DIABETES MELLITUS

DIABETES MELLITUS
DM refers to a group of common metabolic disorders
that share the phenotype of hyperglycemia
DM is a chronic disorder characterized by impaired
metabolism of glucose and other energy-yielding
fuels, as well as the late development of vascular
(involving small and large blood vessels) and
neuropathic complications
DM consists of a group of disorders involving distinct
pathogenic mechanisms in which hyperglycemia is
the common denominator
Regardless of the cause, the disease is associated with
a common hormonal defect, namely, insulin
deficiency, which may be total, partial, or relative
when viewed in the context of coexisting insulin
resistance
 DIABETES MELLITUS

Lack of insulin plays a primary role in

the metabolic derangements linked to
diabetes, and hyperglycemia in turn
plays a key role in the complications of
the disease
Several distinct types of DM exist and are
caused by a complex interaction of
genetics and environmental factors
Depending on the etiology of the DM,
factors contributing to hyperglycemia
include reduced insulin secretion,
decreased glucose utilization, and
increased glucose production
 DIABETES MELLITUS

The metabolic dysregulation associated with DM

causes secondary pathophysiologic changes in
multiple organ systems that impose a tremendous
burden on the individual with diabetes and on the
health care system
In the United States, DM is the leading cause of
end-stage renal disease (ESRD), nontraumatic
lower extremity amputations, and adult blindness
It also predisposes to cardiovascular diseases
With an increasing incidence worldwide, DM will
be a leading cause of morbidity and mortality for
the foreseeable future
 SIGNS AND SYMPTOMS
The two types of diabetes have very similar symptoms
The first symptoms are related to the direct effects of
high blood sugar levels
When the blood sugar level rises above 160 to 180 mg/dL,
sugar spills into the urine
When the level of sugar in the urine rises even higher, the
kidneys excrete additional water to dilute the large
amount of sugar
Because the kidneys produce excessive urine, people with
diabetes urinate large volumes frequently (polyuria)
The excessive urination creates abnormal thirst
(polydipsia)
Because excessive calories are lost in the urine, people
lose weight
To compensate, people often feel excessively hungry
Other symptoms include blurred vision, drowsiness,
nausea, and decreased endurance during exercise
 CLASSIFICATION

DM is classified on the basis of the

pathogenic process that leads to
hyperglycemia, as opposed to earlier
criteria such as age of onset or type of
therapy
The two broad categories of DM are
designated type 1 and type 2
Both types of diabetes are preceded by
a phase of abnormal glucose
homeostasis as the pathogenic
processes progresses
 Etiologic Classification of
Diabetes Mellitus
I. Type 1 diabetes (-cell
destruction, usually leading to
absolute insulin deficiency)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (may range from
predominantly insulin resistance
with relative insulin deficiency to a
predominantly insulin secretory
defect with insulin resistance)
 Etiologic Classification of
Diabetes Mellitus
III. Other specific types of diabetes
A. Genetic defects of cell function
characterized by mutations in:
1. Hepatocyte nuclear transcription factor
(HNF) 4 (MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1 (MODY 3)
4. Insulin promoter factor-1 (IPF-1; MODY 4)
5. HNF-1 (MODY 5)
6. NeuroD1 (MODY 6)
7. Mitochondrial DNA
8. Subunits of ATP-sensitive potassium channel
9. Proinsulin or insulin conversion
***MODY -maturity-onset diabetes of the young
 Etiologic Classification of
Diabetes Mellitus
III. Other specific types of diabetes
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipodystrophy syndromes
C. Diseases of the exocrine pancreas
1. Pancreatitis
2. Pancreatectomy
3. Neoplasia
4. Cystic fibrosis
5. Hemochromatosis
6. Fibrocalculous pancreatopathy
7. Mutations in carboxyl ester lipase
 Etiologic Classification of
Diabetes Mellitus
III. Other specific types of diabetes
D. Endocrinopathies
1. Acromegaly
2. Cushing's syndrome
3. Glucagonoma
4. Pheochromocytoma
5. Hyperthyroidism
6. Somatostatinoma
7. Aldosteronoma
 Etiologic Classification of
Diabetes Mellitus
III. Other specific types of diabetes
E. Drug or chemical-induced
1. Vacor
2. Pentamidine
3. Nicotinic acid
4. Glucocorticoids
5. Thyroid hormone
6. Diazoxide
7. -adrenergic agonists
8. Thiazides
9. Phenytoin
10. -interferon
11. Protease inhibitors
12. Clozapine
 Etiologic Classification of
Diabetes Mellitus
III. Other specific types of diabetes
F. Infections
1. Congenital rubella
2. Cytomegalovirus
3. Coxsackie
G. Uncommon forms of immune-mediated
diabetes
1. "Stiff-person" syndrome
2. Anti-insulin receptor antibodies
 Etiologic Classification of
Diabetes Mellitus
III. Other specific types of diabetes
H. Other genetic syndromes sometimes
associated with diabetes
1. Down's syndrome
2. Klinefelter's syndrome
3. Turner's syndrome
4. Wolfram's syndrome
5. Friedreich's ataxia
6. Huntington's chorea
7. Laurence-Moon-Biedl syndrome
8. Myotonic dystrophy
9. Porphyria
10. Prader-Willi syndrome
IV. Gestational diabetes mellitus (GDM)
PATHOPHYSIOLOGY
BIOSYNTHESIS
 PATHOPHYSIOLOGY
Pancreatic beta cells cosecrete islet amyloid
polypeptide (IAPP) or amylin, a 37-amino-acid
peptide, along with insulin
The role of IAPP in normal physiology is
unclear, but it is the major component of the
amyloid fibrils found in the islets of patients
with type 2 diabetes, and an analogue is
sometimes used in treating both type 1 and
type 2 DM
Human insulin is now produced by
recombinant DNA technology; structural
alterations at one or more residues are useful
for modifying its physical and pharmacologic
characteristics
 PATHOPHYSIOLOGY
SECRETION
 PATHOPHYSIOLOGY
ACTION
 Type 1 Diabetes Mellitus

