ADA Classification and Diagnosis of Diabetes

Diabetes Care Volume 45, Supplement 1, January 2022 S17
2. Classification and Diagnosis of American Diabetes Association

Professional Practice Committee*
Diabetes: Standards of Medical
Care in Diabetes—2022
Diabetes Care 2022;45(Suppl. 1):S17–S38 | https://doi.org/10.2337/dc22-S002
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2. CLASSIFICATION AND DIAGNOSIS OF DIABETES
The American Diabetes Association (ADA) “Standards of Medical Care in Dia-
betes” includes the ADA’s current clinical practice recommendations and is
intended to provide the components of diabetes care, general treatment goals
and guidelines, and tools to evaluate quality of care. Members of the ADA Profes-
sional Practice Committee, a multidisciplinary expert committee (https://doi
.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care
annually, or more frequently as warranted. For a detailed description of ADA
standards, statements, and reports, as well as the evidence-grading system for
ADA’s clinical practice recommendations, please refer to the Standards of Care
Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment
on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
CLASSIFICATION
Diabetes can be classified into the following general categories:
1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to abso-

lute insulin deficiency, including latent autoimmune diabetes of adulthood)
2. Type 2 diabetes (due to a progressive loss of adequate b-cell insulin secretion
frequently on the background of insulin resistance)
3. Specific types of diabetes due to other causes, e.g., monogenic diabetes syn-
dromes (such as neonatal diabetes and maturity-onset diabetes of the young),
diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis),
and drug- or chemical-induced diabetes (such as with glucocorticoid use, in
the treatment of HIV/AIDS, or after organ transplantation)
4. Gestational diabetes mellitus (diabetes diagnosed in the second or third tri-
mester of pregnancy that was not clearly overt diabetes prior to gestation) *A complete list of members of the American
Diabetes Association Professional Practice Com-
mittee can be found at https://doi.org/10.2337/
This section reviews most common forms of diabetes but is not comprehensive. For dc22-SPPC.
additional information, see the American Diabetes Association (ADA) position state-
Suggested citation: American Diabetes Asso-
ment “Diagnosis and Classification of Diabetes Mellitus” (1). ciation Professional Practice Committee. 2. Classi-
fication and diagnosis of diabetes: Standards of
Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical Medical Care in Diabetes—2022. Diabetes Care
2022;45(Suppl. 1):S17–S38
presentation and disease progression may vary considerably. Classification is impor-
tant for determining therapy, but some individuals cannot be clearly classified as © 2021 by the American Diabetes Association.
having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms Readers may use this article as long as the
work is properly cited, the use is educational
of type 2 diabetes occurring only in adults and type 1 diabetes only in children are and not for profit, and the work is not altered.
no longer accurate, as both diseases occur in both age-groups. Children with type More information is available at https://
1 diabetes often present with the hallmark symptoms of polyuria/polydipsia, and diabetesjournals.org/journals/pages/license.
S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 45, Supplement 1, January 2022
approximately half present with diabetic clinical, pathophysiological, and genetic likely to have progressive autoimmune
ketoacidosis (DKA) (2–4). The onset of characteristics to more precisely define b-cell destruction (16), thus accelerating
type 1 diabetes may be more variable the subsets of diabetes that are cur- insulin initiation prior to deterioration of
in adults; they may not present with rently clustered into the type 1 diabetes glucose control or development of DKA
the classic symptoms seen in children versus type 2 diabetes nomenclature (6,17).
and may experience temporary remis- with the goal of optimizing personalized The paths to b-cell demise and dys-
sion from the need for insulin (5–7). treatment approaches. Many of these function are less well defined in type 2
The features most useful in discrimina- studies show great promise and may diabetes, but deficient b-cell insulin
tion of type 1 diabetes include younger soon be incorporated into the diabetes secretion, frequently in the setting of
age at diagnosis (<35 years) with lower classification system (13). insulin resistance, appears to be the
BMI (<25 kg/m2), unintentional weight Characterization of the underlying common denominator. Type 2 diabetes is
loss, ketoacidosis, and glucose >360 pathophysiology is more precisely devel- associated with insulin secretory defects
mg/dL (20 mmol/L) at presentation (8). oped in type 1 diabetes than in type 2 related to genetics, inflammation, and

Occasionally, patients with type 2 diabe- diabetes. It is now clear from prospective metabolic stress. Future classification
tes may present with DKA (9,10), partic- studies that the persistent presence of schemes for diabetes will likely focus on
ularly ethnic and racial minorities (11). two or more islet autoantibodies is a the pathophysiology of the underlying
It is important for the provider to real- near certain predictor of clinical diabetes b-cell dysfunction (12,13,18–20).
ize that classification of diabetes type is (14). The rate of progression is depen-
not always straightforward at presenta- dent on the age at first detection of DIAGNOSTIC TESTS FOR DIABETES
tion and that misdiagnosis is common autoantibody, number of autoantibodies, Diabetes may be diagnosed based on
(e.g., adults with type 1 diabetes mis- autoantibody specificity, and autoanti- plasma glucose criteria, either the fast-
diagnosed as having type 2 diabetes; body titer. Glucose and A1C levels rise ing plasma glucose (FPG) value or the
individuals with maturity-onset diabetes well before the clinical onset of diabetes, 2-h plasma glucose (2-h PG) value dur-
of the young [MODY] misdiagnosed as making diagnosis feasible well before the ing a 75-g oral glucose tolerance test
having type 1 diabetes, etc.). Although onset of DKA. Three distinct stages of (OGTT), or A1C criteria (21) (Table 2.2).
difficulties in distinguishing diabetes type 1 diabetes can be identified (Table Generally, FPG, 2-h PG during 75-g
type may occur in all age-groups at 2.1) and serve as a framework for future OGTT, and A1C are equally appropriate
onset, the diagnosis becomes more research and regulatory decision-making for diagnostic screening. It should be
obvious over time in people with b-cell (12,15). There is debate as to whether noted that the screening tests do not
deficiency. slowly progressive autoimmune diabetes necessarily detect diabetes in the same
In both type 1 and type 2 diabetes, with an adult onset should be termed individuals. The efficacy of interventions
various genetic and environmental fac- latent autoimmune diabetes in adults for primary prevention of type 2 diabe-
tors can result in the progressive loss of (LADA) or type 1 diabetes. The clinical tes (22,23) has mainly been demon-
b-cell mass and/or function that mani- priority with detection of LADA is aware- strated among individuals who have
fests clinically as hyperglycemia. Once ness that slow autoimmune b-cell de- impaired glucose tolerance (IGT) with or
hyperglycemia occurs, people with all struction can occur in adults leading to a without elevated fasting glucose, not
forms of diabetes are at risk for devel- long duration of marginal insulin secre- for individuals with isolated impaired
oping the same chronic complications, tory capacity. For the purpose of this fasting glucose (IFG) or for those with
although rates of progression may differ. classification, all forms of diabetes medi- prediabetes defined by A1C criteria.
The identification of individualized ther- ated by autoimmune b-cell destruction The same tests may be used to
apies for diabetes in the future will be are included under the rubric of type 1 screen for and diagnose diabetes and to
informed by better characterization of diabetes. Use of the term LADA is com- detect individuals with prediabetes
the many paths to b-cell demise or dys- mon and acceptable in clinical practice (Table 2.2 and Table 2.5) (24). Diabetes
function (12). Across the globe many and has the practical impact of heighten- may be identified anywhere along
groups are working on combining ing awareness of a population of adults the spectrum of clinical scenarios—in
Table 2.1—Staging of type 1 diabetes (12,15)

