This document discusses a case of neonatal diabetes mellitus (NDM) in an infant. Key points: 1. The infant presented with hyperglycemia after birth and was diagnosed with NDM after ruling out other causes. 2. Treatment with NPH insulin was initially tried but glycemic control remained inadequate. 3. Insulin glargine was then started and provided much better glycemic control with no episodes of hypoglycemia. 4. NDM is a rare condition characterized by persistent hyperglycemia within the first month of life requiring insulin treatment. It can be transient or permanent and is caused by defects in insulin secretion or beta cell development.

1. NEONATAL DIABETES MELLITUS
Dr. C. Kannan
Postgraduate
Pediatrics
MGMCRI

2. CASE DETAILS
• NAME : B/O Jeevitha
• GA : 35+2 wks
• MOD : Emergency LSCS (Breech / Oligohydraminos)
• DOB : 08-04-17
• TOB : 4 : 31 PM
• APGAR : 7/10 @ 1 minute & 9/10 @ 5 minutes
• B. WT : 1.76 kg
• PERINATAL
• Respiratory distress – NICU stay for one day – Shifted
• One episode of hyperglycemia on D2 – 331 mg/dl
• On IVF 10% D – stopped
• Subsequent CBGs were normal

3. POSTNATAL HISTORY
On D2
• Shifted to ward / doing well
On D6
• USG – KUB – Mild B/L HUN
• USG – Sacrum – Normal (In V/O Sacral dimple)
• RFT / Electrolytes – Normal
• Weight loss 55 gms
• Shifted to stepdown NICU for supportive care

4. HYPERGLYCEMIA
On D9
• CBG @ 7 pm – 353 mg/dl
• CBG @ 8 pm – 364 mg/dl
• Biochemical value @ 8 pm – 424 mg/dl
• CBC done – counts were not S/O sepsis
• Stopped supplements ( HMF / MCT oil )
• Continued DBF
• CBG @ 11: 30 pm – 436 mg/dl
• CBG @ 6 am – 417 mg/dl
• U/O/P - > 4.7 ml/kg/hr

5. NICU
On D-10
• Shifted to NICU
• No family H/O diabetes mellitus in 2 generations
• Blood gas & urine ketones done showed normal
• Started on insulin bolus 0.1 U/kg Q4H
• Hyperglycemia (>200 mg/dl ) persisting despite of 3 boluses
• Insulin infusion started @ 0.8 ml/hr (0.05 U/kg/hr)

6. INSULIN INFUSION
On D-11
• CBG @ 7 am – 74 mg/dl
• Infusion stopped
• CBG @ 12.30 am – 300 mg/dl
• Infusion restarted
• CBG @ 4.30 am – 88 mg/dl
• Infusion stopped
• Sepsis screen sent & started on IV Cefotaxim / amikacin

7. FLUCTUATING SUGARS
On D12
• Infusion restarted in V/O hyperglycemia
• Still fluctuation of sugars persisting
• Endocrinology opinion sought
• Suggested intermediate insulin NPH 0.5 – 1 U/kg/day OD
• Genetic testing
• Email sent to UK for approval for sending sample
• USG – Abdomen – Normal study (To R/O pancreatic defect)

8. NPH
Day 13-16
• D13 – NPH 1 units, S/C, OD was given
• D14 – NPH 2 units, S/C, OD was given
• D15&16 – NPH 1 units, S/C, BD was given
• More than 3 CBG values are >300 mg/dl
• Regular insulin 0.05U/kg S/C stat given
• Most other values are >200 mg/dl
• Weight gain adequate / sensorium normal
• No episodes of hypoglycemia
• In V/O inadequate glycaemic
• Insulin glargine planned after referring literatures

9. GLARGINE – DAY - 1
On day 17
• Inj. Glargine insulin was given 2 units, S/C, OD
• 2 CBG values crossed 200 mg/dl
• Most other values are less than 200 mg/dl
• No CBG values crossed >300 mg/dl
• Weight gain 50 gms
• Inj. Cefotaxim + Amikacin restarted in V/O Reduced activity
• Sepsis screen sent/CRP –Ve/blood C/S awaited
• Urine O/P adequate

10. GLARGINE-DAY-2
On day 18
• Inj. Glargine insulin was given 2 units, S/C, OD
• one CBG values crossed 200 mg/dl
• Most other values are less than 110-120 mg/dl
• No CBG values crossed >300 mg/dl
• Weight gain 20 gms
• Excellent glycaemic control, hence shifted to step down NICU

11. HYPERGLYCEMIA
Common causes in neonates are
• ELBW
• Lipid infusion
• Metabolic stress
• Infection
• Medications
• Exogenous parenteral glucose
• Neonatal DM
• Pancreatic defect
• Hepatic immaturity
• Hypoxia
• Surgical procedures