The result of complete or near-total

insulin deficiency
Most commonly develops before the age of
30, an autoimmune beta cell destructive
process can develop at any age
It is estimated that between 5 and 10% of
individuals who develop DM after age 30
have type 1 DM
Patients with this disorder have little or
no insulin secretory capacity and depend
on exogenous insulin to prevent metabolic
decompensation (e.g., ketoacidosis) and
death
 Type 1 Diabetes Mellitus
Commonly but not always, diabetes appears
abruptly (i.e., over days or weeks) in previously
healthy non-obese children or young adults; in
older age groups it may have a more gradual
onset
At the time of initial evaluation the typical
patient often appears ill, has marked symptoms
(e.g., polyuria, polydipsia, polyphagia, and
weight loss), and may demonstrate ketoacidosis
Type 1 diabetes is believed to have a long
asymptomatic pre-clinical stage often lasting
years, during which pancreatic beta cells are
gradually destroyed by an autoimmune attack
that is influenced by HLA (human lymphocyte antigen)
and other genetic factors, as well as the
environment
 Type 1 Diabetes Mellitus
In some, an acute illness may speed the transition from
the pre-clinical to the clinical stage
Initially, insulin therapy is essential to restore
metabolism toward normal
However, a so-called honeymoon period may follow
and last weeks or months, during which time smaller
doses of insulin are required because of partial
recovery of beta cell function and reversal of insulin
resistance caused by acute illness
Thereafter, insulin secretory capacity is gradually lost
(over several years)
That type 1 diabetes is an autoimmune disease is
supported by its association with specific immune
response (HLA) genes and the presence of antibodies
to islet cells and their constituents
This syndrome accounts for less than 10% of diabetes
in the United States
 Type 2 Diabetes Mellitus
A heterogeneous group of disorders characterized
by variable degrees of insulin resistance, impaired
insulin secretion, and increased glucose
production
Distinct genetic and metabolic defects in insulin
action and/or secretion give rise to the common
phenotype of hyperglycemia in type 2 DM and have
important potential therapeutic implications now
that pharmacologic agents are available to target
specific metabolic derangements
Preceded by a period of abnormal glucose
homeostasis classified as impaired fasting glucose
(IFG) or impaired glucose tolerance (IGT)
More typically develops with increasing age but is
now being diagnosed more frequently in children
and young adults, particularly in obese adolescents
 Type 2 Diabetes Mellitus
Type 2, by far the most common form of
the disease, is found in over 90% of the
diabetic patient population
These patients retain a significant level
of endogenous insulin secretory
capacity
However, insulin levels are low relative
to the magnitude of insulin resistance
and ambient glucose levels
Type 2 patients are not dependent on
insulin for immediate survival and
ketosis rarely develops, except under
conditions of great physical stress
 Type 2 Diabetes Mellitus
Nevertheless, these patients may require insulin
therapy to control hyperglycemia
Type 2 diabetes typically appears after the age of
40 years, has a high rate of genetic penetrance
unrelated to HLA genes, and is associated with
obesity
The clinical features of type 2 diabetes are much
more insidious (gradual and harmful)
The classic symptoms of diabetes may be mild
(fatigue, weakness, dizziness, blurred vision, or
other non-specific complaints may dominate the
picture) or may be tolerated for many years before
the patient seeks medical attention
Moreover, if the level of hyperglycemia is
insufficient to produce symptoms, the disease may
become evident only after complications develop
 Other Types of DM
Other etiologies for DM include specific
genetic defects in insulin secretion or
action, metabolic abnormalities that impair
insulin secretion, mitochondrial
abnormalities, and a host of conditions that
impair glucose tolerance
Maturity onset diabetes of the young
(MODY) is a subtype of DM characterized by
autosomal dominant inheritance, early
