Dr. Rihab Faisal
Diabetes Mellitus
Lecture 1
Definition: According to American Diabetes Association (ADA), DM is defined
as a group of metabolic diseases characterized by hyperglycemia resulting from
defects in insulin secretion, insulin action, or both.
Classification:
Patients with any form of DM may require insulin treatment at some stage of their
disease, such use of insulin dose not, of itself, classify the patient.
DM is classified
according to its etiology as follow: (
ﻟ
ﻼ
ط
ﻼ
ع
)
• Type 1 DM (Beta-cell destruction ultimately leading to complete insulin
deficiency) which may be Immune mediated or Idiopathic.
• Type 2 DM (variable combinations of insulin resistance and insulin
deficiency).
• Genetic defects of Beta-cell function as MODY, Mitochondrial DNA
mutation, etc.
• Drugs or chemical induced as cytotoxic drugs, Glucocorticoid, Vacor, etc.
• Disease of exocrine pancreas as Pancreatitis, Cystic fibrosis,
Hemochromatosis, etc.
• Infections as Congenital rubella.
• Endocrinopathies as Cushing, Pheochromocytoma, Hyperthyroidism.
• Genetic syndromes with DM and insulin resistant/insulin deficiency as
Prader-Willi syndrome, Down syndrome, Turner syndrome, Klinefelter
syndrome, other.
• Gestational DM.
• Neonatal DM whether Transient or Permanent.
Diagnosis of DM:
the followings are DM diagnostic cut point criteria which were recommended by
ADA:
1. A1C ≥6.5%, or
2. FPG ≥126 mg/dl (fasting is defined as no caloric intake for at least 8 h), or
3. 2-h plasma glucose during OGTT ≥200 mg/dl, or
4. Classical symptoms of hyperglycemic crisis (diabetic ketoacidosis, DKA), a
RPG ≥200mg/dl
In the absence of unequivocal symptoms (polyuria and polydipsia), criteria 1-
3 should be confirmed by repeat testing.
DIABETES MELLITUS TYPE 1
INTRODUCTION
Diabetes Mellitus Type 1 (DMT1) is the most common endocrine-metabolic
disorder of childhood and adolescence, and the third most common chronic
disorder in childhood (after asthma and epilepsy).
DMT1 is associated with a
mean reduction in life span of 23 years.
EPIDEMIOLOGY
DMT1 accounts for more than 90% of child DM.
Age: peaks of presentation occur in 2 age groups; at 5-7 year of age (correspond to
the time of increased exposure to infectious agents coincident with the beginning
of school) and at the time of puberty (correspond to the pubertal growth spurt
induced by gonadal steroids and the increased pubertal growth hormone secretion
which antagonizes insulin). Socioeconomic status: no apparent correlation. Sex:
male and females appear to be equally affected. Season: newly recognized cases
appear to occur with greater frequency in autumn and winter with fewer cases
presenting during summer months.
This seasonal variation has decreased over the
past 10 years. Geographical area: generally the further from the equator, the
higher the incidence. Migration from one country to another confers the diabetic
risk of the new country within a generation.
PATHOGENESIS
A genetically susceptible host develops autoimmunity against the host’s own β
cells. What triggers this autoimmune response remains unclear at this time. this
autoimmune process results in progressive destruction of β cells until a critical
mass (80-90%) of β cells is lost and insulin deficiency develops. This process may
take months to years in adolescents and older patients, and weeks in very young
patients. Thus, the natural history of T1DM involves some or all of the following
stages:
1. Initiation of autoimmunity
2. Preclinical autoimmunity with progressive loss of β-cell function
3. Onset of clinical disease (result of insulin deficiency)
4. Transient remission (honeymoon period: At the time of diagnosis, some viable β
cells are still present and these may produce enough insulin to lead to a partial
remission of the disease (honeymoon period) but over time, almost all β cells are
destroyed and the patient becomes totally dependent on exogenous insulin for
survival)
5. Established disease
6. Development of complications (result of hyperglycemia)
Genetics: The following events support the genetic influence:
• Prevalence of DMT1 in the general population in the USA is only 0.4%,
while in siblings is approaching 6%.
• The risk increased when a parent has diabetes: risk is 3-4% if the mother
has DM and 5-6% if the father has DM.
• The concordance rate in monozygotic twins is 30-65, in dizygotic twins is
6-10%.