12. Contd.,
VLBW (<1500 gms)
• Incidence as high as 20% to 86%
ELBW <1000 gms) associated with
• Development of IVH
• Necrotizing enterocolitis
• Retinopathy of prematurity
• Infection
• Late mortality

13. DIAGNOSIS
• Once we rule out other causes of hyperglycemia
• We can start doing work up for NDM
• Diagnostic modalities
• Sr. Insulin/C-peptide levels
• Molecular genetic testing

14. MOLECULAR GENETIC TESTING
• More than a dozen genes/loci associated with NDM
• Mutations can vary from one region to another worldwide
• Following mutations are commonly reported
• Glucokinase (GCK)
• Potassium channel J11 (KCNJ11)
• ATP–binding cassette transporter subfamily C member 8 (ABCC8)
• Insulin promoter factor 1 (IPF1)

15. Contd.,
• Mutations in the pancreatic ATP sensitive K+ channel proteins
• Sulfonylurea receptor 1 (SUR1)
• Inward rectifier K+ channel Kir 6.2 (Kir 6.2)
• May respond well to sulfonylurea therapy instead of insulin.

16. NEONATALDIABETESMELLITUS(NDM)
• NDM
• Persistent hyperglycemia
• Occurs within the first month of life
• Lasting at least 2 weeks
• Requiring management with insulin.
• Caused by defects in
• Insulin secretion
• Beta-cell development

17. NDM
Presents with
• Intrauterine growth retardation
• Volume depletion
• Profound hyperglycemia
• Glycosuria
• Polyuria
• Ketonuria
• Ketoacidosis

18. NDM
• NDM is subclassified into
• Transient neonatal diabetes mellitus (TNDM)
• Permanent neonatal diabetes mellitus (PNDM)
• Similar presenting symptoms in both
• Often requires further workup
• Incidence
• Very rare
• 1:300,000 to 500,000 live births.

19. PNDM
PNDM
• Accounts for 50% of all cases of NDM
• Mutations in K+ channels on pancreatic β cells
• Leads to decreased insulin secretion

20. TNDM
TNDM
• Accounts for remaining half of NDM cases.
• Between 60% and 80% of patients with TNDM
• Display genetic mutations
• Mostly chromosome-6 abnormalities
• Course of TNDM is highly variable
• Permanent resolution within the first several weeks or
• Months of life to recurrence later in childhood

21. LONG-TERM SEQUELAE
Long-term sequelae of either type
• Developmental delay
• Cardiac anomalies
• Seizures
• Poor weight gain
• Recurrence of diabetes at an older age.

22. CHALLENGES IN MANAGEMENT
• Compromise of calories, if glucose is withheld
• Lack of a pharmacokinetic profile for
• S/C administration of insulin in neonates
• Use of small doses that are highly error-prone
• Limited data for dilution of Insulins
• lack of subcutaneous fat deposits in a preterm/IUGR

23. S/C ROUTE & ABSORBTION
Absorption of drugs depends on
• Blood flow to the injection site
• Muscle mass
• Quantity of adipose tissue and muscle
Absorption may also be affected by
• pH of drug
• Ease of diffusion through capillary membranes
• Surface area over which the volume of injection spreads
S/C drug absorption in preterm are reduced
• Lower regional perfusion and reservoir mass

24. INSULIN
Rapid Acting Insulins
• Lispro
• Aspart
Short acting
• Insulin Glulisine
• Regular Insulin
Intermediate acting
• NPH- Neutral Protamine
• Hagedorn
• Pre mixed Insulins
Long Acting
• Glargine
• Detemir

25. INSULIN

26. NPH
• As per endocrinologist opinion
• NPH insulin started 1 units - OD – S/C
• On D2 changed to 2 units - OD – S/C
• On D3 changed to 1 units – BD – S/C
• Over 3 days
• In 24 hours 2-3 values were >300 mg/dl
• No hypoglycemia occurred
• No ketosis
• Weight gain +
• In V/O inadequate glycaemic control
• Unit team planned to start on glargine
• After referring from several literatures

27. GLARGINE
After S/C injection
• Onset 1-2 hrs
• Duration 2-22 hrs
• Disappearance 24 hrs
• Glargine forms microprecipitates at neutral pH
• Which gradually release active insulin monomers
• Over a 24-hour period
• Without a peak typically observed with insulin NPH/Detemir

28. Contd.,
• “The rarity of TNDM has limited the evidence available with which
to validate the use of subcutaneous insulin in neonates”
• “The experience with our patient indicates that the release pattern
of Glargine, as a truly “peak-less” insulin, may be most ideal for
TNDM management during the neonatal period and early infancy,
when patients are frequently or continuously fed”
www.ncbi.nlm.nih.gov/pmc/articles/PMC3385044/

29. THANK YOU