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develops gradually and at earlier stages is forms result from mutations in other tran- With the exception of that caused by
often not severe enough for the patient to scription factors, including HNF-4a, cancer, damage to the pancreas must be
notice any of the classic symptoms of HNF-1b, insulin promoter factor (IPF)- extensive for diabetes to occur; adreno-
diabetes. Nevertheless, such patients are 1, and NeuroD1. carcinomas that involve only a small
at increased risk of developing macro- Point mutations in mitochondrial portion of the pancreas have been associ-
vascular and microvascular complica- DNA have been found to be associated ated with diabetes. This implies a mech-
tions. Whereas patients with this form of with diabetes and deafness The most anism other than simple reduction in
diabetes may have insulin levels that common mutation occurs at position b-cell mass. If extensive enough, cystic fi-
appear normal or elevated, the higher 3,243 in the tRNA leucine gene, leading brosis and hemochromatosis will also
blood glucose levels in these diabetic to an A-to-G transition. An identical damage b-cells and impair insulin secre-
patients would be expected to result in lesion occurs in the MELAS syndrome tion. Fibrocalculous pancreatopathy may
even higher insulin values had their b-cell (mitochondrial myopathy, encephalopa- be accompanied by abdominal pain radi-
function been normal. Thus, insulin se- thy, lactic acidosis, and stroke-like syn- ating to the back and pancreatic calcifica-
cretion is defective in these patients and drome); however, diabetes is not part of tions identified on X-ray examination.
insufficient to compensate for insulin re- this syndrome, suggesting different phe- Pancreatic fibrosis and calcium stones
sistance. Insulin resistance may improve notypic expressions of this genetic lesion. in the exocrine ducts have been found at
with weight reduction and/or pharmaco- Genetic abnormalities that result in autopsy.
logical treatment of hyperglycemia but is the inability to convert proinsulin to in- Endocrinopathies. Several hormones
seldom restored to normal. The risk of sulin have been identified in a few fami- (e.g., growth hormone, cortisol, gluca-
developing this form of diabetes increases lies, and such traits are inherited in an gon, epinephrine) antagonize insulin ac-
with age, obesity, and lack of physical ac- autosomal dominant pattern. The resul- tion. Excess amounts of these hormones
tivity. It occurs more frequently in women tant glucose intolerance is mild. Similarly, (e.g., acromegaly, Cushing’s syndrome,
with prior GDM and in individuals with the production of mutant insulin mole- glucagonoma, pheochromocytoma, re-
hypertension or dyslipidemia, and its fre- cules with resultant impaired receptor spectively) can cause diabetes. This gen-
quency varies in different racial/ethnic sub- binding has also been identified in a few erally occurs in individuals with
groups. It is often associated with a strong families and is associated with an autoso- preexisting defects in insulin secretion,
genetic predisposition, more so than is the mal inheritance and only mildly impaired and hyperglycemia typically resolves
autoimmune form of type 1 diabetes. How- or even normal glucose metabolism. when the hormone excess is resolved.
ever, the genetics of this form of diabetes Genetic defects in insulin action. There Somatostatinoma- and aldostero-
are complex and not clearly defined. are unusual causes of diabetes that result noma-induced hypokalemia can cause
from genetically determined abnormali- diabetes, at least in part, by inhibiting
Other specific types of diabetes ties of insulin action. The metabolic ab- insulin secretion. Hyperglycemia gener-
Genetic defects of the b-cell. Several normalities associated with mutations of ally resolves after successful removal of
forms of diabetes are associated with the insulin receptor may range from the tumor.
monogenetic defects in b-cell function. hyperinsulinemia and modest hyperglyce- Drug- or chemical-induced diabetes.
