DIABETUS

MELLITUS
Bereket Fantahun
Pediatric endocrinology Fellow
December ,2010

Diabetes mellitus (DM)

Is a common, chronic, metabolic syndrome
characterized by hyperglycemia as a cardinal
biochemical feature.
The major forms of diabetes are classified
according to those caused by deficiency of
insulin secretion due to pancreatic -cell
damage (type 1 DM, or T1DM) and those that
are a consequence of insulin resistance
occurring at the level of skeletal muscle, liver,
and adipose tissue, with various degrees of cell impairment (type 2 DM, or T2DM).

Etiologic Classifications of

Diabetes Mellitus

Type I diabetes (-cell destruction, usually leading to

absolute insulin deficiency) Immune mediated ,
Idiopathic
Type 2 diabetes (may range from predominantly
insulin resistance with relative insulin deficiency to a
predominantly secretory defect with insulin
resistance)

Other specific types

Genetic defects of -cell function (MODY 1-6)
- Genetic Defects in insulin action
-Pancreatitis
-Trauma, pancreatectomy
-Cystic fibrosis

Diabetes mellitus
Endocrinopathies
-Acromegaly
-Cushing disease
-Pheochromocytoma
-Hyperthyroidism

Diabetes mellitus
Drug-or chemical-induced

Vacor

Pentamidine

Glucocorticoids

Thyroid hormone

-Adrenergic agonists

Thiazides

Diabetes mellitus
Infections
Congenital rubella, coxsackie virus
Cytomegalovirus
Other genetic syndromes associated
with diabetes

Down syndrome

Klinefelter syndrome

Turner syndrome
prader will syndrome

Diabetes mellitus
Gestational diabetes mellitus
Neonatal diabetes mellitus
Transientwithout recurrence
Transientrecurrence 720 yr
later
Permanent from onset

Type1Diabetes mellitus
T1DM is the most common endocrinemetabolic disorder of childhood and
adolescence, with important consequences
for physical and emotional development.
Individuals with T1DM confront serious
lifestyle alterations that include
-an absolute daily requirement for
exogenous insulin
- the need to monitor their own glucose
level
- and the need to pay attention to dietary
intake.

Type1Diabetes mellitus
Morbidity and mortality is from acute
metabolic derangements and from longterm complications (usually in adulthood)
that affect small and large vessels .
The acute clinical manifestations are due
to hypoinsulinemic hyperglycemic
ketoacidosis.
The long-term complications are related to
metabolic disturbances (hyperglycemia).

The natural history includes 4

distinct stages:
1. preclinical -cell autoimmunity with
progressive defect of insulin secretion,
2. onset of clinical diabetes,
3. transient remission honeymoon
period, and
4. established diabetes associated with
acute and chronic complications and
decreased life expectancy.

Natural History of Type 1

Diabetes
BETA CELL MASS

ENVIRONMENTAL
TRIGGER

CELLULAR (T CELL) AUTOIMMUNITY

HUMORAL AUTOANTIBODIES
(ICA, IAA, GADA etc.)

GENETIC
PREDISPOSITION

INSULITIS
BETA CELL
INJURY

LOSS OF FIRST PHASE

INSULIN RESPONSE
(IVGTT)

GLUCOSE INTOLERANCE
(OGTT)

PREDIABETES

TIME

CLINICAL
ONSET
DIABETES

Type1Diabetes mellitus
The onset occurs predominantly in
childhood, with median age of 7 to 15 yr,
but it may present at any age.
Peaks of presentation occur in 2 age
groups: at 57 yr of age and at the time of
puberty.
T1DM is characterized by autoimmune
destruction of pancreatic islet cells.
T1DM is associated with other autoimmune
diseases such as thyroiditis, celiac disease
and Addison disease. [Schmidt syndrome (w/o
celiac)]

Type1Diabetes mellitus
The most important genes are located
within the MHC HLA class II region on
chromosome 6p21, formally termed
(IDDM1), accounting for about 60% genetic
susceptibility for the disease.
Inheritance of HLA-DR3 or -DR4 antigens
appears to confer a 2- to 3-fold increased
risk for the development of T1DM.
When both DR3 and DR4 are inherited, the
relative risk for the development of
diabetes is increased by 7- to 10-fold.