Stage 1 Stage 2 Stage 3
Characteristics Autoimmunity Autoimmunity Autoimmunity
Normoglycemia Dysglycemia Overt hyperglycemia
Presymptomatic Presymptomatic Symptomatic
Diagnostic criteria Multiple islet autoantibodies Islet autoantibodies (usually multiple) Autoantibodies may become absent
No IGT or IFG Dysglycemia: IFG and/or IGT Diabetes by standard criteria
FPG 100–125 mg/dL (5.6–6.9 mmol/L)
2-h PG 140–199 mg/dL (7.8–11.0 mmol/L)
A1C 5.7–6.4% (39–47 mmol/mol) or $10%
increase in A1C
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; 2-h PG, 2-h plasma glucose.
care.diabetesjournals.org Classification and Diagnosis of Diabetes S19
people with diabetes in both Clinical

Table 2.2—Criteria for the diagnosis of diabetes
Laboratory Improvement Amendments
FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*
(CLIA)-regulated and CLIA-waived set-
OR tings. Point-of-care A1C assays have not
2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described been prospectively studied for the diag-
by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose nosis of diabetes and are not recom-
dissolved in water.* mended for diabetes diagnosis; if used,
OR they should be confirmed with a vali-
A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method dated measure. In the U.S., point-of-
that is NGSP certified and standardized to the DCCT assay.* care A1C is a laboratory test that limits
CLIA regulation. As discussed in Section
OR
6, “Glycemic Targets” (https://doi.org/
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 10.2337/dc22-S006), point-of-care A1C
plasma glucose $200 mg/dL (11.1 mmol/L).

assays may be more generally applied
DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glu- for assessment of glycemic control in the
cose tolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the clinic.
absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from A1C has several advantages com-
the same sample or in two separate test samples.
pared with FPG and OGTT, including
greater convenience (fasting not req-
uired), greater preanalytical stability,
seemingly low-risk individuals who hap- and less day-to-day perturbations dur-
the possibility of A1C assay
pen to have glucose testing, in individu- ing stress, changes in diet, or illness.
interference and consider-
als screened based on diabetes risk However, these advantages may be off-
ation of using an assay with-
assessment, and in symptomatic patients.
out interference or plasma set by the lower sensitivity of A1C at
For additional details on the evidence
blood glucose criteria to the designated cut point, greater cost,
used to establish the criteria for the diag-
diagnose diabetes. B limited availability of A1C testing in cer-
nosis of diabetes, prediabetes and abnor-
2.3 In conditions associated with tain regions of the developing world,
mal glucose tolerance (OFG, IGT), see the
and the imperfect correlation between
ADA position statement “Diagnosis and an altered relationship between
Classification of Diabetes Mellitus” (1) A1C and glycemia, such as A1C and average glucose in certain indi-
and other reports (21,25,26). hemoglobinopathies including viduals. The A1C test, with a diagnostic
sickle cell disease, pregnancy threshold of $6.5% (48 mmol/mol),
Fasting and 2-Hour Plasma Glucose (second and third trimesters diagnoses only 30% of the diabetes
The FPG and 2-h PG may be used to and the postpartum period), cases identified collectively using A1C,
diagnose diabetes (Table 2.2). The con- glucose-6-phosphate dehydro- FPG, or 2-h PG, according to National
cordance between the FPG and 2-h PG genase deficiency, HIV, hemodi- Health and Nutrition Examination Sur-
tests is imperfect, as is the concordance alysis, recent blood loss or vey (NHANES) data (29). Despite these
between A1C and either glucose-based transfusion, or erythropoietin limitations with A1C, in 2009 the Inter-
test. Compared with FPG and A1C cut therapy, only plasma blood glu- national Expert Committee added A1C
points, the 2-h PG value diagnoses cose criteria should be used to the diagnostic criteria with the goal
more people with prediabetes and dia- to diagnose diabetes. (See OTHER of increased screening (21).
betes (27). In people in whom there is CONDITIONS ALTERING THE RELATIONSHIP
When using A1C to diagnose diabe-
discordance between A1C values and OF A1C AND GLYCEMIA below for
tes, it is important to recognize that
glucose values, FPG and 2-h PG are more information.) B A1C is an indirect measure of average
more accurate (28). 2.4 Adequate carbohydrate intake blood glucose levels and to take other
(at least 150 g/day) should be factors into consideration that may
A1C assured for 3 days prior to impact hemoglobin glycation indepen-
oral glucose tolerance testing dently of glycemia, such as hemodialy-
Recommendations
as a screen for diabetes. A sis, pregnancy, HIV treatment (30,31),
2.1 To avoid misdiagnosis or
age, race/ethnicity, genetic background,
missed diagnosis, the A1C
and anemia/hemoglobinopathies. (See
test should be performed
The A1C test should be performed using OTHER CONDITIONS ALTERING THE RELATIONSHIP OF
using a method that is certi-
a method that is certified by the NGSP A1C AND GLYCEMIA below for more
fied by the NGSP and stan-
(www.ngsp.org) and standardized or information.)
dardized to the Diabetes
traceable to the Diabetes Control and
Control and Complications
Complications Trial (DCCT) reference Age
Trial (DCCT) assay. B
assay. Point-of-care A1C assays may be The epidemiologic studies that formed
2.2 Marked discordance between
NGSP certified and cleared by the U.S. the basis for recommending A1C to
measured A1C and plasma
Food and Drug Administration (FDA) for diagnose diabetes included only adult
glucose levels should raise
use in monitoring glycemic control in populations (29). However, recent ADA
clinical guidance concluded that A1C, recent report in Afro-Caribbean people diagnosis is made on the basis of the
FPG, or 2-h PG can be used to test for demonstrated a lower A1C than pre- confirmatory screening test. For exam-
prediabetes or type 2 diabetes in chil- dicted by glucose levels (43). Despite ple, if a patient meets the diabetes cri-
dren and adolescents (see SCREENING AND these and other reported differences, terion of the A1C (two results $6.5%
TESTING FOR PREDIABETES AND TYPE 2 DIABETES IN the association of A1C with risk for [48 mmol/mol]) but not FPG (<126 mg/
CHILDREN AND ADOLESCENTS below for addi- complications appears to be similar in dL [7.0 mmol/L]), that person should
tional information) (32). African Americans and non-Hispanic nevertheless be considered to have
Whites (44,45). In the Taiwanese popu- diabetes.
Race/Ethnicity/Hemoglobinopathies lation, age and sex have been reported Each of the screening tests has pre-
Hemoglobin variants can interfere with to be associated with increased A1C in analytic and analytic variability, so it is
the measurement of A1C, although men (46); the clinical implications of possible that a test yielding an abnor-
most assays in use in the U.S. are unaf- this finding are unclear at this time. mal result (i.e., above the diagnostic
fected by the most common variants. threshold), when repeated, will produce