onset of hyperglycemia (usually <25 years),
and impairment in insulin secretion
Mutations in the insulin receptor cause a
group of rare disorders characterized by
severe insulin resistance
 Other Types of DM
DM can result from pancreatic exocrine
disease when the majority of pancreatic
islets are destroyed
Hormones that antagonize insulin action can
also lead to DM
Thus, DM is often a feature of
endocrinopathies such as acromegaly and
Cushing's disease
Viral infections have been implicated in
pancreatic islet destruction but are an
extremely rare cause of DM
A form of acute onset of type 1 diabetes,
termed fulminant diabetes, has been noted
in Japan and may be related to viral
infection of islets
 Other Types of DM
This category encompasses a variety of
diabetic syndromes attributed to a specific
disease, drug, or condition
Genetic research has provided new insights
into the pathogenesis of maturity-onset
diabetes of the young (MODY), which was
formerly included as a form of type 2
diabetes
MODY encompasses several genetic defects of
beta cell function, among which mutations at
several genetic loci on different chromosomes
have been identified
 Other Types of DM
The most common forms:
MODY type 3 is associated with a mutation
for a transcription factor encoded on
chromosome 12 named hepatocyte nuclear
factor 1 (HNF-1)
MODY type 2 is associated with mutations
of the glucokinase gene (on chromosome 7)
MODY type 1 is associated with mutations
of the HNF-4 gene (on chromosome 20)
Each of these conditions is inherited in an
autosomal dominant pattern
 Other Types of DM
Two new rare forms of MODY are associated
with mutations of the HNF-1 (on
chromosome 17) and an insulin gene
transcription factor termed PDX-1 or 1DX-1
(on chromosome 13)
It should be emphasized that severe illness
(e.g., burns, trauma, sepsis) may also
provoke stress hyperglycemia as a result of
hypersecretion of insulin antagonistic
hormones
Although some of these individuals may
have underlying diabetes, the metabolic
disturbance is often self-limited and should
therefore not be classified as diabetes until
the precipitating illness has fully resolved
 Other Types of DM
Distinction between the various subclasses
of diabetes mellitus is usually made on
clinical grounds
However, a small subgroup of patients are
difficult to classify, that is, they display
features common to both type 1 and 2
diabetes
Such patients are commonly non-obese and
have reduced insulin secretory capacity that
is not sufficient to make them ketosis prone
Many initially respond to oral agents but,
with time, require insulin
Some appear to have a slowly evolving form
of type 1 diabetes, whereas others defy easy
categorization
Gestational Diabetes Mellitus (GDM)
Glucose intolerance may develop during
pregnancy
GDM describes women with impaired
glucose tolerance that appears or is first
detected during pregnancy
Insulin resistance is related to the
metabolic changes of late pregnancy, and
the increased insulin requirements may
lead to IGT
GDM occurs in ~4% of pregnancies in the
United States; most women revert to
normal glucose tolerance post-partum but
have a substantial risk (3060%) of
developing DM later in life
 Gestational Diabetes Mellitus (GDM)
Women with known diabetes before conception
are not considered to have gestational diabetes
GDM usually appears in the 2nd or 3rd trimester,
a time when pregnancy-associated insulin
antagonistic hormones peak
After delivery, glucose tolerance generally (but
not always) reverts to normal
However, within 5 to 10 years, type 2 diabetes
develops in 30 to 40%
Occasionally, pregnancy may precipitate type 1
diabetes
Although patients generally have only mild,
asymptomatic hyperglycemia, rigorous treatment,
often with insulin, is required to protect against
hyperglycemia-associated fetal morbidity and
mortality
 FEATURES TYPE 1 TYPE 2

Age at onset Usually <30 years Usually >30 years

Body mass Low (wasted) to Obese

normal

Plasma insulin Low or absent Normal to high

initially

Plasma glucagon High, can be High, resistant to

suppressed suppression

Plasma glucose Increased Increased

Insulin sensitivity Normal Reduced