Diabetes mellitus
The children and adolescents with type 2
diabetes are usually obese but are not insulin
dependent and infrequently develop ketosis
(during severe infections or other stresses)
which is characterized by insulin resistance
and often a progressive defect in insulin
secretion.
This type of diabetes was formerly known as
adult-onset diabetes mellitus, non-insulindependent diabetes mellitus (NIDDM), or
maturity-onset diabetes of the young (MODY).

Diabetes mellitus
The presentation of T2DM is typically more
insidious than that with T1DM.
A history of polyuria and polydipsia is relatively
uncommon in these patients.
The incidence of T2DM in children has
increased
Acanthosis nigricans (dark pigmentation of skin
creases/flexural areas), a sign of insulin
resistance, is present in the majority of patients
with T2DM and is accompanied by a relative
hyperinsulinemia at the time of the diagnosis

Diabetes mellitus
In MODY, there is no apparent autoimmune
destruction of cells and no HLA association.
This subclass of T2DM consists of specific genetic
disorders involving mutations in the gene
encoding either pancreatic -cell and liver
glucokinase (GK) or in the nuclear transcription
factors hepatocyte nuclear factor (HNF) (1, 4,
or 1).
A defect in the gene regulating glucose transport
into the pancreatic cell, the GLUT2 transporter,
may be responsible for other forms of T2DM.

Diabetes mellitus
OTHER SPECIFIC TYPES OF SECONDARY DIABETES.
Examples include diabetes secondary to exocrine
pancreatic diseases (cystic fibrosis), other
endocrine diseases (Cushing syndrome), and
ingestion of certain drugs or poisons (the
rodenticide Vacor).
Certain genetic syndromes, including those with
abnormalities of the insulin receptor, also are
included in this category.
There are no associations with autoimmunity, or
islet cell antibodies among the entities in this
subdivision.

IMPAIRED GLUCOSE TOLERANCE.

The term impaired glucose tolerance (IGT)
refers to a metabolic stage that is
intermediate between normal glucose
homeostasis and diabetes.
A fasting glucose concentration of 99
mg/dL is the upper limit of normal.
This choice is near the level above which
acute-phase insulin secretion is lost in
response to intravenous administration of
glucose and is associated with a
progressively greater risk of the
development of microvascular and
macrovascular complications.

Diabetes mellitus
IGT is not a clinical entity but rather a risk
factor for future diabetes and cardiovascular
disease.
IGT is often associated with the insulin
resistance syndrome (also known as syndrome
X or the metabolic syndrome), which consists
of insulin resistance, compensatory
hyperinsulinemia to maintain glucose
homeostasis, obesity (especially abdominal or
visceral obesity), dyslipidemia and
hypertension

Diabetes mellitus
Insulin resistance is directly involved
in the pathogenesis of T2DM.
IGT appears as a risk marker for this
type of diabetes at least in part
because of its correlation with insulin
resistance.
The diagnostic criteria for IGT FBS
110-125 mg/dl

Diabetes mellitus
Although most autoimmune diseases are
more common in females, there appears to
be no gender difference in the overall
incidence of childhood type 1 diabetes .
Genetic susceptibilityThe risk of type 1
diabetes is significantly increased in close
relatives of a patient with type 1 diabetes
Environmental factorsIn genetically
susceptible individuals, exposure to one or
more environmental agents appears to
trigger an immune response that ultimately
causes destruction of the insulin-producing
pancreatic beta cells.