Marked discrepancies between mea- Other Conditions Altering the Relationship a value below the diagnostic cut point.
sured A1C and plasma glucose levels of A1C and Glycemia This scenario is likely for FPG and 2-h
should prompt consideration that the In conditions associated with increased PG if the glucose samples remain at
A1C assay may not be reliable for that red blood cell turnover, such as sickle room temperature and are not centri-
individual. For patients with a hemoglo- cell disease, pregnancy (second and fuged promptly. Because of the poten-
bin variant but normal red blood cell third trimesters), glucose-6-phosphate tial for preanalytic variability, it is critical
turnover, such as those with the sickle dehydrogenase deficiency (47,48), he- that samples for plasma glucose be
cell trait, an A1C assay without interfer- modialysis, recent blood loss or transfu- spun and separated immediately after
ence from hemoglobin variants should sion, or erythropoietin therapy, only they are drawn. If patients have test
be used. An updated list of A1C assays plasma blood glucose criteria should be results near the margins of the diagnos-
with interferences is available at www. used to diagnose diabetes (49). A1C is tic threshold, the health care professional
ngsp.org/interf.asp. less reliable than blood glucose mea- should discuss signs and symptoms with
African Americans heterozygous for surement in other conditions such as the patient and repeat the test in 3–6
the common hemoglobin variant HbS the postpartum state (50–52), HIV months.
may have, for any given level of mean treated with certain protease inhibitors People should consume a mixed diet
glycemia, lower A1C by about 0.3% (PIs) and nucleoside reverse transcrip- with at least 150 g of carbohydrate on
compared with those without the trait tase inhibitors (NRTIs) (30), and iron- the 3 days prior to oral glucose toler-
(33). Another genetic variant, X-linked deficient anemia (53). ance testing (55–57). Fasting and carbo-
hydrate restriction can falsely elevate
glucose-6-phosphate dehydrogenase
glucose level with an oral glucose
G202A, carried by 11% of African Amer- Confirming the Diagnosis
challenge.
icans, was associated with a decrease in Unless there is a clear clinical diagnosis
A1C of about 0.8% in homozygous men (e.g., patient in a hyperglycemic crisis or
Diagnosis
and 0.7% in homozygous women com- with classic symptoms of hyperglycemia
pared with those without the variant and a random plasma glucose $200 In a patient with classic symptoms,
measurement of plasma glucose is suffi-
(34). For example, in Tanzania, where mg/dL [11.1 mmol/L]), diagnosis re-
cient to diagnose diabetes (symptoms
there is a high likelihood of hemoglobin- quires two abnormal screening test
of hyperglycemia or hyperglycemic crisis
opathies in people with HIV, A1C may results, either from the same sample
plus a random plasma glucose $200
be lower than expected based on glu- (54) or in two separate test samples. If
mg/dL [11.1 mmol/L]). In these cases,
cose, limiting its usefulness for screen- using two separate test samples, it is
knowing the plasma glucose level is crit-
ing (35). recommended that the second test,
ical because, in addition to confirming
Even in the absence of hemoglobin which may either be a repeat of the ini-
that symptoms are due to diabetes, it
variants, A1C levels may vary with race/ tial test or a different test, be per-
will inform management decisions.
ethnicity independently of glycemia formed without delay. For example, if
Some providers may also want to know
(36–38). For example, African Americans the A1C is 7.0% (53 mmol/mol) and a
the A1C to determine the chronicity of
may have higher A1C levels than non- repeat result is 6.8% (51 mmol/mol),
the hyperglycemia. The criteria to diag-
Hispanic Whites with similar fasting and the diagnosis of diabetes is confirmed. nose diabetes are listed in Table 2.2.
postglucose load glucose levels (39). If two different tests (such as A1C and
Though conflicting data exists, African FPG) are both above the diagnostic
TYPE 1 DIABETES
Americans may also have higher levels threshold when analyzed from the same
of fructosamine and glycated albumin sample or in two different test samples, Recommendations
and lower levels of 1,5-anhydroglucitol, this also confirms the diagnosis. On the 2.5 Screening for presympto-
suggesting that their glycemic burden other hand, if a patient has discordant matic type 1 diabetes using
(particularly postprandially) may be results from two different tests, then screening tests that detect
higher (40,41). Similarly, A1C levels may the test result that is above the diag- autoantibodies to insulin, glu-
be higher for a given mean glucose nostic cut point should be repeated,
tamic acid decarboxylase (GAD),
concentration when measured with with careful consideration of the possi-
islet antigen 2, or zinc transporter
continuous glucose monitoring (42). A bility of A1C assay interference. The
insulin needs for months or years and alone or in combination with other
8 is currently recommended in
eventually become dependent on insulin checkpoint inhibitors (70). To date, risk
the setting of a research study
for survival and are at risk for DKA cannot be predicted by family history or
or can be considered an option
(5–7,64,65). At this latter stage of the dis- autoantibodies, so all providers adminis-
for first-degree family members
ease, there is little or no insulin secretion, tering these medications should be
of a proband with type 1 diabe- as manifested by low or undetectable mindful of this adverse effect and edu-
tes. B levels of plasma C-peptide. Immune- cate patients appropriately.
2.6 Development of and persis- mediated diabetes is the most common
tence of multiple islet auto- form of diabetes in childhood and adoles- Idiopathic Type 1 Diabetes
antibodies is a risk factor for cence, but it can occur at any age, even Some forms of type 1 diabetes have no
clinical diabetes and may in the 8th and 9th decades of life. known etiologies. These patients have
serve as an indication for Autoimmune destruction of b-cells has permanent insulinopenia and are prone
intervention in the setting of multiple genetic factors and is also to DKA but have no evidence of b-cell