It should be kept in mind that although there is a large genetic component in
T1DM, 85% of newly diagnosed type 1 diabetic patients do not have a family
member with T1DM. Thus, we cannot rely on family history to identify patients
who may be at risk for the future development of T1DM as most cases will
develop in individuals with no such family history.
HLA Class II genes on chromosome 6 are the most strongly associated with risk of
T1DM, Some of the known associations include the HLA DR3/4-DQ2/8 genotype
(if 1 sibling has T1DM and shares the same high-risk DR3/4-DQ2/8 haplotype
with another sibling, then the risk of autoimmunity in the other sibling is 50%, and
this risk 80% when share both HLA haplotypes). Homozygous absence of aspartic
acid at position 57 of the HLA DQ b chain confers 100-fold relative risk for
developing DMT1.
Environmental Factors:
significant role of environmental factors in the causation
of T1DM is provided by:
• 50% or so of monozygotic twins are discordant for T1DM.
• Variation seen in urban and rural areas populated by the same ethnic
group.
• Change in incidence that occurs with migration.
• Increase in incidence that has been seen in almost all populations in the
last few decades, and
• Seasonality.
Environmental factors are:
*Viral infection: Invoked mechanisms involved:
• Direct infection of β cells by viruses resulting in lysis and release of self-
antigens.
• Direct viral infection of antigen-presenting cells causing increased
expression of cytokines, and
• “Molecular mimicry,” that viral antigens exhibit homology to self-epitopes.
The clearest evidence of a role for viral infection in human T1DM is seen in
congenital rubella syndrome with development of T1DM in up to 40% of infected
children. The time lag between infection and development of diabetes may be as
high as 20 yr. the role of enterovirus and mumps remains unknown at this time.
*The hygiene hypothesis: T1DM is a disease of industrialized countries. The
hygiene hypothesis states that lack of exposure to childhood infections may
increase an individual’s chances of developing autoimmune diseases, including
T1DM as fewer infections implies that the immune system is less-well trained for
its main task, namely host defense.
*Diet: Breastfeeding may lower the risk of T1DM, either directly or by delaying
exposure to cow’s milk protein. Early introduction of cow’s milk protein and early
exposure to gluten are implicated in the development of autoimmunity. Other
dietary factors include omega-3 fatty acids, vitamin D, ascorbic acid, zinc, and
vitamin E; but the evidence is not yet conclusive.
*Psychologic Stress: Several studies show an increased prevalence of stressful
psychologic situations among children who subsequently developed T1DM.
Whether these stresses only aggravate preexisting autoimmunity or whether they
can actually trigger autoimmunity remains unknown.
Autoimmunity: Markers of autoimmunity are much more prevalent than clinical
T1DM, indicating that initiation of autoimmunity is a necessary but not a
sufficient condition for T1DM. Antibodies (ab) are a marker for the presence of
autoimmunity, but the actual damage to the β cells is primarily T-cell mediated,
and they may detected months to years before clinical diabetes becomes evident.
These antibodies include insulin autoantibody (IAA), islet cell ab (ICA), glutamic
acid decarboxylase ab (GAD), and the more recently described ab; zinc transporter
(ZnT8). IAAs are usually the first to appear in young children, followed by GAD
and later by ICA and ZnT8.
The risk of developing clinical disease increases dramatically with:
• An increasing in the number of ab.
• Higher antibody titers.
• Younger age at which autoimmunity develops.
PATHOPHYSIOLOGY
With moderate insulinopenia, glucose utilization by muscle and fat decreases and
postprandial hyperglycemia appears. At lower insulin levels, the liver produces
excessive glucose via glycogenolysis and gluconeogenesis, and fasting
hyperglycemia begins. Hyperglycemia produces an osmotic diuresis (glycosuria)
when the renal threshold is exceeded (180 mg/dl). The resulting loss of calories
and electrolytes, as well as the worsening dehydration, produces a physiologic
stress with hypersecretion of stress hormones (epinephrine, cortisol, growth
hormone, and glucagon). The combination of insulin deficiency and elevated
plasma values of the counterregulatory hormones is responsible for accelerated
lipolysis, impaired lipid synthesis and shunts the free fatty acids into ketone body
formation. The rate of formation of these ketone bodies, principally β-
hydroxybutyrate and acetoacetate, exceeds the capacity for peripheral utilization
and renal excretion. Accumulation of these ketoacids results in metabolic acidosis
(diabetic ketoacidosis [DKA]) and compensatory rapid deep breathing in an
attempt to excrete excess CO2 (Kussmaul respiration). Acetone, formed by
nonenzymatic conversion of acetoacetate, is responsible for the characteristic
fruity odor of the breath. Ketones are excreted in the urine in association with
cations and thus further increase losses of water and electrolyte. With progressive
dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen
utilization, consciousness becomes impaired, and the patient ultimately becomes
comatose.
