1. Diabetes Mellitus in the Pediatric Population
Sioksoan Chan-Cua, MD
Pediatric Endocrinologist
S Chan-Cua

2. Diabetes Mellitus in the Pediatric Population
Diagnosis
Types and Pathophysiology
Clinical Presentation
Management
Acute complications
Diagnose diabetes mellitus in the children and adolescents
Provide diabetes care of children and diabetes
Manage acute complications (I) – diabetic ketoacidosisManage
acute complications (II) – hypoglycemia
“ The incidence of Type 1 diabetes in children age 0-14 years old in our country in 1998 is 0.41/100,000 population “
Prevalence of Type 1 DM in Childhood And Adolescent in Metro Manila, Philippines;
Diabetes Watch; July-December 2000
S Chan-Cua

3. Diabetes Mellitus (DM)
A heterogeneous group of disorders
Insulin production and/or insulin action  hyperglycemia
S Chan-Cua

4. Diagnosis of DM Diseases of abnormal carbohydrate metabolism
FPG 126 mg/dl (7.0 mmol/l)
RBS 200 mg/dl (11.1 mmol/l) & symptoms of DM
2-h plasma glucose 200mg/dl (11.1mmol/l) during an OGTT
The FPG is the preferred test to diagnose diabetes in children and nonpregnant adults.
The American Diabetes Association (ADA)
The diagnosis is based on one of three abnormalities: fasting plasma glucose, random elevated glucose with symptoms, or abnormal oral glucose tolerance test (OGTT)
The 2003 criteria lowered the fasting plasma glucose level used to define impaired fasting glucose (IFG) from the 1997 criteria but maintained the same definitions for diabetes and for impaired glucose tolerance (IGT) as measured by an oral glucose tolerance test
Patients with IFG and/or IGT are now referred to as having "pre-diabetes" indicating the relatively high risk for development of diabetes in these patients
FPG AND OGTT AS PREDICTORS OF DIABETES — Although the natural history of IFG and IGT is variable, approximately 25 percent of subjects with either will progress to diabetes over three to five years. Subjects with additional diabetes risk factors, including obesity and family history, are more likely to develop diabetes.
S Chan-Cua

5. Clinical Presentation
Polyuria, polydipsia, polyphagia and unexplained weight loss
S Chan-Cua

6. Clinical Presentations of DM
Non-emergency:
Recent onset of enuresis in a previously toilet-trained child
Vaginal candidiasis, especially in prepubertal girls
Vomiting
Irritability and decreasing school performance
Recurrent skin infections
Emergency: DKA
S Chan-Cua

7. Classification and Pathophysiology
TYPE
PATHOPHYSIOLOGY /
Insulin secretion (IS) / Insulin resistance (IR)
Type 1
Autoimmune destruction of β cells
Type 2
↑ IR and β cell insufficiency
Monogenic
↓ IS
Secondary
Various: ↓ IS, ↑ IR
S Chan-Cua

8. T1DM Triggering factors Genes DIABETES Susceptibility Autoantigens
β cell
specific
autoimmunity
Autoantigens
Triggering factors
Susceptibility
Autoantibodies
Genes
Viruses
Toxins
Diet
DIABETES
S Chan-Cua

9. T1DM
Type 1 DM
characterized by destruction of the pancreatic beta cells, leading to absolute insulin deficiency
autoimmune destruction of the pancreatic beta cells
autoantibodies to
islet-cell (ICA)
glutamic acid decarboxylase (anti-GAD)
Insulin (IAA)
tyrosine phosphatase IA-2
Markers of pancreatic autoimmunity
islet cell antibodies (ICA)
glutamic acid decarboxylase antibodies (GADA)
insulin autoantibodies (IAA)
tyrosine phosphatase-like protein autoantibodies
often absent in T2DM, monogenic diabetes and medication-induced diabetes
S Chan-Cua

10. T1 DM Local study (Metro Manila, 1998-1999) 99 children (1-14 yr)
56 girls
33 boys
Prevalence:
2.8 cases /100,000
Incidence:
0.55 – 0.60 cases /100,000
S Chan-Cua
Sy RA, Chan-Cua S, 1999