a clinical trial or screening for related to environmental factors that are autoimmunity. However, only a minority
stage 2 type 1 diabetes. B still poorly defined. Although patients do of patients with type 1 diabetes fall into
not typically have obesity when they pre- this category. Individuals with autoanti-
sent with type 1 diabetes, obesity is body-negative type 1 diabetes of Afri-
Immune-Mediated Diabetes
increasingly common in the general pop- can or Asian ancestry may suffer from
This form, previously called “insulin-
ulation; as such, obesity should not pre- episodic DKA and exhibit varying
dependent diabetes” or “juvenile-onset
clude testing for type 1 diabetes. People degrees of insulin deficiency between
diabetes,” accounts for 5–10% of diabe-
with type 1 diabetes are also prone to episodes (possibly ketosis-prone diabe-
tes and is due to cellular-mediated auto-
other autoimmune disorders such as tes [71]). This form of diabetes is
immune destruction of the pancreatic
Hashimoto thyroiditis, Graves disease,
b-cells. Autoimmune markers include strongly inherited and is not HLA associ-
celiac disease, Addison disease, vitiligo, ated. An absolute requirement for insu-
islet cell autoantibodies and autoanti- autoimmune hepatitis, myasthenia gravis,
bodies to GAD (glutamic acid decarboxyl- lin replacement therapy in affected
and pernicious anemia (see Section 4,
ase, GAD65), insulin, the tyrosine patients may be intermittent. Future
“Comp-rehensive Medical Evaluation and
phosphatases islet antigen 2 (IA-2) and research is needed to determine the
Assessment of Comorbidities,” https://
IA-2b, and zinc transporter 8. Numerous cause of b-cell destruction in this rare
doi.org/10.2337/dc22-S004). Type 1 dia-
clinical studies are being conducted to clinical scenario.
betes can be associated with monogenic
test various methods of preventing type polyglandular autoimmune syndromes
1 diabetes in those with evidence of islet Screening for Type 1 Diabetes Risk
including immune dysregulation, polyen-
autoimmunity (www.clinicaltrials.gov and The incidence and prevalence of type 1
docrinopathy, enteropathy, and X-linked
www.trialnet.org/our-research/prevention- diabetes are increasing (72). Patients with
(IPEX) syndrome, which is an early-onset
studies) (14,17,58–61). Stage 1 of type 1 type 1 diabetes often present with acute
systemic autoimmune genetic disorder
diabetes is defined by the presence of symptoms of diabetes and markedly ele-
caused by mutation of the forkhead box
two or more of these autoimmune protein 3 (FOXP3) gene, and another vated blood glucose levels, and 40–60%
markers. The disease has strong HLA asso- caused by the autoimmune regulator are diagnosed with life-threatening DKA
ciations, with linkage to the DQB1 and (AIRE) gene mutation (66,67). As indi- (2–4). Multiple studies indicate that mea-
DRB1 haplotypes, and genetic screening cated by the names, these disorders are suring islet autoantibodies in relatives of
has been used in some research studies associated with other autoimmune and those with type 1 diabetes (15) or in
to identify high risk populations. Specific rheumatological diseases. children from the general population
alleles in these genes can be either predis- Introduction of immunotherapy, spe- (73,74) can effectively identify those who
posing or protective (Table 2.1). cifically checkpoint inhibitors, for cancer will develop type 1 diabetes. A study
The rate of b-cell destruction is quite treatment has led to unexpected adverse reported the risk of progression to type 1
variable, being rapid in some individuals events including immune system activa- diabetes from the time of seroconversion
(particularly but not exclusively in infants tion precipitating autoimmune disease. to autoantibody positivity in three pediat-
and children) and slow in others (mainly Fulminant onset of type 1 diabetes can ric cohorts from Finland, Germany, and
but not exclusively adults) (62,63). Chil- develop, with DKA and low or undetect- the U.S. Of the 585 children who devel-
dren and adolescents often present with able levels of C-peptide as a marker of oped more than two autoantibodies,
DKA as the first manifestation of the dis- endogenous b-cell function (68,69). nearly 70% developed type 1 diabetes
ease, and the rates in the U.S. have Fewer than half of these patients have within 10 years and 84% within 15 years
increased dramatically over the past 20 autoantibodies that are seen in type 1 (14). These findings are highly significant
years (2–4). Others have modest fasting diabetes, supporting alternate pathobiol- because while the German group was
hyperglycemia that can rapidly change to ogy. This immune-related adverse event recruited from offspring of parents with
severe hyperglycemia and/or DKA with occurs in just under 1% of checkpoint type 1 diabetes, the Finnish and American
infection or other stress. Adults may inhibitor–treated patients but most com- groups were recruited from the general
retain sufficient b-cell function to pre- monly occurs with agents that block the population. Remarkably, the findings in all
vent DKA for many years; such individu- programmed cell death protein 1/pro- three groups were the same, suggesting
als may have remission or decreased grammed cell death ligand 1 pathway that the same sequence of events led to
clinical disease in both “sporadic” and