These forms of diabetes are frequently mia to severe diabetes. Some individuals Many drugs can impair insulin secretion.
characterized by onset of hyperglycemia with these mutations may have acanthosis These drugs may not cause diabetes by
at an early age (generally before age 25 nigricans. Women may be virilized and themselves, but they may precipitate di-
years). They are referred to as maturity- have enlarged, cystic ovaries. In the past, abetes in individuals with insulin resis-
onset diabetes of the young (MODY) and this syndrome was termed type A insulin tance. In such cases, the classification is
are characterized by impaired insulin se- resistance. Leprechaunism and the Rabson- unclear because the sequence or relative
cretion with minimal or no defects in in- Mendenhall syndrome are two pediatric importance of b-cell dysfunction and in-
sulin action. They are inherited in an syndromes that have mutations in the sulin resistance is unknown. Certain tox-
autosomal dominant pattern. Abnormali- insulin receptor gene with subsequent ins such as Vacor (a rat poison) and
ties at six genetic loci on different chro- alterations in insulin receptor function intravenous pentamidine can perma-
mosomes have been identified to date. and extreme insulin resistance. The former nently destroy pancreatic b-cells. Such
The most common form is associated has characteristic facial features and is drug reactions fortunately are rare. There
with mutations on chromosome 12 in a usually fatal in infancy, while the latter is are also many drugs and hormones that
hepatic transcription factor referred to as associated with abnormalities of teeth and can impair insulin action. Examples in-
hepatocyte nuclear factor (HNF)-1a. A nails and pineal gland hyperplasia. clude nicotinic acid and glucocorticoids.
second form is associated with mutations Alterations in the structure and func- Patients receiving a-interferon have been
in the glucokinase gene on chromosome tion of the insulin receptor cannot be reported to develop diabetes associated
7p and results in a defective glucokinase demonstrated in patients with insulin- with islet cell antibodies and, in certain
molecule. Glucokinase converts glucose resistant lipoatrophic diabetes. Therefore, instances, severe insulin deficiency. The
to glucose-6-phosphate, the metabolism it is assumed that the lesion(s) must reside list shown in Table 1 is not all-inclusive,
of which, in turn, stimulates insulin secre- in the postreceptor signal transduction but reflects the more commonly recog-
tion by the b-cell. Thus, glucokinase pathways. nized drug-, hormone-, or toxin-induced
serves as the “glucose sensor” for the Diseases of the exocrine pancreas. Any forms of diabetes.
b-cell. Because of defects in the glucoki- process that diffusely injures the pancreas Infections. Certain viruses have been
nase gene, increased plasma levels of glu- can cause diabetes. Acquired processes associated with b-cell destruction. Diabe-
cose are necessary to elicit normal levels include pancreatitis, trauma, infection, pan- tes occurs in patients with congenital ru-
of insulin secretion. The less common createctomy, and pancreatic carcinoma. bella, although most of these patients
Table 1dEtiologic classification of diabetes mellitus have HLA and immune markers charac-
teristic of type 1 diabetes. In addition,
I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deficiency)
A. Immune mediated coxsackievirus B, cytomegalovirus, ade-
B. Idiopathic novirus, and mumps have been impli-
II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency cated in inducing certain cases of the
to a predominantly secretory defect with insulin resistance) disease.
III. Other specific types
A. Genetic defects of b-cell function
Uncommon forms of immune-mediated
1. Chromosome 12, HNF-1a (MODY3) diabetes. In this category, there are two
2. Chromosome 7, glucokinase (MODY2) known conditions, and others are likely
3. Chromosome 20, HNF-4a (MODY1) to occur. The stiff-man syndrome is an
4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) autoimmune disorder of the central ner-
5. Chromosome 17, HNF-1b (MODY5)
6. Chromosome 2, NeuroD1 (MODY6) vous system characterized by stiffness of
7. Mitochondrial DNA the axial muscles with painful spasms.
8. Others Patients usually have high titers of the
B. Genetic defects in insulin action GAD autoantibodies, and approximately
1. Type A insulin resistance
2. Leprechaunism
one-third will develop diabetes.