Environmental Factors
Viral infections like coxsackie B3, coxsackie
B4, cytomegalovirus, rubella, and mumps
can infect human cell.
Diet especially exposure to cow's milk at an
early age. The likely mechanism is the
molecular mimicry between a 17-amino-acid
peptide of the bovine serum albumin and the
islet antigen 69.
Drugs like pentamidine and Vacor are directly
cytotoxic to cells and cause diabetes

Family history of DM
10% (only)of the children with diabetes
have diabetes type 1 among relatives
If both parents are affected by type 1
diabetes, they will have a child with
diabetes in about 20-25 %
1 parent: about 5 % (less if the mother has
diabetes, higher if the father has diabetes)
1 sibling with diabetes: about 5 % risk
1 twin (identical): risk 30 -40%

PATHOGENESIS
The autoimmune attack on the
pancreatic islets leads to a gradual
and progressive destruction of
cells, with loss of insulin secretion.
It is estimated that, at the onset of
clinical diabetes, 8090% of the
pancreatic islets are destroyed.

PATHOGENESIS
Regeneration of new islets has been
detected at onset of T1DM, and it is
thought to be responsible for the
honeymoon phase (a transient
decrease in insulin requirement
associated with improved -cell
function).

PATHOGENESIS
Genetic markers for type 1 diabetes are
present from birth (related to Chromosome
6 HLA types)
Immune markers are detectable after the
onset of the autoimmune process,
(ICA,IAA and IGAD)and
Metabolic markers can be detected with
sensitive tests once enough -cell
damage has occurred, but before the onset
of symptomatic hyperglycemia

PATHOPHYSIOLOGY.
Insulin performs a critical role in the
storage and retrieval of cellular fuel.
Its secretion in response to feeding is
modulated by the interplay of neural,
hormonal, and substrate-related
mechanisms to permit controlled
disposition of ingested foodstuff as
energy for immediate or future use.

PATHOPHYSIOLOGY
Insulin is our most important anabolic
hormone!
Saving, storing and up building of
carbohydrate, protein and fat.
Carbohydrate -Insulin stimulates the insulin
receptor on the cell surface Glut 4 , a glucose
transporter, is sent to the cell surface of the
muscle to pick up glucose by endocytosis.
The more insulin the more transporter!
Glucose is phosphorylated and ready for
either storing as glycogen or glycolysis and
energy production (ATP)

PATHOPHYSIOLOGY
Fat -Insulin preserves the fat stores
(It antagonizes the adrenaline
sensitive lipase in fat tissue)
Protein amino acid uptake in the
cells is stimulated and breakdown of
protein is reduced.

PATHOPHYSIOLOGY.
Insulin levels must be lowered to then
mobilize stored energy during the
fasted state.
Thus, in normal metabolism, there
are regular swings between the
postprandial, high-insulin
anabolic state and the fasted, lowinsulin catabolic state that affect
liver, muscle, and adipose tissue .

High Plasma
Insulin(post prandial
state)

Low plasma
insulin(Fasted state)

Liver

-Glucose uptake
-glycogen synthesis
-lipogenesis
-absence of
gluconeogenesis and
ketogenesis

-Glucose production
-glycogenolysis
-ketogenesis
-absence of lipogenesis

Muscle

-Glucose uptake
-Glucose oxidation
-Glycogen synthesis
-Protein synthesis

-Absence of glucose uptake

-Fatty acid and ketone
oxidation
-Glycogenolysis
-Protein degradation and
aminoacid release

Adipose
tissue

-Gulucose uptake
-Lipid synthesis
-Triglyceride uptake

-Absence of glucose uptake

-Lipolysis and fatty acid
release
-Absence of triglyceride
uptake.

PATHOPHYSIOLOGY.

T1DM is a progressive low-insulin catabolic

state in which feeding does not reverse
but rather exaggerates these catabolic
processes.
With moderate insulinopenia, glucose
utilization by muscle and fat decreases
and postprandial hyperglycemia appears
At even lower insulin levels, the liver
produces excessive glucose via
glycogenolysis and gluconeogenesis, and
fasting hyperglycemia begins.