2.8 Testing for prediabetes and/ 2.14 Risk-based screening for predi-
familial cases of type 1 diabetes. Indeed,
or type 2 diabetes in asymp- abetes and/or type 2 diabetes
the risk of type 1 diabetes increases as
tomatic people should be should be considered after the
the number of relevant autoantibodies
considered in adults of any onset of puberty or after 10
detected increases (60,75,76). In The
age with overweight or obe- years of age, whichever occurs
Environmental Determinants of Diabetes
sity (BMI $25 kg/m2 or $23 earlier, in children and adoles-
in the Young (TEDDY) study, type 1 diabe-
kg/m2 in Asian Americans) cents with overweight (BMI
tes developed in 21% of 363 subjects
who have one or more risk $85th percentile) or obesity
with at least one autoantibody at 3 years factors (Table 2.3). B
of age (77). Such testing, coupled with (BMI $95th percentile) and
2.9 For all people, screening should who have one or more risk
education about diabetes symptoms and begin at age 35 years. B
close follow-up, has been shown to factor for diabetes. (See Table
2.10 If tests are normal, repeat 2.4 for evidence grading of
enable earlier diagnosis and prevent DKA screening recommended at a

(78,79). risk factors.) B
minimum of 3-year intervals 2.15 People with HIV should be
While widespread clinical screening of is reasonable, sooner with
asymptomatic low-risk individuals is not screened for diabetes and
symptoms or change in risk
currently recommended due to lack of prediabetes with a fasting
(i.e., weight gain). C
approved therapeutic interventions, sev- glucose test before starting
2.11 To screen for prediabetes and
eral innovative research screening pro- antiretroviral therapy, at the
type 2 diabetes, fasting plasma
grams are available in Europe (e.g., Fr1da, time of switching antiretrovi-
glucose, 2-h plasma glucose
www.gppad.org) and the U.S. (www ral therapy, and 3 6 months
during 75-g oral glucose toler-
.trialnet.org, www.askhealth.org). Partici- ance test, and A1C are each after starting or switching
pation should be encouraged to acceler- appropriate (Table 2.2 and antiretroviral therapy. If ini-
ate development of evidence-based Table 2.5). B tial screening results are nor-
clinical guidelines for the general popula- 2.12 When using oral glucose tol- mal, fasting glucose should
tion and relatives of those with type 1 erance testing as a screen for be checked annually. E
diabetes. Individuals who test positive diabetes, adequate carbohy-
should be counseled about the risk of drate intake (at least 150 g/
developing diabetes, diabetes symptoms, Prediabetes
day) should be assured for 3
and DKA prevention. Numerous clinical “Prediabetes” is the term used for indi-
days prior to testing. A
studies are being conducted to test vari- viduals whose glucose levels do not
2.13 In people with prediabetes
ous methods of preventing and treating meet the criteria for diabetes yet have
and type 2 diabetes, identify
stage 2 type 1 diabetes in those with evi- abnormal carbohydrate metabolism
and treat cardiovascular dis-
dence of autoimmunity with promising (44,45). People with prediabetes are
ease risk factors. A
results (see www.clinicaltrials.gov and defined by the presence of IFG and/or
www.trialnet.org). Delay of overt diabetes
development in stage 2 type 1 diabetes Table 2.3—Criteria for screening for diabetes or prediabetes in asymptomatic
with the anti-CD3 antibody teplizumab in adults
relatives at risk for type 1 diabetes was 1. Testing should be considered in adults with overweight or obesity (BMI $25 kg/m2 or
reported in 2019, with an extension of $23 kg/m2 in Asian Americans) who have one or more of the following risk factors:
the randomized controlled trial in 2021 First-degree relative with diabetes
(80,81). Based on these data, this agent High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian
has been submitted to the FDA for the American, Pacific Islander)
indication of delay or prevention of clini- History of CVD
Hypertension ($140/90 mmHg or on therapy for hypertension)
cal type 1 diabetes in at-risk individuals.
HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL
Neither this agent nor others in this cate- (2.82 mmol/L)
gory are currently available for clinical Women with polycystic ovary syndrome
use. Physical inactivity
Other clinical conditions associated with insulin resistance (e.g., severe obesity,
acanthosis nigricans)
PREDIABETES AND TYPE 2 2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly.
DIABETES
3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years.
Recommendations 4. For all other patients, testing should begin at age 35 years.
2.7 Screening for prediabetes and
5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with
type 2 diabetes with an infor- consideration of more frequent testing depending on initial results and risk status.
mal assessment of risk factors
or validated risk calculator 6. People with HIV
should be done in asymptom- CVD, cardiovascular disease; GDM, gestational diabetes mellitus; IFG, impaired fasting glu-
atic adults. B cose; IGT, impaired glucose tolerance.
Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in

Hence, it is reasonable to consider an
asymptomatic children and adolescents in a clinical setting (254) A1C range of 5.7–6.4% (39–47 mmol/
Screening should be considered in youth* who have overweight ($85th percentile) or mol) as identifying individuals with predi-
obesity ($95th percentile) A and who have one or more additional risk factors based on abetes. Similar to those with IFG and/or
the strength of their association with diabetes: IGT, individuals with A1C of 5.7–6.4%
Maternal history of diabetes or GDM during the child’s gestation A (39–47 mmol/mol) should be informed
Family history of type 2 diabetes in first- or second-degree relative A of their increased risk for diabetes and
Race/ethnicity (Native American, African American, Latino, Asian American, Pacific
Islander) A
CVD and counseled about effective strat-
Signs of insulin resistance or conditions associated with insulin resistance (acanthosis egies to lower their risks (see Section 3,
nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for- “Prevention or Delay of Type 2 Diabetes
gestational-age birth weight) B and Associated Comorbidities,” https://
GDM, gestational diabetes mellitus. *After the onset of puberty or after 10 years of age, doi.org/10.2337/dc22-S003). Similar to
whichever occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals glucose measurements, the continuum of

