A clinical case of neonatal diabetes caused by INS gene mutation

Neonatal diabetes mellitus (NDM) is a severe endocrine pathology diagnosed in children during the first months of life. It comprises rare (1:300 000–1:400 000 newborns) metabolic disorders with postnatal pancreatic β-cell dysfunction, manifested by hyperglycaemia and hypoinsulinaemia. It is currently established that molecular genetic diagnosis of neonatal diabetes forms can influence treatment and prognosis. Interestingly, most identified mutations in the insulin gene are not inherited, but are sporadic. There is evidence that, in addition to heterozygous INS mutations, NDM can be caused by homozygous or compound-heterozygous mutations.

The present article presents the clinical case of a girl with NDM associated with an INS gene mutation. INS gene mutations cause permanent diabetes and require children to undergo genetic examination, especially patients with type 1 diabetes in the absence of antibodies.

Currently, there are no data that allow to determine a phenotypic and genotypic ‘portrait’ of NDM forms or to explain the factors determining their occurrence. Further studies of clinical cases of neonatal diabetes are therefore required to determine the characteristics of NDM subtypes with subsequent disease prognosis.

neonatal diabetes, permanent form, pump insulin therapy

1. De Franco E, Flanagan SE, Houghton JAL, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386(9997):957-963. doi: https://doi.org/10.1016/s0140-6736(15)60098-8

2. Grulich-Henn J, Wagner V, Thon A, et al. Entities and frequency of neonatal diabetes: data from the diabetes documentation and quality management system (DPV). Diabet Med. 2010;27(6):709-712. doi: https://doi.org/10.1111/j.1464-5491.2010.02965.x

3. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1. doi: https://doi.org/10.1186/2046-4053-4-1

4. Petropoulos AC, Xudiyeva A, Ismaylova M. Congenital Heart Disease and Maternal Diabetes Mellitus. Int J Diabetes Clin Diagn. 2016;3:118. doi: https://doi.org/10.15344/2394-1499/2016/118

5. Avital-Shmilovici M, Whittaker J, Weiss MA, Kent SB. Deciphering a molecular mechanism of neonatal diabetes mellitus by the chemical synthesis of a protein diastereomer, [D-AlaB8]human proinsulin. J Biol Chem. 2014;289(34):23683-23692. doi: https://doi.org/10.1074/jbc.M114.572040

6. Nansseu JR, Ngo-Um SS, Balti EV. Incidence, prevalence and genetic determinants of neonatal diabetes mellitus: a systematic review and meta-analysis protocol. Syst Rev. 2016;5(1):188-194. doi: https://doi.org/10.1186/s13643-016-0369-3

7. Docherty LE, Kabwama S, Lehmann A, et al. Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients. Diabetologia. 2013;56(4):758-762. doi: https://doi.org/10.1007/s00125-013-2832-1

8. Rearson MA, McKnight-Menci H, Steinkrauss L. Neonatal diabetes: current trends in diagnosis and management. MCN Am J Matern Child Nurs. 2011;36(1):17-22; quiz 23-14. doi: https://doi.org/10.1097/NMC.0b013e3181fc06cd

9. Deeb A, Habeb A, Kaplan W, et al. Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates. Am J Med Genet A. 2016;170(3):602-609. doi: https://doi.org/10.1002/ajmg.a.37419

10. Globa E, Zelinska N, Mackay DJ, et al. Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment. J Pediatr Endocrinol Metab. 2015;28(11-12):1279-1286. doi: https://doi.org/10.1515/jpem-2015-0170

11. Avital-Shmilovici M, Mandal K, Gates ZP, et al. Fully convergent chemical synthesis of ester insulin: determination of the high-resolution X-ray structure by racemic protein crystallography. J Am Chem Soc. 2013;135(8):3173-3185. doi: https://doi.org/10.1021/ja311408y

12. Mackay DJ, Temple IK. Transient neonatal diabetes mellitus type 1. Am J Med Genet C Semin Med Genet. 2010;154C(3):335-342. doi: https://doi.org/10.1002/ajmg.c.30272

13. Menting JG, Whittaker J, Margetts MB, et al. How insulin engages its primary binding site on the insulin receptor. Nature. 2013;493(7431):241-245. doi: https://doi.org/10.1038/nature11781

14. Habeb AM, Al-Magamsi MS, Eid IM, et al. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia. Pediatr Diabetes. 2012;13(6):499-505. doi: https://doi.org/10.1111/j.1399-5448.2011.00828.x

15. Sovik O, Aagenaes O, Eide SA, et al. Familial occurrence of neonatal diabetes with duplications in chromosome 6q24: treatment with sulfonylurea and 40-yr follow-up. Pediatr Diabetes. 2012;13(2):155-162. doi: https://doi.org/10.1111/j.1399-5448.2011.00776.x

16. Wiedemann B, Schober E, Waldhoer T, et al. Incidence of neonatal diabetes in Austria-calculation based on the Austrian Diabetes Register. Pediatr Diabetes. 2010;11(1):18-23. doi: https://doi.org/10.1111/j.1399-5448.2009.00530.x

17. Kim YH, Kastner K, Abdul-Wahid B, Izaguirre JA. Evaluation of conformational changes in diabetes-associated mutation in insulin a chain: a molecular dynamics study. Proteins. 2015;83(4):662-669. doi: https://doi.org/10.1002/prot.24759

18. Letourneau LR, Carmody D, Philipson LH, Greeley SAW. Early Intensive Insulin Use May Preserve beta-Cell Function in Neonatal Diabetes Due to Mutations in the Proinsulin Gene. J Endocr Soc. 2018;2(1):1-8. doi: https://doi.org/10.1210/js.2017-00356

19. Naylor RN, Greeley SA, Bell GI, Philipson LH. Genetics and pathophysiology of neonatal diabetes mellitus. J Diabetes Investig. 2011;2(3):158-169. doi: https://doi.org/10.1111/j.2040-1124.2011.00106.x

20. Iafusco D, Massa O, Pasquino B, et al. Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births. Acta Diabetol. 2012;49(5):405-408. doi: https://doi.org/10.1007/s00592-011-0331-8