PATHOPHYSIOLOGY.

Hyperglycemia produces an osmotic

diuresis (glycosuria) when the renal
threshold is exceeded (180 mg/dL;
10 mmol/L).
The resulting loss of calories and
electrolytes, as well as the persistent
dehydration, produce a physiologic
stress with hypersecretion of stress
hormones (epinephrine, cortisol,
growth hormone, and glucagon).

PATHOPHYSIOLOGY.

These hormones, in turn, contribute to the

metabolic decompensation by further impairing
insulin secretion (epinephrine)
by antagonizing its action (epinephrine, cortisol,
growth hormone), and
by promoting glycogenolysis, gluconeogenesis,
lipolysis, and ketogenesis (glucagon,
epinephrine, growth hormone, and cortisol)
while decreasing glucose utilization and glucose
clearance (epinephrine, growth hormone,
cortisol).

PATHOPHYSIOLOGY

CLINICAL PRESENTATION
Childhood type 1 diabetes can present in
several different ways.
Classic new onset
Diabetic ketoacidosis
Silent (asymptomatic) incidental
discovery

Classic new onset-Hyperglycemia

without acidosis is the most common presentation

of childhood type 1 diabetes. Symptoms are caused
by hyperglycemia and include polyuria, polydipsia,
weight loss despite increased appetite initially
(polyphagia), and lethargy.

CLINICAL PRESENTATION

As diabetes develops, symptoms steadily increase,

reflecting the decreasing -cell mass, worsening
insulinopenia, progressive hyperglycemia, and
eventual ketoacidosis.
Initially, when only insulin reserve is limited,
occasional hyperglycemia occurs. When the serum
glucose increases above the renal threshold,
intermittent polyuria or nocturia begins.
With further -cell loss, chronic hyperglycemia
causes a more persistent diuresis, often with
nocturnal enuresis, and polydipsia becomes more
apparent.
Female patients may develop monilial vaginitis
due to the chronic glycosuria

Diabetic ketoacidosis
Children with type 1 diabetes often present with
diabetic ketoacidosis (hyperglycemia and
ketoacidosis). Symptoms are similar but usually
more severe than those of patients without
acidosis.
The reported frequency of diabetic ketoacidosis
(DKA) as the initial presentation for childhood
type 1 diabetes varies from 15 to 67%.
Young children (<6 years of age) or from a low
socioeconomic background are more likely to
have DKA as their initial presentation of type 1
diabetes.
In our set up more than 80% of patients will
present with DKA at the initial presentation.

Diabetic ketoacidosis
As an initial presentation or in a known
case of DM when they omit their insulin or
when there is infection or stress.
Can be classified as mild,moderate and
severe Normal
DKA
Mild
Moderate
Severe
CO 2
meq/l(veno
us)

20-28

16-20

10-15

<10

PH(venous)

7.35-7.45

7.25-7.35

7.15-7.25

<7.15

Clinical

No change

Alert but
fatigued

Kussmal
breathing,
sleepy

comatous

Diabetic ketoacidosis
When extremely low insulin levels are reached,
keto acids accumulate. Keto acids produce
abdominal discomfort, nausea, and emesis.
Dehydration accelerates, causing weakness
and polyuria persists. As in any hyperosmotic
state, the degree of dehydration may be
clinically underestimated [due to expansion of
intravascular volume from intracellular source]
Ketoacidosis exacerbates prior symptoms and
leads to Kussmaul respirations (deep, heavy,
rapid breathing), fruity breath odor (acetone),
diminished neurocognitive function, and
possible coma.

CLINICAL PRESENTATION

Silent presentationSome children

will be diagnosed with type 1 diabetes before the
onset of clinical symptoms.
This presentation is least common and typically
occurs in children who have another close family
member with type 1 diabetes and are being
closely monitored .
A rare presentation.