(or more frequently if BMI is increasing or risk factor profile deteriorating) is recommended. risk is curvilinear, so as A1C rises, the dia-
Reports of type 2 diabetes before age 10 years exist, and this can be considered with betes risk rises disproportionately (84).
numerous risk factors. Aggressive interventions and vigilant fol-
low-up should be pursued for those con-
IGT and/or A1C 5.7–6.4% (39–47 mmol/ defined by A1C criteria demonstrated a sidered at very high risk (e.g., those with
mol) (Table 2.5). Prediabetes should not strong, continuous association between A1C >6.0% [42 mmol/mol]).
be viewed as a clinical entity in its own A1C and subsequent diabetes. In a sys- Table 2.5 summarizes the categories
right, but rather as risk factor for pro- tematic review of 44,203 individuals from of prediabetes and Table 2.3 the criteria
gression to diabetes and cardiovascular 16 cohort studies with a follow-up inter- for screening for prediabetes. The ADA
disease (CVD). Criteria for screening for val averaging 5.6 years (range 2.8–12 diabetes risk test is an additional option
diabetes or prediabetes in asymptom- years), those with A1C between 5.5% for assessment to determine the appro-
atic adults are outlined in Table 2.3. and 6.0% (between 37 and 42 mmol/ priateness of screening for diabetes or
Prediabetes is associated with obesity mol) had a substantially increased risk of prediabetes in asymptomatic adults
(especially abdominal or visceral obe- diabetes (5-year incidence from 9% to (Fig. 2.1) (diabetes.org/socrisktest). For
sity), dyslipidemia with high triglycerides 25%). Those with an A1C range of additional background regarding risk
and/or low HDL cholesterol, and hyper- 6.0–6.5% (42–48 mmol/mol) had a 5- factors and screening for prediabetes,
tension. The presence of prediabetes year risk of developing diabetes between see SCREENING AND TESTING FOR PREDIABETES AND
should prompt comprehensive screen- 25% and 50% and a relative risk 20 times TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS and
ing for cardiovascular risk factors. higher compared with A1C of 5.0% (31 also SCREENING AND TESTING FOR PREDIABETES AND
mmol/mol) (84). In a community-based TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS
Diagnosis study of African American and non-His- below. For details regarding individuals
IFG is defined as FPG levels from 100 to panic White adults without diabetes, with prediabetes most likely to benefit
125 mg/dL (from 5.6 to 6.9 mmol/L) baseline A1C was a stronger predictor of from a formal behavioral or lifestyle
(82,83) and IGT as 2-h PG levels during subsequent diabetes and cardiovascular intervention, see Section 3, “Prevention
75-g OGTT from 140 to 199 mg/dL events than fasting glucose (85). Other or Delay of Type 2 Diabetes and Associ-
(from 7.8 to 11.0 mmol/L) (25). It analyses suggest that A1C of 5.7% (39 ated Comorbidities” (https://doi.org/
should be noted that the World Health mmol/mol) or higher is associated with a 10.2337/dc22-S003).
Organization and numerous other dia- diabetes risk similar to that of the high-
betes organizations define the IFG lower risk participants in the Diabetes Preven- Type 2 Diabetes
limit at 110 mg/dL (6.1 mmol/L). tion Program (DPP) (86), and A1C at Type 2 diabetes, previously referred to
As with the glucose measures, several baseline was a strong predictor of the as “noninsulin-dependent diabetes” or
prospective studies that used A1C to pre- development of glucose-defined diabetes “adult-onset diabetes,” accounts for
dict the progression to diabetes as during the DPP and its follow-up (87). 90–95% of all diabetes. This form
encompasses individuals who have rel-
Table 2.5—Criteria defining prediabetes* ative (rather than absolute) insulin
FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) deficiency and have peripheral insulin
OR
resistance. At least initially, and often
throughout their lifetime, these indi-
2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT)
viduals may not need insulin treat-
OR ment to survive.
A1C 5.7–6.4% (39–47 mmol/mol) There are various causes of type 2
diabetes. Although the specific etiolo-
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; gies are not known, autoimmune
OGTT, oral glucose tolerance test; 2-h PG, 2-h plasma glucose. *For all three tests, risk is
continuous, extending below the lower limit of the range and becoming disproportionately
destruction of b-cells does not occur,
greater at the higher end of the range. and patients do not have any of the
other known causes of diabetes. Most,
Figure 2.1—ADA risk test (diabetes.org/socrisktest).
but not all, patients with type 2 diabe- distributed predominantly in the certain drugs (e.g., corticosteroids, atyp-
tes have overweight or obesity. Excess abdominal region. ical antipsychotics, and sodium–glucose
weight itself causes some degree of DKA seldom occurs spontaneously in cotransporter 2 inhibitors) (88,89). Type
insulin resistance. Patients who do not type 2 diabetes; when seen, it usually 2 diabetes frequently goes undiagnosed
have obesity or overweight by tradi- arises in association with the stress of for many years because hyperglycemia
tional weight criteria may have an another illness such as infection, myo- develops gradually and, at earlier
increased percentage of body fat cardial infarction, or with the use of stages, is often not severe enough for
the patient to notice the classic diabe- a diagnostic test (Table 2.2) is appropri- of childbearing age is underdiagnosed
tes symptoms caused by hyperglycemia, ate. Prediabetes and type 2 diabetes (105). Employing a probabilistic model,
such as dehydration or unintentional meet criteria for conditions in which Peterson et al. (106) demonstrated cost
weight loss. Nevertheless, even undiag- early detection via screening is appropri- and health benefits of preconception
nosed patients are at increased risk of ate. Both conditions are common and screening.
developing macrovascular and microvas- impose significant clinical and public A large European randomized con-
cular complications. health burdens. There is often a long pre- trolled trial compared the impact of
Patients with type 2 diabetes may symptomatic phase before the diagnosis screening for diabetes and intensive
have insulin levels that appear normal of type 2 diabetes. Simple tests to detect multifactorial intervention with that of
or elevated, yet the failure to normalize preclinical disease are readily available screening and routine care (107). Gen-
blood glucose reflects a relative defect (99). The duration of glycemic burden is a eral practice patients between the ages
in glucose-stimulated insulin secretion. strong predictor of adverse outcomes. of 40 and 69 years were screened for
Thus, insulin secretion is defective in There are effective interventions that prediabetes and randomly assigned by