11. 47% overweight, 16% obese (Definition/ cut-off: Cole TF. BMJ. 2000)
Eppens MC, et al. Current Medical Research and Opinion®
Vol. 22, No.5 , 2006, 1013–1020
Type 2 diabetes in youth from the Western Pacific region: glycemic control, diabetes care and complications
Philippines:
Age of onset: 11 (9-13) yr;
M:42%, F 58%;
47% overweight, 16% obese (Definition/ cut-off: Cole TF. BMJ. 2000)
S Chan-Cua

12. T2DM Characterized by Insulin resistance secretory defect
Obesity (BMI >95thP for age & gender)
Family hx: T2DM in a 1st or 2nd degree relative
High-risk ethnic group (e.g., Aboriginal, African, Hispanic, South-Asian)
A history of exposure to DM in utero
Acanthosis nigricans (insulin resistance)
Polycystic ovarian syndrome (PCOS) 
Unraveling non-type 1 diabetes mellitus in childhood
Shazhan Amed, MD, The Hospital for Sick Children
Heather Dean, MD, Winnipeg Children’s Hospital
Jill Hamilton, MD, The Hospital for Sick Children
In the normoglycemic, insulin sensitive individual, there is a precise balance between insulin secretion and insulin sensitivity.
Data on the pathophysiology of T2DM in children are sparse.
S Chan-Cua

13. T1 & T2 DM in children and adolescents
Type 1
Type 2
Age of onset
Throughout childhood
Pubertal
Prominent race
All (low in Asians)
Asians
Onset
Acute, severe
Subtle to severe
Islet autoimmunity
Present
Unusual
Insulin secretion
Very low
Variable
Insulin sensitivity
Normal
Decreased
Ketosis, DKA at onset
Common, up to 40%
Uncommon
Obesity
As in population
>90%
% of probands with affected 1o relatives
5-10%
~80%
Mode of inheritance
Non-Mendelian, gen’ly sporadic
Non-Mendelian, strongly familial
S Chan-Cua

14. Differentiating T1 from T2DM in Children and Adolescents
Demographics
Type 1
Type 2
Family history
3-5% %
Age or pubertal status
Variable
>10 yr or pubertal
Presentation
Asymptomatic
Rare
Common
Symptom duration
Days or weeks
Weeks or months
Physical findings
BMI at diagnosis
≤ 75th P
≥ 85th P
Acanthosis nigricans No
Insulin/ C-peptide
Low (may be normal early)
Normal-high
S Chan-Cua

15. Monogenic diabetes - MODY
Maturity onset diabetes of the young (MODY)
Autosomal dominant -
(+) Family history
Account for 1–5% of all cases of diabetes
Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 1995;38(12):1482.
6 causative gene mutations in insulin and glucose regulation and pancreatic beta cell function
Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001;345(13):971-80
Genetic defects of beta-cell function — Approximately two to five percent of patients with type 2 diabetes present at a young age, have mild disease, and autosomal dominant transmission. This condition was formerly called maturity-onset diabetes of the young MODY [14] . These patients are quite heterogeneous and clinical characteristics are not reliable in predicting the underlying pathogenesis [15,16 UpToDate] .
Six different genetic abnormalities have been identified with types 3 and 2 accounting for 65 and 15 percent of cases, respectively [16] . Some members of a family have the genetic defect but do not develop diabetes; the reason for this is unclear.
In the new classification, the MODY subtypes have been eliminated, and replaced by specific descriptions of the known genetic defects. It is anticipated that other subtypes of type 1 and type 2 diabetes will become more clearly defined in the future.
References
1. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9.
2. Ho J, Pacaud D. Secondary diabetes in children. Can J Diabetes 2004;28(4):400-5.
3. Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8.
4. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol 2002;17(4):
5. Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 1995;38(12):1482.
6. 7. Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001;15(3):
8. Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002;25(12):
9. Canadian Diabetes Association 2003 Clinical Practise Guidelines for the Prevention and Management of Diabetes in Canada: Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories. Can J Diabetes 2003;27(supplement 2):S7-S9.
10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8):
11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102.
S Chan-Cua

