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Gene Mutations in Newborns Linked to Neonatal Diabetes Mellitus

  • Posted on May 14, 2015 by Pharma Models Blogging Team in Diabetes

Diabetes is a serious condition that affects the young and old. One of the most shocking realizations is when parents learn their newborn baby has a form of this disease. Neonatal diabetes mellitus presents itself in the first few months of a baby’s life as mild-to-severe hyperglycemia.

A published paper from The New England Journal of Medicine explains that there are two types of neonatal diabetes mellitus: a permanent one and a transient one. The former requires lifelong treatment while the latter departs with a possibility of relapse in adolescence.

The disease is associated with genetic mutations on a region of chromosome 6q24. Sometimes permanent neonatal diabetes mellitus is caused by abnormalities in the KCNJ11 gene, which incorrectly encodes a potassium-channel subunit present on the exterior of pancreatic beta cells.

The genetic mutation also affects ATP-sensitive potassium channels (KATP), which manage insulin release in pancreatic beta cells. The effects have decreased both calcium influx and insulin secretion.

Drs. Andrey Babenko and Michel Polak along with their team found that a mutant form of the gene Kir6.2 leads to neonatal diabetes in both mice and humans while abnormalities in the ABCC8 gene brings about persistent hyperinsulinemic hypoglycemia.

The researchers looked at 73 subjects from the French Network for the Study of Neonatal Diabetes Mellitus between the years 1995 to 2005. Out of the 73 patients, 44 were diagnosed with transient neonatal diabetes while 29 had permanent neonatal diabetes.

Babenko and his team tested the patients for mutations on chromosome 6q24 and in the KCNJ11 gene. The findings show that 25 patients had abnormalities in chromosome 6q24 while 13 patients had mutations in the KCNJ11 gene. The remaining 34 patients were screened for ABCC8 gene mutations including their familial relations. Informed parental consent was obtained from each family along with oral consent from children capable of giving assent.

During the clinical studies, two patients with permanent neonatal diabetes received a glyburide stimulation test and a glucagon stimulation test. The researchers kept track of glucose levels and, once metabolic control was attained, insulin was stopped.

The ABCC8 and KCNJ11 mutations of patients with transient neonatal diabetes mellitus were compared with differentiations of chromosome 6. The investigators found as many as seven heterozygous ABCC8 mutations in nine out of the 34 patients. Other animal models like the rat, mouse, and chicken were also compared with regard to their amino acids.

One subject with permanent neonatal diabetes exhibited developmental delays and motor problems including dyspraxia. There were no seizures or muscle weaknesses, however. Another patient showed dystonia while a subsequent one with transient neonatal diabetes displayed minor visual and spatial dyspraxia.

The overall research points to heterozygous activating mutations in ABCC8 causing both permanent and transient neonatal diabetes mellitus among newborns. The researchers discussed how their findings are consistent with previous reports explaining transgenic mice with a mutant Kir6.2 subunit and mutations in the KCNJ11 gene tend to develop neonatal diabetes. Once again, this type of study exhibits how vital preclinical animal models are to future discoveries within diabetes research.

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Categories: Diabetes

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