these patients and insufficient to com- vent progression from prediabetes to practice to intensive treatment of multi-
pensate for insulin resistance. Insulin diabetes. It is important to individualize ple risk factors or routine diabetes care.
resistance may improve with weight risk/benefit of formal intervention for After 5.3 years of follow-up, CVD risk
reduction, exercise, and/or pharmaco- patients with prediabetes and consider factors were modestly but significantly
logic treatment of hyperglycemia but is patient-centered goals. Risk models have improved with intensive treatment com-
seldom restored to normal. Recent explored the benefit, in general finding pared with routine care, but the inci-
interventions with intensive diet and higher benefit of intervention in those at dence of first CVD events or mortality
exercise or surgical weight loss have led highest risk (100) (see Section 3, was not significantly different between
to diabetes remission (90–96) (see “Prevention or Delay of Type 2 Diabetes the groups (25). The excellent care pro-
Section 8, “Obesity and Weight Man- and Associated Comorbidities,” https:// vided to patients in the routine care
agement for the Prevention and Treat- doi.org/10.2337/dc22-S003) and reduce group and the lack of an unscreened
ment of Type 2 Diabetes,” https://doi the risk of diabetes complications (101) control arm limited the authors’ ability
.org/10.2337/dc22-S008). (see Section 10, “Cardiovascular Disease to determine whether screening and
The risk of developing type 2 diabetes and Risk Management,” https://doi.org/ early treatment improved outcomes
increases with age, obesity, and lack of 10.2337/dc22-S010, Section 11, “Chronic compared with no screening and later
physical activity (97,98). It occurs more Kidney Disease and Risk Management,” treatment after clinical diagnoses. Com-
frequently in women with prior gesta- https://doi.org/10.2337/dc22-S011, and puter simulation modeling studies sug-
tional diabetes mellitus (GDM) or poly- Section 12, “Retinopathy, Neuropathy, gest that major benefits are likely to
cystic ovary syndrome. It is also more and Foot Care,” https://doi.org/10.2337/ accrue from the early diagnosis and
common in people with hypertension or dc22-S012). In the most recent National treatment of hyperglycemia and cardio-
dyslipidemia and in certain racial/ethnic Institutes of Health (NIH) Diabetes vascular risk factors in type 2 diabetes
subgroups (African American, Native Prevention Program Outcomes Study (108); moreover, screening, beginning at
American, Hispanic/Latino, and Asian (DPPOS) report, prevention of progres- age 30 or 45 years and independent
American). It is often associated with a sion from prediabetes to diabetes (102) of risk factors, may be cost-effective
strong genetic predisposition or family resulted in lower rates of developing reti- (<$11,000 per quality-adjusted life year
history in first-degree relatives (more so nopathy and nephropathy (103). Similar gained—2010 modeling data) (109).
than type 1 diabetes). However, the impact on diabetes complications was Cost-effectiveness of screening has
genetics of type 2 diabetes are poorly reported with screening, diagnosis, and been reinforced in cohort studies
understood and under intense investiga- comprehensive risk factor management (110,111).
tion in this era of precision medicine in the U.K. Clinical Practice Research Additional considerations regarding
(18). In adults without traditional risk Datalink database (101). In that report, testing for type 2 diabetes and predia-
factors for type 2 diabetes and/or of progression from prediabetes to diabetes betes in asymptomatic patients include
younger age, consider islet autoanti- augmented risk of complications. the following.
body testing (e.g., GAD65 autoantibod- Approximately one-quarter of people
ies) to exclude the diagnosis of type 1 with diabetes in the U.S. and nearly Age
diabetes (8). half of Asian and Hispanic Americans Age is a major risk factor for diabetes.
with diabetes are undiagnosed (82,83). Testing should begin at no later than
Screening and Testing for Although screening of asymptomatic age 35 years for all patients (111a).
Prediabetes and Type 2 Diabetes individuals to identify those with predia- Screening should be considered in
in Asymptomatic Adults betes or diabetes might seem reason- adults of any age with overweight or
Screening for prediabetes and type 2 able, rigorous clinical trials to prove the obesity and one or more risk factors for
diabetes risk through an informal assess- effectiveness of such screening have diabetes.
ment of risk factors (Table 2.3) or with not been conducted and are unlikely to
an assessment tool, such as the ADA occur. Clinical conditions, such as hyper- BMI and Ethnicity
risk test (Fig. 2.1) (online at diabetes. tension, hypertensive pregnancy, and In general, BMI $25 kg/m2 is a risk fac-
org/socrisktest), is recommended to obesity, enhance risk (104). Based on a tor for diabetes. However, data suggest
guide providers on whether performing population estimate, diabetes in women that the BMI cut point should be lower
for the Asian American population PIs are associated with insulin resistance that 30% of patients $30 years of age
(112,113). The BMI cut points fall con- and may also lead to apoptosis of pan- seen in general dental practices had
sistently between 23 and 24 kg/m2 creatic b-cells. NRTIs also affect fat dis- dysglycemia (124,125). A similar study
(sensitivity of 80%) for nearly all Asian tribution (both lipohypertrophy and in 1,150 dental patients >40 years old
American subgroups (with levels slightly lipoatrophy), which is associated with in India reported 20.69% and 14.60%
lower for Japanese Americans). This insulin resistance. For patients with HIV meeting criteria for prediabetes and
makes a rounded cut point of 23 kg/m2 and ARV-associated hyperglycemia, it diabetes, respectively, using random
practical. An argument can be made to may be appropriate to consider discon- blood glucose. Further research is
push the BMI cut point to lower than tinuing the problematic ARV agents if needed to demonstrate the feasibility,
23 kg/m2 in favor of increased sensitiv- safe and effective alternatives are avail- effectiveness, and cost-effectiveness of
ity; however, this would lead to an able (119). Before making ARV substitu-
screening in this setting.
unacceptably low specificity (13.1%). tions, carefully consider the possible
Data from the World Health Organiza- effect on HIV virological control and the

