Dr. C. Kannan Resident MD Pediatrics, MGMCRI

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