16. Monogenic Diabetes - MODY
Genetic defects of β-cell function
MODY 1
MODY 2
MODY 3
MODY 4
MODY 5
MODY 6
Gene mutated
Hepatocyte nuclear factor 4 α (HNF-4a)
Glucokinase (GCK) - mild
Hepatic nuclear factor 1 α (HNF-1α)
early treatment with insulin
Insulin promoter factor-1 (IPF1)
Hepatic transcription factor 1 b (HNF-1b)
Neuro D1
Chromosome 20 7 12 13 17 2
Hepatocyte nuclear factor-4-alpha — Mutations in the (HNF-4-alpha) gene on chromosome 20 cause the condition formerly called MODY1 [17] . HNF-4-alpha is expressed both in the liver and in pancreatic beta cells. One of its functions is to regulate positively the activity of HNF-1-alpha, the affected gene in the previously labeled MODY3 syndrome. The precise mechanism by which a defect in HNF-4-alpha causes hyperglycemia is not clear, but it has been associated with a reduced insulin secretory response to glucose, suggesting a primary genetic defect in insulin secretion [18-20] .
Although HNF-4-alpha plays a central role in the hepatic synthesis of lipoprotein and coagulation proteins, these functions are largely maintained in HNF-4-alpha diabetes, suggesting that this disorder is primarily one of impaired pancreatic beta-cell function [19] .
Glucokinase gene — Over a dozen mutations in the glucokinase gene on chromosome 7 have been described, and were formerly called MODY2 [21] . Defects in the expression of glucokinase, which phosphorylates glucose to glucose-6-phosphate and probably acts as a glucose sensor, result in deficient insulin secretion. On occasion, the expressed enzyme functions but is unstable, again leading to an insulin secretory deficit [22] . (See "Insulin secretion and pancreatic beta-cell function").
Markers in the glucokinase locus have been linked to type 2 diabetes in American blacks [23] and some other ethnic groups, but not in whites. The resulting hyperglycemia is often mild and is not associated with the vascular complications that are so common in other types of diabetes mellitus [24] .
Hepatocyte nuclear factor-1-alpha — One of several mutations in the HNF-1-alpha gene on chromosome 12 was formerly called MODY3 [25] . This form of diabetes is more common among European patients [26,27] . HNF-1-alpha is a weak transactivator of the insulin gene in beta cells. Mutations of HNF-1-alpha can lead to abnormal insulin secretion; whether this or some other action is defective enough to cause diabetes mellitus is unclear [27] . Prior to onset of diabetes, mutation carriers have detectable glycosuria provoked by glucose loading [28] . Testing for glycosuria two hours after a glucose load could be used to screen children of mutation carriers and guide the need for further evaluation.
Patients with HNF-1-alpha diabetes have increased insulin sensitivity and marked sensitivity to the hypoglycemic effects of sulfonylureas compared to metformin (fall in FPG 85 versus 16 mg/dL [4.7 versus 0.9 mmol/L]) and compared to patients with type 2 diabetes (3.9 fold greater reduction in FPG) [29] .
Insulin promoter factor 1 — Mutations in the insulin promoter factor 1 (IPF-1) gene can lead to what was called MODY4 by reduced binding of the protein to the insulin gene promoter [30,31] and perhaps by altering fibroblast growth factor signaling in beta cells [32] . Less severe mutations in IPF-1 may predispose to late onset type 2 diabetes [31,33] . In addition, nondiabetic carriers have higher blood glucose concentrations and lower insulin-to-glucose ratios than nondiabetic family members without a mutation [34] .
Hepatocyte nuclear factor-1-beta — Mutations in the HNF-1-beta gene produce a syndrome that was formerly called MODY5 [35-38] . Affected patients can develop a variety of manifestations in addition to early onset diabetes. These include pancreatic atrophy (on CT scan), abnormal renal development (renal dysplasia that can be detected on ultrasonography in the fetus, single or multiple renal cysts, glomerulocystic disease, oligomeganephronia), slowly progressive renal insufficiency, elevated serum aminotransferases, and genital abnormalities (epididymal cysts, atresia of vas deferens, and bicornuate uterus) [36] . (See "Renal cystic diseases in children" section on Cortical cystic diseases).
In addition, some patients have a phenotype consistent with familial juvenile hyperuricemic nephropathy [39] . (See "Uric acid renal diseases", section on Familial juvenile hyperuricemic nephropathy).
One of the functions of HNF-1-beta is the regulation of tissue-specific gene expression. In the kidney, the proximal promoter of the Pkhd1 gene has a binding site for HNF-1-beta. Mutations in HNF-1-beta inhibit the expression of Pkhd1 and lead to cyst formation [38] . This is not surprising since mutations in Pkhd1 are responsible for the autosomal recessive form of polycystic kidney disease. (See "Autosomal recessive and dominant polycystic kidney disease in children", section on Pathogenesis).
Neurogenic differentiation factor-1 — Mutations in the gene for neurogenic differentiation factor-1 (also called NEUROD1 or BETA2) can lead to what was called MODY6 [40,41] . NEUROD1 normally functions as a regulatory switch for endocrine pancreatic development.
References
1. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9.
2. Ho J, Pacaud D. Secondary diabetes in children. Can J Diabetes 2004;28(4):400-5.
3. Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8.
4. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol 2002;17(4):
5. Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 1995;38(12):1482.
6. 7. Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001;15(3):
8. Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002;25(12):
9. Canadian Diabetes Association 2003 Clinical Practise Guidelines for the Prevention and Management of Diabetes in Canada: Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories. Can J Diabetes 2003;27(supplement 2):S7-S9.
10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8):
11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102.
Confirmed diagnosis by genetic testing
S Chan-Cua
Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001;15(3):309-23