3. Rabson-Mendenhall syndrome Anti-insulin receptor antibodies can
4. Lipoatrophic diabetes cause diabetes by binding to the insulin
5. Others receptor, thereby blocking the binding of
C. Diseases of the exocrine pancreas insulin to its receptor in target tissues.
1. Pancreatitis
2. Trauma/pancreatectomy However, in some cases, these antibodies
3. Neoplasia can act as an insulin agonist after binding
4. Cystic fibrosis to the receptor and can thereby cause
5. Hemochromatosis hypoglycemia. Anti-insulin receptor anti-
6. Fibrocalculous pancreatopathy
7. Others
bodies are occasionally found in patients
D. Endocrinopathies with systemic lupus erythematosus and
1. Acromegaly other autoimmune diseases. As in other
2. Cushing’s syndrome states of extreme insulin resistance, pa-
3. Glucagonoma tients with anti-insulin receptor antibod-
4. Pheochromocytoma
5. Hyperthyroidism ies often have acanthosis nigricans. In the
6. Somatostatinoma past, this syndrome was termed type B
7. Aldosteronoma insulin resistance.
8. Others Other genetic syndromes sometimes
E. Drug or chemical induced
1. Vacor
associated with diabetes. Many genetic
2. Pentamidine syndromes are accompanied by an in-
3. Nicotinic acid creased incidence of diabetes. These in-
4. Glucocorticoids clude the chromosomal abnormalities of
5. Thyroid hormone Down syndrome, Klinefelter syndrome,
6. Diazoxide
7. b-adrenergic agonists and Turner syndrome. Wolfram’s syn-
8. Thiazides drome is an autosomal recessive disorder
9. Dilantin characterized by insulin-deficient diabe-
10. g-Interferon tes and the absence of b-cells at autopsy.
11. Others
F. Infections
Additional manifestations include diabetes
1. Congenital rubella insipidus, hypogonadism, optic atrophy,
2. Cytomegalovirus and neural deafness. Other syndromes are
3. Others listed in Table 1.
G. Uncommon forms of immune-mediated diabetes
1. “Stiff-man” syndrome
2. Anti-insulin receptor antibodies Gestational diabetes mellitus
3. Others For many years, GDM has been defined as
H. Other genetic syndromes sometimes associated with diabetes any degree of glucose intolerance with
1. Down syndrome onset or first recognition during preg-
2. Klinefelter syndrome
3. Turner syndrome
nancy. Although most cases resolve with
4. Wolfram syndrome delivery, the definition applied whether
5. Friedreich ataxia or not the condition persisted after preg-
6. Huntington chorea nancy and did not exclude the possibility
7. Laurence-Moon-Biedl syndrome that unrecognized glucose intolerance
8. Myotonic dystrophy
9. Porphyria may have antedated or begun concomi-
10. Prader-Willi syndrome tantly with the pregnancy. This definition
11. Others facilitated a uniform strategy for detection
IV. Gestational diabetes mellitus and classification of GDM, but its limi-
Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of tations were recognized for many years.
insulin does not, of itself, classify the patient. As the ongoing epidemic of obesity and
practice, a large portion of the population that when a test whose result was above Table 4dScreening for and diagnosis of
with type 2 diabetes remains unaware of the diagnostic threshold is repeated, the GDM
their condition. Thus, it is conceivable second value will be below the diagnostic Perform a 75-g OGTT, with plasma glucose
that the lower sensitivity of A1C at the cut point. This is least likely for A1C, measurement fasting and at 1 and 2 h, at
designated cut point will be offset by the somewhat more likely for FPG, and most 24-28 of weeks gestation in women not
test’s greater practicality, and that wider likely for the 2-h PG. Barring a laboratory previously diagnosed with overt diabetes.
application of a more convenient test error, such patients are likely to have test The OGTT should be performed in the
(A1C) may actually increase the number results near the margins of the threshold morning after an overnight fast of at least
of diagnoses made. for a diagnosis. The healthcare profes- 8 h.