DIAGNOSIS
Fasting plasma glucose 126 mg/dL (7 mmol/L)
on two occasions Symptoms of hyperglycemia
and
a random venous plasma glucose 200 mg/dL
(11.1 mmol/L)
Abnormal oral glucose tolerance test (OGTT)
defined as a plasma glucose 200 mg/dL (11.1
mmol/L) measured two hours after a glucose load
of 1.75 g/kg (maximum dose of 75 g)
Most children and adolescents are symptomatic
and have plasma glucose concentrations well
above 200 mg/dL (11.1 mmol/L); thus, OGTT is
seldom necessary to diagnose type 1 diabetes.

DIAGNOSIS
HbA1c determination is said to be a
very sensitive diagnostic tool of new
onset diabetes and very use full
parameter to monitor the
management and a good predictor of
chronic complication of diabetes

Challenges in pediatrics DM
There are unique challenges in caring for
children and adolescents with diabetes that
differentiate pediatric from adult care.
These include the obvious differences in the
size of the patients, developmental issues
such as the unpredictability of a toddler's
dietary intake and activity level, and medical
issues such as the increased risk of
hypoglycemia and diabetic ketoacidosis.
Because of these considerations, the
management of a child with type 1 diabetes
must take into account the age and
developmental maturity of the child.

GOALS
Successful management of children with
diabetes includes the following :
Balancing strict glycemic control, which
reduces the risk of long-term sequelae,
and avoidance of severe hypoglycemia,
which is more likely with stricter control.
In children, targeted glycemic goals define
what is thought to be the best balance
between these long- and short-term
complications.

GOALS
Maintaining normal growth,
development, and emotional
maturation.
Increasing self-independent
management as the child grows is an
ongoing goal.
Training the patient and family to
provide appropriate daily diabetes care
in order to attain glucose control within
the range of predetermined goals, and
to recognize and treat hypoglycemia.

DKA Management

1.Volume expansion
10-20 ml/kg R/L or N/S over 1 hour
2.Insulin therapy and K+ replacement
- 0.1u /kg/hr continuous insulin mxt
-0.5 u/kg/ every 4-6 hourly intermittent
insulin mxt
-K + 20-40 meq/L of fluid
3. Fluid mxt 85 ml/kg + maintenance fluid
bolus/23 hrs(0.45 % N/S and when glucose
is < 250 mg/dl change the fluid to 5 % D/W
4.Treat the precipitating factors

DKA mxt Risks

Hypoglycemia
Cerebral edema
Hypokalemia
So we need to follow the child with
V/S, frequent glucose and electrolyte
measurement to act accordingly.
Bed side mannitol 1gm/kg is
important

Treatment
Insulin Therapy.
Children with long-standing diabetes and
no insulin reserve require about 0.7 U/kg/d
if prepubertal, 1.0 U/kg/d at midpuberty,
and 1.2 U/kg/d by the end of puberty
Basic education about the insulin
injection , meal planning ,exercise, about
symptoms of hypo/hyperglycemia and
importance of SMBG [self-monitoring blood
glucose] and the impact of poor control of
DM.

Serum insulin concentration ( U/mL)

0
7:00

3:00

23:00

19:00

15:00

60

11:00

9:00

7:00

3:00

23:00

21:00

19:00

Breakfast
Lunch

17:00

15:00

13:00

11:00

100

9:00

7:00

Normal Endogenous Insulin Secretion

Dinner Bedtime
meal

80

Fasting

40

20

Nutritional management
55% CHO,30 %fat and 15 % protein and the
CHO should be complex CHO
The total daily caloric intake is divided to provide
20% at breakfast, 20% at lunch, and 30% at dinner,
leaving 10% for each of the midmorning, mid
afternoon, and evening snacks, if they are desired.

Monitoring-SMBG, insulin dose adjustment.