17. Monogenic Diabetes - MODY
Resembles T2DM
Relatively mild
May need no insulin
(-) antibodies
Different from T2DM
not obese
not insulin resistant
S Chan-Cua

18. Monogenic diabetes - NDM
Neonatal Diabetes Mellitus (NDM): β-cell dysfunction
Transient
Half of NDM
No need of insulin after a few weeks or months of age
2 genes (chromosome 6q24) HYMA1 and ZAC expressed only from paternal copy
A double dose of one or both genes
Permanent – diverse etiology
Mutation of KCNJ11 gene
Encoding Kir6.2, a β-cell K channel crucial in regulation of insulin
Response to sulfonylureas (glibenclamide/ glyburide)
Mutations of EIF2AK3 gene
S Chan-Cua

19. NDM - Mutation of KCNJ11 Gene Encoding Kir6.2
Insulin secretion
NORMAL
No insulin exocytosis
NDM
Abnormal KATP channels with ↑open probability
Hyperpolarization
Diabetes, in neonatal period
KATP channels affect insulin secretion - its closure is a central step in glucose-stimulated insulin release
Targeted overactivity of ß-cell KATP channels induces profound NDM
S Chan-Cua

20. NDM - Wolcott-Rallison syndrome (WRS)
Mutations of EIF2AK3 gene –
pancreatic eukaryotic initiation factor 2 kinase (2p12) AR
Neonatal onset / < 6 months
Multiple epiphyseal dysplasia
Convulsions
Retarded development
Short stature
Liver disease
Nephropathy
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by the association of
permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation,
and other variable multisystemic clinical manifestations.
Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2 (eIF2) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With
the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions
of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and
sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and
found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably,
the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective
EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with
other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other
variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity
between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity. Diabetes
53:1876–1883, 2004
S Chan-Cua
TD Manna. J Pediatr (Rio J). 2007;83(5 Suppl):S
Valerie Senee, et al.Diabetes 53:1876–1883, 2004

