1. What is Neonatal Diabetes?

Neonatal Diabetes mellitus is a relatively rare genetic disease (approximately 1 in 90,000 live births). It is characterized by the presence of severe hyperglycemia with insufficient or no circulating insulin, occurring mainly in infants before six months of age and rarely between 6 months and one year[source] .

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2. What are the types of Neonatal Diabetes?

Two clinical forms have been distinguished based on the duration of the treatment: a so-called “transient form” and a permanent form. In the transient form, treatment may be stopped anytime from the first weeks of life to 5 years of age. In the permanent forms, life-long therapy is necessary.

Two major groups of mechanisms explain the disease: malformation of the pancreas or abnormal function of the pancreatic β cell that secretes insulin (by poor insulin cell mass development) or malfunction of a cell component or by the destruction of the β cell) .

Most patients diagnosed with diabetes between 6 and 12 months of age will have the “typical” type 1 diabetes mellitus seen in older children with positive autoantibodies against the beta-cell. 

 Distinct molecular mechanisms do not always underpin the clinical difference between transient and permanent neonatal diabetes. Abnormalities of the 6q24 locus are exclusively linked to transient neonatal diabetes. However, mutations of the ABCC8, KCNJ11, and INS genes are linked to both permanent and transient forms

3. How does Neonatal Diabetes present?

Neonatal diabetes may not always present in the immediate neonatal period. 

Patients may present insidiously (with polyuria, polydipsia, or failure to thrive), acutely (with ketoacidosis or altered mental status), or incidentally without symptoms.

Neonatologists should become suspicious of diabetes when hyperglycemia persists for longer than seven to ten days. 

4. How is Neonatal Diabetes diagnosed?

 It is crucial to distinguish neonatal diabetes mellitus from other causes of hyperglycemia in the newborn. Other causes include infection, stress, and inadequate pancreatic insulin production in the preterm infant.

NDM should be considered in infants with insulin-dependent hyperglycemia, with blood glucose persistently greater than 250 mg/dL, without an alternative etiology.

The genetic analysis enables the diagnosis of monogenic diabetes in nearly 83% of diabetes diagnosed before six months. The genetic diagnosis is essential as it will both influence the treatment and make it possible to predict potential diabetes-related complications or illnesses. The genetic analysis must be carried out when diagnosing diabetes mellitus in all of the following children: age <6 months when diabetes mellitus is detected, or between 6 months and one year if extra-pancreatic features and/or no evidence of pancreas autoimmunity and/or multiple autoimmune disorders or unusual family history or associated congenital defects

5 . How is Neonatal Diabetes treated?

Monitoring is crucial. The treatment consists of the balance between a calorie and carbohydrate intake necessary to restore normal weight without being excessive to avoid the risk of future insulin resistance (15–18 g/kg/d carbohydrate) and sufficient insulin-based treatment to achieve the correct metabolic equilibrium.

Insulin-based treatment is challenging to manage due to the very low weight. The therapeutic margins between hypoglycemia and hyperglycemia are small, and both are harmful to the neurological development of the newborn. Using an insulin pump with or without dilution of the insulin to 1:10 in 0.9% NaCl (or with an appropriate diluent ) will improve the manageability of the insulin during the first weeks of life.

Patients with ABCC8 or KCNJ11 mutations are treated successfully using hypoglycemic sulfonylureas, which act by binding to the regulator SUR1 subunit of the potassium channel.

This emphasizes the importance of making a genetic diagnosis rapidly after diagnosing neonatal diabetes, especially the early introduction of sulphonylureas.

A trial of glyburide may be considered in newly diagnosed neonatal diabetes because of the relatively high chance of having a mutation responsive to treatment. 

Due to the potential neurocognitive effects of delaying therapy, a trial of sulfonylurea therapy can be considered even before a genetic diagnosis is made, although genetic testing must be done in all cases.

Long-term follow-up should be implemented, including for the so-called “transient” forms of neonatal diabetes.

Best Practices and Summary

• Neonatal diabetes mellitus is highly likely due to an underlying monogenic defect when it occurs under six months of age.
• Genetic testing should be pursued in an infant with neonatal diabetes, even if hyperglycemia resolves. An underlying monogenic cause can lead to significant differences in clinical management and is highly likely when diabetes is diagnosed under six months, and less likely but still possible in infants with diabetes between 6-12 months of age.
• Hyperglycemia due to stress or illness may occur in neonates, especially in those who are premature or have very low birth weight. Diagnosis of diabetes (and genetic testing) should be considered:
  • When hyperglycemia (glucose >250 mg/dL) persists beyond a few days without alternative explanation.
  • When true serum glucose levels exceed 300 mg/dL, regardless of the time course.
  • In any infant requiring insulin before 6-12 months of age.
• Sulfonylurea-responsive mutations are the most common causes of neonatal diabetes, and early treatment with sulfonylureas may improve neurocognitive deficits associated with these mutations. A sulfonylurea trial (glyburide) may be considered even before genetic testing results are available.

More on Diabetes:

Diabetes Care: The little Secret No One Tells You

Diabetes in ENT practice

Genes and Genetic Disorders: The Human Body for Kids

Cow Milk Pros and Cons

 Reference:

Nelson Text Book of Pediatrics