Further research is needed to better sional might opt to follow the patient The diagnosis of GDM is made when any of the
characterize those patients whose glyce- closely and repeat the testing in 3–6 following plasma glucose values are
mic status might be categorized differ- months. exceeded
ently by two different tests (e.g., FPG and The decision about which test to use c Fasting: $92 mg/dl (5.1 mmol/l)
A1C), obtained in close temporal approx- to assess a specific patient for diabetes c 1 h: $180 mg/dl (10.0 mmol/l)
imation. Such discordance may arise from should be at the discretion of the health c 2 h: $153 mg/dl (8.5 mmol/l)
measurement variability, change over care professional, taking into account the
time, or because A1C, FPG, and post- availability and practicality of testing an
challenge glucose each measure different individual patient or groups of patients.
physiological processes. In the setting of Perhaps more important than which di- These new criteria will significantly
an elevated A1C but “nondiabetic” FPG, agnostic test is used, is that the testing for increase the prevalence of GDM, primar-
the likelihood of greater postprandial glu- diabetes be performed when indicated. ily because only one abnormal value, not
cose levels or increased glycation rates There is discouraging evidence indicating two, is sufficient to make the diagnosis.
for a given degree of hyperglycemia may that many at-risk patients still do not re- The ADA recognizes the anticipated sig-
be present. In the opposite scenario (high ceive adequate testing and counseling for nificant increase in the incidence of GDM
FPG yet A1C below the diabetes cut this increasingly common disease, or for its to be diagnosed by these criteria and is
point), augmented hepatic glucose pro- frequently accompanying cardiovascular sensitive to concerns about the “medical-
duction or reduced glycation rates may risk factors. The current diagnostic criteria ization” of pregnancies previously catego-
be present. for diabetes are summarized in Table 3. rized as normal. These diagnostic criteria
As with most diagnostic tests, a test changes are being made in the context of
result diagnostic of diabetes should be Diagnosis of gestational diabetes worrisome worldwide increases in obe-
repeated to rule out laboratory error, GDM carries risks for the mother and sity and diabetes rates, with the intent of
unless the diagnosis is clear on clinical neonate. The Hyperglycemia and Adverse optimizing gestational outcomes for
grounds, such as a patient with classic Pregnancy Outcomes (HAPO) study women and their babies.
symptoms of hyperglycemia or hypergly- (11), a large-scale (;25,000 pregnant Admittedly, there are few data from
cemic crisis. It is preferable that the same women) multinational epidemiologic randomized clinical trials regarding ther-
test be repeated for confirmation, since study, demonstrated that risk of adverse apeutic interventions in women who will
there will be a greater likelihood of con- maternal, fetal, and neonatal outcomes now be diagnosed with GDM based on
currence in this case. For example, if the continuously increased as a function of only one blood glucose value above the
A1C is 7.0% and a repeat result is 6.8%, maternal glycemia at 24-28 weeks, even specified cutpoints (in contrast to the
the diagnosis of diabetes is confirmed. within ranges previously considered nor- older criteria that stipulated at least two
However, there are scenarios in which re- mal for pregnancy. For most complica- abnormal values). Expected benefits to
sults of two different tests (e.g., FPG and tions, there was no threshold for risk. their pregnancies and offspring is inferred
A1C) are available for the same patient. In These results have led to careful reconsid- from intervention trials that focused on
this situation, if the two different tests are eration of the diagnostic criteria for GDM. women with more mild hyperglycemia
both above the diagnostic thresholds, the After deliberations in 2008-2009, the than identified using older GDM diag-
diagnosis of diabetes is confirmed. IADPSG, an international consensus nostic criteria and that found modest
On the other hand, when two differ- group with representatives from multiple benefits (13,14). The frequency of their
ent tests are available in an individual and obstetrical and diabetes organizations, in- follow-up and blood glucose monitoring
the results are discordant, the test whose cluding ADA, developed revised recom- is not yet clear but likely to be less inten-
result is above the diagnostic cut point mendations for diagnosing GDM. The sive than women diagnosed by the older
should be repeated, and the diagnosis is group recommended that all women not criteria. Additional well-designed clinical
made on the basis of the confirmed test. known to have diabetes undergo a 75-g studies are needed to determine the op-
That is, if a patient meets the diabetes OGTT at 24-28 weeks of gestation. Addi- timal intensity of monitoring and treat-
criterion of the A1C (two results $6.5%) tionally, the group developed diagnostic ment of women with GDM diagnosed
but not the FPG (,126 mg/dl or 7.0 cutpoints for the fasting, 1-h, and 2-h by the new criteria (that would not
mmol/l), or vice versa, that person should plasma glucose measurements that con- have met the prior definition of GDM).