21. Genetic Defects/ Syndromes
Genetic defects in insulin action
Type A insulin resistance
Leprechaunism
Rabson-Mendenhall syndrome
Lipoatrophic diabetes
Genetic Syndromes
Down syndrome
Klinefelter syndrome
Turner syndrome
Prader-Willi syndrome
Wolfram syndrome (DIDMOAD)
DI, DM, optic nerve atrophy, sensorineural deafness
Wolfram syndrome (DIDMOAD) is characterized by the presence of diabetes insipidus, DM, atrophy of the optic nerve
and sensorineural deafness and has autosomal recessive inheritance associated with non-immunological degeneration
of pancreatic beta cells. The WSF-1 gene linked to the syndrome is located on chromosome 4.17
Clinical manifestations include:
- DM (mean age 8.2 years);
- Atrophy of the optic nerve (mean age 13.1 years);
- Diabetes insipidus (mean age 14.1 years);
- Sensorineural deafness (mean age 15 years);
- Neurological degeneration (atrophy of the central nervous system seen on magnetic resonance imaging);
- Psychiatric disorders;
- Death (mean age 28 years).
S Chan-Cua

22. Medication-induced DM
Glucocorticoids- severe hyperglycemia requiring insulin therapy
Chemo-therapeutic agents (L-asparaginase) and immunosuppressants (cyclosporine and tacrolimus)
direct pancreatic beta cell toxicity
interference with insulin secretion
induction of insulin resistance
Atypical anti-psychotics and anti-seizure medications
Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8.
References
1. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9.
2. Ho J, Pacaud D. Secondary diabetes in children. Can J Diabetes 2004;28(4):400-5.
3. Lindenmayer JP, Nathan AM, Smith RC. Hyperglycemia associated with the use of atypical antipsychotics. J Clin Psychiatry 2001;62 Suppl 23:30-8.
4. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol 2002;17(4):
5. Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 1995;38(12):1482.
6. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001;345(13):
7. Owen K, Hattersley AT. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 2001;15(3):
8. Sellers EA, Triggs-Raine B, Rockman-Greenberg C, Dean HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care 2002;25(12):
9. Canadian Diabetes Association 2003 Clinical Practise Guidelines for the Prevention and Management of Diabetes in Canada: Definition, Classification and Diagnosis of Diabetes and Other Dysglycemic Categories. Can J Diabetes 2003;27(supplement 2):S7-S9.
10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8):
11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102.
S Chan-Cua

23. Mostly ↑ counter-regulatory hormone effects
Endocrine Diosorders
Mostly ↑ counter-regulatory hormone effects
Acromegaly
Cushing's syndrome
Glucagonoma
Pheochromocytoma
↓ glucose uptake/ ↑ gluconeogenesis
↓ glucose uptake
↑ gluconeogenesis/ ↑ glycogenolysis
↓ glucose uptake/ ↑ glycogenolysis
S Chan-Cua

24.
S Chan-Cua

25. Summary
T1DM is generally seen in lean children with pancreatic autoimmunity.
T2DM is generally seen in obese children with insulin resistance
Monogenic DM generally have a strong family history of diabetes affecting multiple generations, a classically normal weight, and do not have features of insulin resistance or evidence of pancreatic autoimmunity
Secondary DM: Medication-induced DM is diagnosed when hyperglycemia develops following the initiation of a known diabetogenic medication
10. Sellers EA, Dean HJ. Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth. Diabetes Care 2000;23(8):
11. Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001;107(6):E102.
S Chan-Cua

26. DM Children differ from adults
Insulin sensitivity related to sexual maturity
Physical growth
Ability to provide self-care
Neurologic vulnerability to hypoglycemia
S Chan-Cua

27. Principles of DM Management
Aims –
To attain good glycemic control
To ensure normal growth (height & weight)
To prevent acute complications
To prevent long-term vascular complications
S Chan-Cua

28. Management of Diabetes Mellitus
Monitoring
Nutrition Exercise/
Insulin/ OHA Sport
Multidisciplinary team of specialists
Child & Family
S Chan-Cua

29. Insulin Types and Action Profiles
Rapid- acting
Short-acting
Intermediate –acting (NPH)
Intermediate-acting (Lente)
Long-acting
Premixed (75/25)
Premixed (70/30)
Premixed (50/50)
Make a choice
Combination
Teach injection
How
Where
Dosage
0.5-1 U/ kg / day
S Chan-Cua

