Diagnosis and Classification of Diabetes
Mellitus
AMERICAN DIABETES ASSOCIATION
DEFINITION AND
DESCRIPTION OF DIABETES
MELLITUSdDiabetes is a group of
metabolic diseases characterized by hy-
perglycemia resulting from defects in in-
sulin secretion, insulin action, or both.
The chronic hyperglycemia of diabetes is
associated with long-term damage, dys-
function, and failure of different organs,
especially the eyes, kidneys, nerves, heart,
and blood vessels.
Several pathogenic processes are in-
volved in the development of diabetes.
These range from autoimmune destruc-
tion of the b-cells of the pancreas with
consequent insulin deficiency to abnor-
malities that result in resistance to insulin
action. The basis of the abnormalities in
carbohydrate, fat, and protein metabo-
lism in diabetes is deficient action of in-
sulin on target tissues. Deficient insulin
action results from inadequate insulin se-
cretion and/or diminished tissue respon-
ses to insulin at one or more points in the
complex pathways of hormone action.
Impairment of insulin secretion and de-
fects in insulin action frequently coexist in
the same patient, and it is often unclear
which abnormality, if either alone, is the
primary cause of the hyperglycemia.
Symptoms ofmarked hyperglycemia in-
cludepolyuria,polydipsia,weight loss,some-
times with polyphagia, and blurred vision.
Impairment of growth and susceptibility to
certain infections may also accompany
chronic hyperglycemia. Acute, life-threaten-
ing consequences of uncontrolled diabetes
are hyperglycemia with ketoacidosis or the
nonketotic hyperosmolar syndrome.
Long-term complications of diabetes
include retinopathy with potential loss
of vision; nephropathy leading to renal
failure; peripheral neuropathy with risk
of foot ulcers, amputations, and Charcot
joints; and autonomic neuropathy caus-
ing gastrointestinal, genitourinary, and
cardiovascular symptoms and sexual dys-
function. Patients with diabetes have an
increased incidence of atherosclerotic car-
diovascular, peripheral arterial, and cere-
brovascular disease. Hypertension and
abnormalities of lipoprotein metabolism
are often found in people with diabetes.
The vast majority of cases of diabetes
fall into two broad etiopathogenetic cate-
gories (discussed in greater detail below).
In one category, type 1 diabetes, the cause
is an absolute deficiency of insulin secre-
tion. Individuals at increased risk of de-
veloping this type of diabetes can often be
identified by serological evidence of an
autoimmune pathologic process occurring
in the pancreatic islets and by genetic
markers. In the other, much more preva-
lent category, type 2 diabetes, the cause is a
combination of resistance to insulin action
and an inadequate compensatory insulin
secretory response. In the latter category, a
degree of hyperglycemia sufficient to cause
pathologic and functional changes in var-
ious target tissues, but without clinical
symptoms, may be present for a long
period of time before diabetes is detected.
During this asymptomatic period, it is
possible to demonstrate an abnormality in
carbohydrate metabolism by measurement
of plasma glucose in the fasting state or
after a challenge with an oral glucose load
or by A1C.
The degree of hyperglycemia (if any)
may change over time, depending on the
extent of the underlying disease process
(Fig. 1). A disease process may be present
but may not have progressed far enough
to cause hyperglycemia. The same disease
process can cause impaired fasting glu-
cose (IFG) and/or impaired glucose toler-
ance (IGT) without fulfilling the criteria
for the diagnosis of diabetes. In some indi-
viduals with diabetes, adequate glycemic
control can be achieved with weight reduc-
tion, exercise, and/or oral glucose-lowering
agents. These individuals therefore do
not require insulin. Other individuals
who have some residual insulin secretion
but require exogenous insulin for ade-
quate glycemic control can survive with-
out it. Individuals with extensive b-cell
destruction and therefore no residual in-
sulin secretion require insulin for survival.
The severity of the metabolic abnormality
can progress, regress, or stay the same.
Thus, the degree of hyperglycemia reflects
the severity of the underlying metabolic
process and its treatment more than the
nature of the process itself.