be considered to have diabetes. Admit- veyed an odds ratio for adverse outcomes It is important to note that 80-90% of
tedly, in most circumstance the “nondia- of at least 1.75 compared with women women in both of the mild GDM studies
betic” test is likely to be in a range very with mean glucose levels in the HAPO (whose glucose values overlapped with
close to the threshold that defines diabetes. study. Current screening and diagnostic the thresholds recommended herein)
Since there is preanalytic and analytic strategies, based on the IADPSG state- could be managed with lifestyle therapy
variability of all the tests, it is also possible ment (12), are outlined in Table 4. alone.
practice, a large portion of the population that when a test whose result was above Table 4dScreening for and diagnosis of
with type 2 diabetes remains unaware of the diagnostic threshold is repeated, the GDM
their condition. Thus, it is conceivable second value will be below the diagnostic Perform a 75-g OGTT, with plasma glucose
that the lower sensitivity of A1C at the cut point. This is least likely for A1C, measurement fasting and at 1 and 2 h, at
designated cut point will be offset by the somewhat more likely for FPG, and most 24-28 of weeks gestation in women not
test’s greater practicality, and that wider likely for the 2-h PG. Barring a laboratory previously diagnosed with overt diabetes.
application of a more convenient test error, such patients are likely to have test The OGTT should be performed in the
(A1C) may actually increase the number results near the margins of the threshold morning after an overnight fast of at least
of diagnoses made. for a diagnosis. The healthcare profes- 8 h.
Further research is needed to better sional might opt to follow the patient The diagnosis of GDM is made when any of the
characterize those patients whose glyce- closely and repeat the testing in 3–6 following plasma glucose values are
mic status might be categorized differ- months. exceeded
ently by two different tests (e.g., FPG and The decision about which test to use c Fasting: $92 mg/dl (5.1 mmol/l)
A1C), obtained in close temporal approx- to assess a specific patient for diabetes c 1 h: $180 mg/dl (10.0 mmol/l)
imation. Such discordance may arise from should be at the discretion of the health c 2 h: $153 mg/dl (8.5 mmol/l)
measurement variability, change over care professional, taking into account the
time, or because A1C, FPG, and post- availability and practicality of testing an
challenge glucose each measure different individual patient or groups of patients.
physiological processes. In the setting of Perhaps more important than which di- These new criteria will significantly
an elevated A1C but “nondiabetic” FPG, agnostic test is used, is that the testing for increase the prevalence of GDM, primar-
the likelihood of greater postprandial glu- diabetes be performed when indicated. ily because only one abnormal value, not
cose levels or increased glycation rates There is discouraging evidence indicating two, is sufficient to make the diagnosis.