30. Plasma blood glucose goals for T1DM by age-group
Values by age (years)
Plasma glucose goal range before meals
Plasma glucose goal range at bedtime
Toddlers and preschoolers
(0 – <6)
100–180
110–200
School age
(>6 –12)
90–180
Adolescents and young adults (13–19)
90–130
90–150
In toddlers and prescchool group: High risk and vulnerability to hypoglycemia
In school age group: Risks of hypoglycemia and relatively low risk of complications prior to puberty
In adolescents group:
● Risk of severe hypoglycemia
● Developmental and psychological
issues
● A lower goal (7.0%) is reasonable if
it can be achieved without excessive
hypoglycemia
S Chan-Cua

31. Diabetes Mellitus in the Pediatric Population
Acute Complications
DKA
S Chan-Cua

32. DKA – Presenting S/Sx and Diagnosis
Polyuria
Polydipsia
Weight loss
Tiredness
Abdominal pain
Vomiting
Confusion
Dehydration
Deep sighing respiration (Kussmaul)
Smell of ketones
Disordered sensorium
Shock and hypotension
The biochemical criteria:
Hyperglycemia
(BG >11 mmol/L = 200 mg/dL)
Venous pH <7.3
Bicarbonate <15 mmol/L
Ketonemia and ketonuria
Clinical History
Polyuria
Polydipsia
Weight loss (Weigh)
Abdominal pain
Tiredness
Vomiting
Confusion
The biochemical criteria for the diagnosis of DKA
are (4):
¤ Hyperglycemia (blood glucose . 11 mmol/L [200
mg/dL])
¤ Venous pH , 7.3 or bicarbonate , 15 mmol/L
¤ Ketonemia and ketonuria
S Chan-Cua

33. Decreased Glucose Utilization &
Islets of
Langerhans
b-cell destruction
Insulin Deficiency
Epi,Cortisol GH
Decreased Glucose Utilization &
Increased Production
Stress
Glucagon
Muscle
Liver
Increased
Protein
Catabolism
Adipocytes
Increased
Ketogenesis
Gluconeogenesis,
Glycogenolysis
Increased Lipolysis
Polyuria
Volume Depletion
Ketonuria
Threshold
180 mg/dl
Hyperglycemia
Ketoacidosis
HyperTG
S Chan-Cua

34. Management of DKA Assess clinical severity of dehydration
Assess level of consciousness
Obtain a blood sample for laboratory measurement of
glucose, electrolytes, ketones
venous / arterial (in critically ill patient) pH, HCO3, PCO2
BUN, Cr, osmolality
CBC
an ↑ WBC count in response to stress is characteristic of DKA and is not indicative of infection
HbA1c
Check urine for ketones
S Chan-Cua

35. Management of DKA Provide fluid therapy to correct dehydration
Correct electrolyte imbalance and acidosis
Give insulin to restore blood glucose to near normal
Monitor blood glucose
Correct dehydration
Correct acidosis and reverse ketosis
Restore blood glucose to near normal
Avoid complications of therapy
Identify and treat any precipitating event
S Chan-Cua

36. DKA
The 3 useful signs for assessing dehydration in young children and predicting acidosis are:
prolonged capillary refill time
(normal capillary refill is 1.5–2 s)
abnormal skin turgor (tenting or inelastic skin)
abnormal respiratory pattern (hyperpnea)
10% dehydration is suggested by the presence of
weak or impalpable peripheral pulses
hypotension
oliguria
The 3 most useful signs for assessing dehydration in young children and predicting at least 5% dehydration and acidosis are:
s prolonged capillary refill time (normal capillary
refill is 1.5–2 s)
s abnormal skin turgor (tenting’ or inelastic skin)
s abnormal respiratory pattern (hyperpnea)
Other useful signs in assessing degree of dehydration
include dry mucus membranes, sunken eyes,
absent tears, weak pulses, and cool extremities.
S Chan-Cua