CLINICAL MANIFESTATIONS
*The classic presentation of diabetes in children is a history of polyuria,
polydipsia, polyphagia, and weight loss. The duration of these symptoms varies
but is often less than 1 month.
*An insidious onset with lethargy, weakness, and weight loss is also quite
common.
Calories are lost in the urine (glycosuria), triggering a compensatory
hyperphagia. If this hyperphagia does not keep pace with the glycosuria, loss of
body fat ensues, with clinical weight loss and diminished subcutaneous fat stores.
*Pyogenic skin infections and candidal vaginitis in girls or candidal balanitis in
uncircumcised boys are occasionally present at the time of diagnosis of diabetes.
They are rarely the sole clinical manifestations of diabetes in children, and a
careful history will invariably reveal the coexistence of polyuria, polydipsia, and
perhaps weight loss.
*Ketoacidosis is responsible for the initial presentation of many (about 20% to
40%) diabetic children and often in children younger than 5 years of age because
the diagnosis may not be suspected
and a history of polyuria and polydipsia may
be difficult to elicit. For diagnosis, it requires clinical and laboratory findings.
Clinically it presented as vomiting, polyuria, dehydration (as in any hyperosmotic
state, the degree of dehydration may be clinically underestimated because
intravascular volume is conserved at the expense of intracellular volume),
Kussmaul respiration (may be confused with bronchiolitis or asthma and be
treated with steroids or adrenergic agents that worsen diabetes), an odor of acetone
on the breath, abdominal pain or rigidity (may mimic appendicitis or pancreatitis),
cerebral obtundation and (ultimately) coma ensue and are related to the degree of
hyperosmolarity. Laboratory findings for diagnosis include glucosuria, ketonuria,
hyperglycemia (glucose ≥ 200 mg/dl), ketonemia, and metabolic acidosis (CO2 ≤
15 mEq/L; HCO3 ≤ 15 mEq/L, pH ≤ 7.30). Other findings are leukocytosis, a
nonspecific serum amylase levels may be elevated (serum lipase level is usually
not elevated), and prolonged corrected QT interval.
In any child, the progression of symptoms may be accelerated by the stress of an
intercurrent illness or trauma, when counterregulatory (stress) hormones
overwhelm the limited insulin secretory capacity.
MANAGEMENT
The management of DMT1 is divided into three phases, depending on the initial
presentation:
• Ketoacidosis.
• Postacidotic transition (corresponds to presentations with polyuria,
polydipsia, and weight loss but without biochemical decompensation to
DKA).
• Continuing phase of guidance of the child and his or her family (insulin,
nutritional intake, exercise, monitoring)
While the Management of DKA and post-acidotic transition period should be
carried out at hospital, initial presentation with hyperglycemia without acidosis,
especially if blood sugar in the range of 200-300mg/dl, can be managed in
outpatient environment if adequate and trained staff is available to administer
education. Hospitalization does not have to continue until blood sugar control is
optimal as patient will be more active at home. Before discharge from initial
hospitalization, patient should know the followings:
• Measure blood sugar by glucometer.
• Measure insulin from bottle or pen.
• Administer the injection.
• Intramuscular glucagon injection for hypoglycemia.
• Choosing a reasonable diet.
• Recognizing the symptoms and signs of hypoglycemia or impending DKA.
Management is best accomplished by a multidisciplinary team consisting of child,
family, physicians, nurse educators, dietitians, and mental health professionals,
and the child should be seen by this team every 3 months.
There is no one appropriate insulin regimen or meal plan, the principle is that the
diabetic care should fit wherever possible into the surrounding home, family's food
preferences and habits, school environments, and the primary child tasks of
education, socialization, growth, and maturity.
The goals of treatment of child with DMT1 are to:
• Achieve as close to metabolic normalcy.
• Avoid acute complications (DKA and hypoglycemia).
• Minimize the risk of long term microvascular and macrovascular
complications.
• Permit normal growth and development with minimal effects on lifestyle.
Management of DKA:
The followings should be done in parallel:
• Determine patients who should be treated in intensive care unit:
§
pH ≤ 7.00
§
Age < 2 years
§
Unconscious
§
Blood glucose ≥ 1000 mg/dL
• Assess for precipitating factors and treat it (if possible): Delayed diagnosis,
infection, noncompliance, trauma.