CLASSIFICATION OF
DIABETES MELLITUS AND
OTHER CATEGORIES
OF GLUCOSE
REGULATIONdAssigning a type of
diabetes to an individual often depends
on the circumstances present at the time
of diagnosis, and many diabetic individ-
uals do not easily fit into a single class. For
example, a person diagnosed with gesta-
tional diabetes mellitus (GDM) may con-
tinue to be hyperglycemic after delivery
and may be determined to have, in fact,
type 2 diabetes. Alternatively, a person
who acquires diabetes because of large
doses of exogenous steroids may become
normoglycemic once the glucocorticoids
are discontinued, but then may develop
diabetes many years later after recurrent
episodes of pancreatitis. Another example
would be a person treated with thiazides
who develops diabetes years later. Because
thiazides in themselves seldomcause severe
hyperglycemia, such individuals probably
have type 2 diabetes that is exacerbated by
the drug. Thus, for the clinician andpatient,
it is less important to label the particular
type of diabetes than it is to understand the
pathogenesis of the hyperglycemia and to
treat it effectively.
Type 1 diabetes (b-cell destruction,
usually leading to absolute insulin
deficiency)
Immune-mediated diabetes. This form
of diabetes, which accounts for only
5–10% of those with diabetes, previously
encompassed by the terms insulin-
dependent diabetes or juvenile-onset di-
abetes, results from a cellular-mediated
autoimmune destruction of the b-cells of
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
Updated Fall 2012.
DOI: 10.2337/dc13-S067
© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
care.diabetesjournals.org DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 S67
P O S I T I O N S T A T E M E N T
the pancreas. Markers of the immune de-
struction of the b-cell include islet cell au-
toantibodies, autoantibodies to insulin,
autoantibodies toGAD (GAD65), and auto-
antibodies to the tyrosine phosphatases
IA-2 and IA-2b. One and usually more of
these autoantibodies are present in 85–
90% of individuals when fasting hyper-
glycemia is initially detected. Also, the
disease has strong HLA associations,
with linkage to the DQA and DQB genes,
and it is influenced by the DRB genes.
These HLA-DR/DQ alleles can be either
predisposing or protective.
In this form of diabetes, the rate of
b-cell destruction is quite variable, being
rapid in some individuals (mainly infants
and children) and slow in others (mainly
adults). Some patients, particularly chil-
dren and adolescents, may present with
ketoacidosis as the first manifestation of
the disease. Others have modest fasting
hyperglycemia that can rapidly change
to severe hyperglycemia and/or ketoaci-
dosis in the presence of infection or other
stress. Still others, particularly adults,
may retain residual b-cell function suffi-
cient to prevent ketoacidosis for many
years; such individuals eventually be-
come dependent on insulin for survival
and are at risk for ketoacidosis. At this
latter stage of the disease, there is little
or no insulin secretion, as manifested by
low or undetectable levels of plasma
C-peptide. Immune-mediated diabetes
commonly occurs in childhood and ado-
lescence, but it can occur at any age, even
in the 8th and 9th decades of life.
Autoimmune destruction of b-cells
has multiple genetic predispositions and
is also related to environmental factors
that are still poorly defined. Although pa-
tients are rarely obese when they present
with this type of diabetes, the presence of
obesity is not incompatible with the diag-
nosis. These patients are also prone to
other autoimmune disorders such as
Graves’ disease, Hashimoto’s thyroiditis,
Addison’s disease, vitiligo, celiac sprue,
autoimmune hepatitis, myasthenia gravis,
and pernicious anemia.
Idiopathic diabetes. Some forms of type
1 diabetes have no known etiologies.
Some of these patients have permanent
insulinopenia and are prone to ketoaci-
dosis, but have no evidence of autoim-
munity. Although only a minority of
patients with type 1 diabetes fall into this
category, of those who do, most are of
African or Asian ancestry. Individuals
with this form of diabetes suffer from
episodic ketoacidosis and exhibit vary-
ing degrees of insulin deficiency be-
tween episodes. This form of diabetes
is strongly inherited, lacks immunolog-
ical evidence for b-cell autoimmunity,
and is not HLA associated. An absolute
requirement for insulin replacement
therapy in affected patients may come
and go.
Type 2 diabetes (ranging from
predominantly insulin resistance
with relative insulin deficiency to
predominantly an insulin secretory
defect with insulin resistance)
This form of diabetes, which accounts for
;90–95% of those with diabetes, previ-
ously referred to as non–insulin-depen-
dent diabetes, type 2 diabetes, or adult-
onset diabetes, encompasses individuals
who have insulin resistance and usually
have relative (rather than absolute) insu-
lin deficiency At least initially, and often
throughout their lifetime, these individu-
als do not need insulin treatment to sur-
vive. There are probably many different
causes of this form of diabetes. Although
the specific etiologies are not known, au-
toimmune destruction of b-cells does not
occur, and patients do not have any of the
other causes of diabetes listed above or
below.