37. Fluid Therapy Begin with fluid replacement before insulin therapy
Volume expansion (resuscitation) is required only if needed to restore peripheral circulation
Subsequent fluid administration (including oral fluids) should rehydrate evenly over 48 h at a rate rarely in excess of 1.5–2 times the usual daily maintenance
S Chan-Cua

38. Fluid Therapy Calculate fluid requirements Correct over 48 hours
NSS (Saline) 0.9%
A failure of measured serum Na levels to ↑, or a further ↓ in serum Na levels with therapy is thought to be a potentially ominous sign of impending cerebral edema
When CBG <250 mg/dl, may add 5% glucose
Monitor urine output
S Chan-Cua

39. Insulin Insulin drip at 0.1 U / kg / hour
10 U regular insulin +100 ml NSS
(1 U insulin in 10 ml solution)
10 kg child: 0.1 x 10 = 1U insulin / 10 ml NSS /hr
10 U regular insulin +10 ml NSS
(1 insulin in 1 ml solution)
30 kg child: 0.1 x 30 = 3U insulin / 3 ml NSS /hr
S Chan-Cua

40. Correction of Electrolytes Imbalance
Even with normal or high levels of serum K at presentation, there is always a total body deficit of K
Add KCl 20 – 40 mmol K/ L IVF
If the patient is hyperkalemic, defer K replacement therapy until urine output is documented
S Chan-Cua

41. Bicarbonate administration
Generally, not needed
Patients with severe acidemia (pH < 6.9) in whom
decreased cardiac contractility and peripheral vasodilatation can further impair tissue perfusion
patients with life-threatening hyperkalemia
There is no evidence that bicarbonate is either necessary or safe in DKA.
S Chan-Cua

42. Anion gap = Na - (Cl + HCO3)
normal is 12 ± 2 mmol/L
In DKA the anion gap is typically 20–30 mmol/L;
an anion gap >35 mmol/L suggests concomitant lactic acidosis
Na corrected = Na measured +2 x ([glucose - 5.6] / 5.6) mmol/L
Effective osmolality = 2 x (Na + K) + glucose mOsm/kg
S Chan-Cua

43. Supportive measures Secure the airway
Give oxygen to patients with severe circulatory impairment or shock
Insert NGT – to empty the stomach
Place a peripheral IV catheter
Use a cardiac monitor for continuous ECG monitoring to assess T waves for evidence of hyper- or hypo-K
Place urinary catheter to monitor urine output
Give antibiotics to febrile patients after obtaining appropriate cultures of body fluids
S Chan-Cua

44. Critical Observations
Hourly blood glucose monitoring
Hourly fluid input & output
Neurological status at least hourly
Repeat electrolytes after start of IV therapy
Monitor ECG for T-wave changes
S Chan-Cua

45. Warning signs and symptoms of cerebral edema
Headache & slowing of heart rate
Change in neurological status (restlessness, irritability, increased drowsiness, incontinence)
Specific neurological signs (e.g., cranial nerve palsies)
Rising BP
Decreased O2 saturation
Management
Give mannitol g/kg
Restrict IV fluids by one-third
Call senior staff
Move to ICU
Consider cranial imaging
only after patient stabilised
Warning signs and symptoms of cerebral edema
include:
Headache & slowing of heart rate
Change in neurological status (restlessness, irritability,
increased drowsiness, incontinence)
Specific neurological signs (e.g., cranial nerve palsies)
Rising blood pressure
Decreased O2 saturation
S Chan-Cua

46. Admit to ICU Children with severe DKA long duration of symptoms
compromised circulation
depressed level of consciousness
those who are at increased risk for cerebral edema
5 yr of age
severe acidosis
low PCO2, high BUN
S Chan-Cua

47. Hypoglycemia Sweating Trembling Dizziness Mood changes Hunger Headache
Blurred vision
Extreme tiredness
Paleness
S Chan-Cua

48. Management of complications: Hypoglycemia
Immediate source of glucose
Juice
Milk
Glucagon
Dextrose infusion
Identify the precipitating factors
S Chan-Cua