• Start DKA protocol.
• Monitor for development of cerebral edema (the major cause of morbidity
and mortality in children and adolescents with T1DM). The majority have
sub clinical cerebral brain swelling, but only 1-2.5 % have clinical
manifestation of cerebral edema. imaging is frequently unhelpful,
Consequently, each patient must be clinically closely monitored. Clinically
cerebral edema developed several hours after the therapy of DKA, and when
clinical and biochemical test indicate improvement. The followings herald
evolving edema: headache, change in consciousness level/response, unequal
dilated pupils, delirium, incontinence, vomiting, bradycardia. If cerebral
edema is clinically apparent: reduce IV rate, give mannitol 1 g/kg iv
infusion (repeat in 2 to 4 hours if indicated).
DKA protocol
• Fluid therapy:
Regarding amount, for all patients we consider the degree of dehydration as 8.5, so
deficit will be 85 cc/kg. maintenance is calculated as 100 cc/kg for first 10 kg, 50
cc for second 10 kg, and 25 cc for every kg above 20. This maintenance and
deficit should be given through 24 hr, but initially (during the first hr) patients
should receive bolus fluid as 10-20 cc/kg which can be repeated as needed. So iv
rate will be as follow:
(Deficit + maintenance) - bolus/23hr
Regarding type of fluid, bolus is 0.9 saline or RL, while the subsequent fluid is
0.45% saline, and when blood sugar < 250 add 5% dextrose ( 5% glucose in
0.45% saline).
• Insulin:
Soluble insulin .05-0.1 U/kg/hr infusion started in the first hour and continue till
acidosis is resolved. But recent guidelines discourage its use in the first hour as its
use is associated with an increased risk of cerebral edema.
• Potassium therapy:
Should be used after
the patient has received the initial bolus fluid and when he
passed urine. The dose is 40 meq/L (10 cc/ pint), and if serum k < 3 meq/L, the
dose will be 80 meq/L (20 cc/ pint).
• NaHCO3 therapy:
Bicarbonate buffers, regenerated by the distal renal tubule and by metabolism of
ketone bodies, steadily repair the acidosis once ketoacid production is controlled
by exogenous insulin. So, bicarbonate therapy is rarely necessary and may even
increase the risk of hypokalemia and cerebral edema. It indicated only when pH ≤
7.1, as severe acidosis causes depression of respiratory and cardiovascular
functions and may also be a factor in insulin resistance. At pH of 7 to 7.1, we
recommend that 40 mEq of HCO32/m2 (at pH of less than 7, 80 mEq of
HCO32/m2) should be infused over a period of 2 hours. Acid-base status should
then be reevaluated before further alkali therapy. Bicarbonate should not be given
by bolus infusion because it may precipitate cardiac arrhythmias.
During treatment of DKA, no oral intake is allowed, and we should monitor fluid
input and output, vital signs, neurologic status, blood sugar and electrolytes.
There should be a steady increase in pH, serum bicarbonate and sodium (Na
increase by approximately 1.6 mmol/L for each 100 mg/dl decline in the glucose)
and decrease in BS (not more than 100mg/dl/hr) as therapy progresses to decrease
the risk of cerebral edema. Kussmaul respirations should abate and abdominal pain
resolve. Persistent acidosis may indicate:
• Inadequate insulin or fluid therapy.
• Infection, or rarely
• Lactic acidosis.
When DKA has resolved (total CO2 >15 mEq/L; pH >7.30; sodium stable
between 135 and 145 mEq/L; no emesis), the child can be easily transitioned to
oral intake and subcutaneous insulin ( the doses and regimens are as in
management of hyperglycemia without acidosis). The first dose of short acting
subcutaneous insulin is given with a meal, and the insulin drip is discontinued
approximately 30 min later.
More than 15 yrs ago, they used sliding scale for calculation of post DKA insulin
dose (it still be used in some hospitals in our country, although it is an old
regimen). It uses soluble insulin that had been given s.c. every 6 hours for 48 hrs
in doses according to blood sugar and as follow: (
ﻟ
ﻼ
ط
ﻼ
ع
)
≤ 90mg/dl …. No insulin.
>90 mg/dl….. 0.1 U/kg.
>180 mg/dl…0.2 U/kg.
>270 mg/dl…0.3 U/kg.
>360 mg/dl…0.4U/kg.
Then the mean is used for calculating the required insulin dose per day.