Ideally, the blood glucose concentration
should range from approximately 80 mg/dL
in the fasting state to 140 mg/dL after meals.
In practice, however, a range of 60220
mg/dL is acceptable

Target BG and HbA1c level

Age

Pre meal BG
level(mg/dl)

30 days
average BG
level (mg/dl)

Target HbA1c

<5 years

100-200

180-250

7.59.0

5-11 years

80-150

150-200

6.58.0

11-15 years

80-130

120-180

6.07.5

15-18 years

70-120

100-150

5.5-7

The non diabetic reference range for HbA1c is 4.55.7%

HbA1c
A reliable index of long-term glycemic control is
provided by measurement of glycosylated
hemoglobin.
HbA1C represents the fraction of hemoglobin to
which glucose has been non enzymatically
attached in the bloodstream. Will be measured 34 x /year.
In non diabetic individuals, the HbA1C fraction is
usually less than 6%;
In diabetics, values of 67.9% represent good
metabolic control, values of 8.09.9%, fair
control, and values of 10.0% or higher, poor
control.

Exercise
No form of exercise, including
competitive sports, should be
forbidden to the diabetic child.
But the risk of hypoglycemia is there
during or within hours after exercise so
BG measurement is important.
They have to take candy or carbonated
juice to take immediately if there are
symptoms of hypoglycemia

Insulin treatment modalities

1921-22 to mid thirties: crystalized
animal insulin (only rapid acting)
Depot insulins (i.e NPH Protamin) and
Lente (Zink)
Human insulin
Analogues: direct action, Humalog and
NovoRapid(max peak in 1 hr)
Depot (Glargine and Detemir): more
predictable action than intermediate and
lente

Insulin Preparations
Kinetics following s.c. injection

Insulin

Onset of action

Peak of action Duration of action

Soluble - Regular 30-60 minutes

2-4 hours

6-8 hours

Lispro- Aspart

5-15 minutes

1-2 hours

4-5 hours

NPH

1-2 hours

5-7 hours

13-18 hours

Glargine-Detemir

1-3 hours

4-8 hours

13-20 hours

Combinations

0.5-1 hours

dual

10-16 hours

Schematic Time-Activity Curves for Available Insulin Formulations

McMahon G and Dluhy R. N Engl J Med 2007;10.1056/NEJMe078196

57

Insulin injection
Conventional way(twice daily injection)
Regular insulin with intermediate
acting insulin (NPH/Lente insulin)
Multiple daily injection using
basal(Glargine /Detemir) and bolus
insulin(Lispro/Asparte/Regular insulin)
CSII (continuous subcutaneous insulin
injection or pump therapy) using short
acting insulin

Other important Issues

1.Hypoglycemic reactions
2.The Dawn and somogy phenomenon
3.Non Adherance
4.Anxiety and depression
5.Fear of self injecting and self testing
6.Management during infections and
surgery

T2DM management
Weight loss and physical exercise are
said to be the main strategies in
controlling glucose level in T2DM
patients
Oral hypoglycemic agents like
metformin [a biguanide] can be tried
Insulin if they have ketonuria

Why we need good control

Acute diabetic complication is a risk
It predicts the occurrence of chronic
complication
It was not known until 1993 if the degree
and duration of hyperglycemia can
influence the onset and progression of
chronic complications of the disease
DCCT studies finally proved that
complications increased with higher
blood sugars, i.e HbA1C

Long term complications

-microvascular complications (Retinopathy,
nephropathy)
-Macrovascular complication
-Growth failure and delayed puberty

Prognosis
Their life span is 10 yrs shorter
visual, renal and neuropathic
complications are common
Puberty may be delayed and final Ht
is less than the genetic Ht

Injection models
Repeted injections

Future
intelligent
pumps
with reliable
sensors for
glucose levels
= mechanical
pancreas

Glucometers

PANCREAS AND ISLET TRANSPLANTATION AND

REGENERATION

In an attempt to cure T1DM, transplantation

of a segment of the pancreas or of isolated
islets has been performed.
These procedures are both technically
demanding and associated with the risks of
disease recurrence and complications of
rejection or its treatment by
immunosuppression.
Complications of immunosuppression include
the development of malignancy.