Most patients with this form of di-
abetes are obese, and obesity itself causes
some degree of insulin resistance. Patients
who are not obese by traditional weight
criteria may have an increased percentage
of body fat distributed predominantly in
the abdominal region. Ketoacidosis sel-
dom occurs spontaneously in this type of
diabetes; when seen, it usually arises in
association with the stress of another
illness such as infection. This form of
diabetes frequently goes undiagnosed for
many years because the hyperglycemia
Figure 1dDisorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normo-
glycemia without requiring continuous therapy (i.e., “honeymoon” remission); **in rare instances, patients in these categories (e.g., Vacor toxicity,
type 1 diabetes presenting in pregnancy) may require insulin for survival.
S68 DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 care.diabetesjournals.org
Position Statement
develops gradually and at earlier stages is
often not severe enough for the patient to
notice any of the classic symptoms of
diabetes. Nevertheless, such patients are
at increased risk of developing macro-
vascular and microvascular complica-
tions. Whereas patients with this form of
diabetes may have insulin levels that
appear normal or elevated, the higher
blood glucose levels in these diabetic
patients would be expected to result in
even higher insulin values had their b-cell
function been normal. Thus, insulin se-
cretion is defective in these patients and
insufficient to compensate for insulin re-
sistance. Insulin resistance may improve
with weight reduction and/or pharmaco-
logical treatment of hyperglycemia but is
seldom restored to normal. The risk of
developing this form of diabetes increases
with age, obesity, and lack of physical ac-
tivity. It occurs more frequently in women
with prior GDM and in individuals with
hypertension or dyslipidemia, and its fre-
quency varies in different racial/ethnic sub-
groups. It is often associated with a strong
genetic predisposition, more so than is the
autoimmune form of type 1 diabetes. How-
ever, the genetics of this form of diabetes
are complex and not fully defined.
Other specific types of diabetes
Genetic defects of the b-cell. Several
forms of diabetes are associated with
monogenetic defects in b-cell function.
These forms of diabetes are frequently
characterized by onset of hyperglycemia
at an early age (generally before age 25
years). They are referred to as maturity-
onset diabetes of the young (MODY) and
are characterized by impaired insulin se-
cretion with minimal or no defects in in-
sulin action. They are inherited in an
autosomal dominant pattern. Abnormali-
ties at six genetic loci on different chro-
mosomes have been identified to date.
The most common form is associated
with mutations on chromosome 12 in a
hepatic transcription factor referred to as
hepatocyte nuclear factor (HNF)-1a. A
second form is associated with mutations
in the glucokinase gene on chromosome
7p and results in a defective glucokinase
molecule. Glucokinase converts glucose
to glucose-6-phosphate, the metabolism
of which, in turn, stimulates insulin secre-
tion by the b-cell. Thus, glucokinase
serves as the “glucose sensor” for the
b-cell. Because of defects in the glucoki-
nase gene, increased plasma levels of glu-
cose are necessary to elicit normal levels
of insulin secretion. The less common
forms result frommutations in other tran-
scription factors, including HNF-4a,
HNF-1b, insulin promoter factor (IPF)-
1, and NeuroD1.
Diabetes diagnosed in the first 6
months of life has been shown not to be
typical autoimmune type 1 diabetes. This
so-called neonatal diabetes can either be
transient or permanent. The most com-
mon genetic defect causing transient
disease is a defect on ZAC/HYAMI im-
printing, whereas permanent neonatal
diabetes is most commonly a defect in the
gene encoding the Kir6.2 subunit of the
b-cell KATP channel. Diagnosing the latter
has implications, since such children can
be well managed with sulfonylureas.
Point mutations in mitochondrial
DNA have been found to be associated
with diabetes and deafness The most
common mutation occurs at position
3,243 in the tRNA leucine gene, leading
to an A-to-G transition. An identical
lesion occurs in the MELAS syndrome
(mitochondrial myopathy, encephalop-
athy, lactic acidosis, and stroke-like syn-
drome); however, diabetes is not part
of this syndrome, suggesting different
phenotypic expressions of this genetic
lesion.
Genetic abnormalities that result in
the inability to convert proinsulin to in-
sulin have been identified in a few fami-
lies, and such traits are inherited in an
autosomal dominant pattern. The resul-
tant glucose intolerance is mild. Similarly,
the production of mutant insulin mole-
cules with resultant impaired receptor
binding has also been identified in a few
families and is associated with an autoso-
mal inheritance and only mildly impaired
or even normal glucose metabolism.
