We first introduced the concept of the mTOR pathway’s involvement in congenital hyperinsulinism of infancy (CHI), based largely on morphoproteomic observations and clinical outcomes using sirolimus (rapamycin) as a therapeutic agent in infants refractory to octreotide and diazoxide treatment. Subsequent publications have verified the efficacy of such treatment in some cases but limited and variable in others. We present further evidence of a constant but variable role for the mTOR pathway in the biology of CHI and provide a strategy that allows for the short-term testing of sirolimus in individual CHI patients.
The severe form of diffuse hyperinsulinemic hypoglycemia is mainly associated with mutations in ABCC8 and KCNJ11 that are unresponsive to diazoxide and/or octreotide therapy [1, 2]. This poses a threat to the infants with CHI not only by causing potential neurological damage leading to epilepsy, cerebral palsy and adverse neurological development in up to 40% of cases [3, 4] but also necessitating in some, near total pancreatectomy. Furthermore, 59% of such surgically treated patients can show persistent hyperinsulinemic hypoglycemia for up to 5 years post-surgery, and eventually diabetes mellitus will be manifested in all by the time they reach early adolescence .
Biomedical analytics using Ingenuity Pathway Analysis and data mining of the National Library of Medicine’s Medline Data Base confirms the role of the mTOR pathway  in the biology of CHI with actionable therapeutic targets. A CHI network was constructed using the known CHI-associated genes described by Dunne and Banerjee’s associates : GLUD1, SLC16A1, HADH, UCP2, KCNJ11, ABCC8, HNF1A, GCK, HNF4A.
Parenthetically, the contention by Banerjee and colleagues  that mTOR mRNA equates to mTOR gene in pancreases from normal, focal CHI, and diffuse CHIexpression could be accurate. Alternatively in the context of the morphoproteomic evidence of variable but constant activation and overexpression of the mTOR pathway in pancreases from diffuse CHI, it could represent the resultant of a steady state of transcription, translation and utilization of mTOR mRNA  following the integration of genomic, proteomic and pathway biology. Notably pathway ontology associated with the CHI disease network includes mTOR signaling . Moreover, the clinical outcomes coincide with the findings of a variable therapeutic success in using sirolimus in the treatment of CHI [2, 12–18]. In the context of risk [3–5] versus benefit, we hold that severe diffuse CHI infants deserve a trial with an appropriate dose of sirolimus to see whether it is effective keeping in mind and monitoring for the potential immunosuppressive and adverse consequences of sirolimus . We agree that sirolimus with or without other combinatorial therapies (octreotide, nifedipine, exendin-(9-39) and metformin) to counter the variable but constant activation of the mTOR biology in CHI should be explored in larger clinical trials.
The authors thank Pamela K Johnston, HT, ASCP for her technical expertise and Ms. Bheravi Patel for help with the graphics.
The authors have no financial relationships relevant to this article to disclose. Funding has been provided through the morphoproteomic initiative as part of the Harvey S. Rosenberg, M.D. Endowed Chair in Pathology and Laboratory Medicine.
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REB and MFM drafted the initial manuscript and co-wrote the final manuscript. SS and KH critically reviewed the manuscript and co-wrote the final manuscript. All authors approved the final manuscript as submitted.
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