for a given degree of hyperglycemia may that many at-risk patients still do not re- The ADA recognizes the anticipated sig-
be present. In the opposite scenario (high ceive adequate testing and counseling for nificant increase in the incidence of GDM
FPG yet A1C below the diabetes cut this increasingly common disease, or for its to be diagnosed by these criteria and is
point), augmented hepatic glucose pro- frequently accompanying cardiovascular sensitive to concerns about the “medical-
duction or reduced glycation rates may risk factors. The current diagnostic criteria ization” of pregnancies previously catego-
be present. for diabetes are summarized in Table 3. rized as normal. These diagnostic criteria
As with most diagnostic tests, a test changes are being made in the context of
result diagnostic of diabetes should be Diagnosis of gestational diabetes worrisome worldwide increases in obe-
repeated to rule out laboratory error, GDM carries risks for the mother and sity and diabetes rates, with the intent of
unless the diagnosis is clear on clinical neonate. The Hyperglycemia and Adverse optimizing gestational outcomes for
grounds, such as a patient with classic Pregnancy Outcomes (HAPO) study women and their babies.
symptoms of hyperglycemia or hypergly- (11), a large-scale (;25,000 pregnant Admittedly, there are few data from
cemic crisis. It is preferable that the same women) multinational epidemiologic randomized clinical trials regarding ther-
test be repeated for confirmation, since study, demonstrated that risk of adverse apeutic interventions in women who will
there will be a greater likelihood of con- maternal, fetal, and neonatal outcomes now be diagnosed with GDM based on
currence in this case. For example, if the continuously increased as a function of only one blood glucose value above the
A1C is 7.0% and a repeat result is 6.8%, maternal glycemia at 24-28 weeks, even specified cutpoints (in contrast to the
the diagnosis of diabetes is confirmed. within ranges previously considered nor- older criteria that stipulated at least two
However, there are scenarios in which re- mal for pregnancy. For most complica- abnormal values). Expected benefits to
sults of two different tests (e.g., FPG and tions, there was no threshold for risk. their pregnancies and offspring is inferred
A1C) are available for the same patient. In These results have led to careful reconsid- from intervention trials that focused on
this situation, if the two different tests are eration of the diagnostic criteria for GDM. women with more mild hyperglycemia
both above the diagnostic thresholds, the After deliberations in 2008-2009, the than identified using older GDM diag-
diagnosis of diabetes is confirmed. IADPSG, an international consensus nostic criteria and that found modest
On the other hand, when two differ- group with representatives from multiple benefits (13,14). The frequency of their
ent tests are available in an individual and obstetrical and diabetes organizations, in- follow-up and blood glucose monitoring
the results are discordant, the test whose cluding ADA, developed revised recom- is not yet clear but likely to be less inten-
result is above the diagnostic cut point mendations for diagnosing GDM. The sive than women diagnosed by the older
should be repeated, and the diagnosis is group recommended that all women not criteria. Additional well-designed clinical
made on the basis of the confirmed test. known to have diabetes undergo a 75-g studies are needed to determine the op-
That is, if a patient meets the diabetes OGTT at 24-28 weeks of gestation. Addi- timal intensity of monitoring and treat-
criterion of the A1C (two results $6.5%) tionally, the group developed diagnostic ment of women with GDM diagnosed
but not the FPG (,126 mg/dl or 7.0 cutpoints for the fasting, 1-h, and 2-h by the new criteria (that would not
mmol/l), or vice versa, that person should plasma glucose measurements that con- have met the prior definition of GDM).
be considered to have diabetes. Admit- veyed an odds ratio for adverse outcomes It is important to note that 80-90% of
tedly, in most circumstance the “nondia- of at least 1.75 compared with women women in both of the mild GDM studies
betic” test is likely to be in a range very with mean glucose levels in the HAPO (whose glucose values overlapped with
close to the threshold that defines diabetes. study. Current screening and diagnostic the thresholds recommended herein)
Since there is preanalytic and analytic strategies, based on the IADPSG state- could be managed with lifestyle therapy
variability of all the tests, it is also possible ment (12), are outlined in Table 4. alone.