Genetic defects in insulin action. There
are unusual causes of diabetes that result
from genetically determined abnormali-
ties of insulin action. The metabolic ab-
normalities associated with mutations of
the insulin receptor may range from
hyperinsulinemia and modest hyperglyce-
mia to severe diabetes. Some individuals
with these mutations may have acanthosis
nigricans. Women may be virilized and
have enlarged, cystic ovaries. In the past,
this syndrome was termed type A insulin
resistance. Leprechaunism and the Rabson-
Mendenhall syndrome are two pediatric
syndromes that have mutations in the
insulin receptor gene with subsequent
alterations in insulin receptor function
and extreme insulin resistance. The former
has characteristic facial features and is
usually fatal in infancy, while the latter is
associated with abnormalities of teeth and
nails and pineal gland hyperplasia.
Alterations in the structure and func-
tion of the insulin receptor cannot be
demonstrated in patients with insulin-
resistant lipoatrophic diabetes. Therefore,
it is assumed that the lesion(s) must reside
in the postreceptor signal transduction
pathways.
Diseases of the exocrine pancreas. Any
process that diffusely injures the pancreas
can cause diabetes. Acquired processes
include pancreatitis, trauma, infection, pan-
createctomy, and pancreatic carcinoma.
With the exception of that caused by
cancer, damage to the pancreas must be
extensive for diabetes to occur; adreno-
carcinomas that involve only a small
portion of the pancreas have been associ-
ated with diabetes. This implies a mech-
anism other than simple reduction in
b-cell mass. If extensive enough, cystic fi-
brosis and hemochromatosis will also
damage b-cells and impair insulin secre-
tion. Fibrocalculous pancreatopathy may
be accompanied by abdominal pain radi-
ating to the back and pancreatic calcifica-
tions identified on X-ray examination.
Pancreatic fibrosis and calcium stones
in the exocrine ducts have been found at
autopsy.
Endocrinopathies. Several hormones
(e.g., growth hormone, cortisol, gluca-
gon, epinephrine) antagonize insulin ac-
tion. Excess amounts of these hormones
(e.g., acromegaly, Cushing’s syndrome,
glucagonoma, pheochromocytoma, re-
spectively) can cause diabetes. This gen-
erally occurs in individuals with
preexisting defects in insulin secretion,
and hyperglycemia typically resolves
when the hormone excess is resolved.
Somatostatinomas, and aldostero-
noma-induced hypokalemia, can cause
diabetes, at least in part, by inhibiting
insulin secretion. Hyperglycemia gener-
ally resolves after successful removal of
the tumor.
Drug- or chemical-induced diabetes.
Many drugs can impair insulin secretion.
These drugs may not cause diabetes by
themselves, but they may precipitate di-
abetes in individuals with insulin resis-
tance. In such cases, the classification is
unclear because the sequence or relative
importance of b-cell dysfunction and in-
sulin resistance is unknown. Certain tox-
ins such as Vacor (a rat poison) and
intravenous pentamidine can perma-
nently destroy pancreatic b-cells. Such
drug reactions fortunately are rare. There
are also many drugs and hormones that
care.diabetesjournals.org DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 S69
Position Statement
can impair insulin action. Examples in-
clude nicotinic acid and glucocorticoids.
Patients receiving a-interferon have been
reported to develop diabetes associated
with islet cell antibodies and, in certain
instances, severe insulin deficiency. The
list shown in Table 1 is not all-inclusive,
but reflects the more commonly recog-
nized drug-, hormone-, or toxin-induced
forms of diabetes.
Infections. Certain viruses have been as-
sociated with b-cell destruction. Diabetes
occurs in patients with congenital rubella,
although most of these patients have HLA
and immune markers characteristic of type
1 diabetes. In addition, coxsackievirus B,
cytomegalovirus, adenovirus, and mumps
have been implicated in inducing certain
cases of the disease.
Uncommon forms of immune-mediated
diabetes. In this category, there are two
known conditions, and others are likely
to occur. The stiff-man syndrome is an
autoimmune disorder of the central ner-
vous system characterized by stiffness of
the axial muscles with painful spasms.
Patients usually have high titers of the
GAD autoantibodies, and approximately
one-third will develop diabetes.
Anti-insulin receptor antibodies can
cause diabetes by binding to the insulin
receptor, thereby blocking the binding of
insulin to its receptor in target tissues.
However, in some cases, these antibodies
can act as an insulin agonist after binding to
the receptor and can thereby cause hypo-
glycemia. Anti-insulin receptor antibodies
are occasionally found in patients with
systemic lupus erythematosus and other
autoimmune diseases. As in other states of
extreme insulin resistance, patients with
anti-insulin receptor antibodies often have
acanthosis nigricans. In the past, this syn-
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