tion also suggest that a BMI of $23 kg/ potential adverse effects of new ARV Screening and Testing for
m2 should be used to define increased agents. In some cases, antihyperglyce- Prediabetes and Type 2 Diabetes in
risk in Asian Americans (114). The find- mic agents may still be necessary. Children and Adolescents
ing that one-third to one-half of diabe- In the last decade, the incidence and
tes in Asian Americans is undiagnosed Testing Interval prevalence of type 2 diabetes in chil-
suggests that testing is not occurring at The appropriate interval between dren and adolescents has increased dra-
lower BMI thresholds (97,115). screening tests is not known (120). The
matically, especially in racial and ethnic
Evidence also suggests that other rationale for the 3-year interval is that
minority populations (72). See Table 2.4
populations may benefit from lower with this interval, the number of false-
for recommendations on risk-based
BMI cut points. For example, in a large positive tests that require confirmatory
screening for type 2 diabetes or predia-
multiethnic cohort study, for an equiva- testing will be reduced and individuals
lent incidence rate of diabetes, a BMI of with false-negative tests will be betes in asymptomatic children and
30 kg/m2 in non-Hispanic Whites was retested before substantial time elap- adolescents in a clinical setting (32). See
equivalent to a BMI of 26 kg/m2 in Afri- ses and complications develop (120). Table 2.2 and Table 2.5 for the criteria
can Americans (116). In especially high-risk individuals, par- for the diagnosis of diabetes and predia-
ticularly with weight gain, shorter betes, respectively, that apply to chil-
Medications intervals between screening may be dren, adolescents, and adults. See
Certain medications, such as glucocorti- useful. Section 14, “Children and Adolescents”
coids, thiazide diuretics, some HIV medi- (https://doi.org/10.2337/dc22-S014) for
cations (30), and atypical antipsychotics Community Screening additional information on type 2 diabe-
(90), are known to increase the risk of Ideally, screening should be carried out tes in children and adolescents.
diabetes and should be considered within a health care setting because of Some studies question the validity of
when deciding whether to screen. the need for follow-up and treatment. A1C in the pediatric population, espe-
Community screening outside a health cially among certain ethnicities, and
HIV care setting is generally not recom- suggest OGTT or FPG as more suitable
Individuals with HIV are at higher risk mended because people with positive diagnostic tests (126). However, many
for developing prediabetes and diabetes tests may not seek, or have access to, of these studies do not recognize that
on antiretroviral (ARV) therapies, so a appropriate follow-up testing and care. diabetes diagnostic criteria are based
screening protocol is recommended However, in specific situations where an on long-term health outcomes, and vali-
(117). The A1C test may underestimate adequate referral system is established dations are not currently available in
glycemia in people with HIV; it is not beforehand for positive tests, commu- the pediatric population (127). The
recommended for diagnosis and may nity screening may be considered. Com- ADA acknowledges the limited data
present challenges for monitoring (31). munity screening may also be poorly
supporting A1C for diagnosing type 2
In those with prediabetes, weight loss targeted; i.e., it may fail to reach the
diabetes in children and adolescents.
through healthy nutrition and physical groups most at risk and inappropriately
Although A1C is not recommended
activity may reduce the progression test those at very low risk or even those
for diagnosis of diabetes in children
toward diabetes. Among patients with who have already been diagnosed
HIV and diabetes, preventive health (121). with cystic fibrosis or symptoms sug-
care using an approach used in patients gestive of acute onset of type 1 dia-
without HIV is critical to reduce the Screening in Dental Practices betes and only A1C assays without
risks of microvascular and macrovascu- Because periodontal disease is associ- interference are appropriate for chil-
lar complications. Diabetes risk is ated with diabetes, the utility of dren with hemoglobinopathies, the
increased with certain PIs and NRTIs. screening in a dental setting and refer- ADA continues to recommend A1C
New-onset diabetes is estimated to ral to primary care as a means to and the criteria in Table 2.2 for diag-
occur in more than 5% of patients improve the diagnosis of prediabetes nosis of type 2 diabetes in this cohort
infected with HIV on PIs, whereas more and diabetes has been explored to decrease barriers to screening
than 15% may have prediabetes (118). (122–124), with one study estimating (128,129).
CYSTIC FIBROSIS–RELATED A1C is not recommended for screening POSTTRANSPLANTATION

DIABETES (133). Regardless of age, weight loss or DIABETES MELLITUS
failure of expected weight gain is a risk
Recommendations for CFRD and should prompt screening Recommendations
2.16 Annual screening for cystic (131,132). The Cystic Fibrosis Founda- 2.20 After organ transplantation,
fibrosis–related diabetes with tion Patient Registry (134) evaluated screening for hyperglycemia
an oral glucose tolerance test 3,553 cystic fibrosis patients and diag- should be done. A formal
should begin by age 10 years nosed 445 (13%) with CFRD. Early diag- diagnosis of posttransplanta-
in all patients with cystic fibro- nosis and treatment of CFRD was tion diabetes mellitus is best
sis not previously diagnosed associated with preservation of lung made once the individual is
with cystic fibrosis-related dia- function. The European Cystic Fibrosis stable on an immunosuppres-
betes. B Society Patient Registry reported an sive regimen and in the
2.17 A1C is not recommended as a increase in CFRD with age (increased absence of an acute infec-

screening test for cystic fibro- 10% per decade), genotype, decreased tion. B
sis–related diabetes. B lung function, and female sex (135,136). 2.21 The oral glucose tolerance
2.18 People with cystic fibrosis– Continuous glucose monitoring or test is the preferred test to
related diabetes should be HOMA of b-cell function (137) may be make a diagnosis of post-
treated with insulin to attain more sensitive than OGTT to detect risk transplantation diabetes mel-
individualized glycemic goals. A for progression to CFRD; however, evi- litus. B
2.19 Beginning 5 years after the dence linking these results to long-term 2.22 Immunosuppressive regimens
diagnosis of cystic fibrosis– outcomes is lacking, and these tests are shown to provide the best
related diabetes, annual moni- not recommended for screening outside outcomes for patient and graft
toring for complications of dia- of the research setting (138). survival should be used, irre-
betes is recommended. E CFRD mortality has significantly de- spective of posttransplantation
creased over time, and the gap in mor- diabetes mellitus risk. E
tality between cystic fibrosis patients
Cystic fibrosis–related diabetes (CFRD) is with and without diabetes has consider-
the most common comorbidity in peo- ably narrowed (139). There are limited Several terms are used in the literature to
ple with cystic fibrosis, occurring in clinical trial data on therapy for CFRD. describe the presence of diabetes follow-
about 20% of adolescents and 40–50% The largest study compared three regi- ing organ transplantation (142). “New-
of adults (130). Diabetes in this popula- mens: premeal insulin aspart, repagli- onset diabetes after transplantation”
tion, compared with individuals with nide, or oral placebo in cystic fibrosis (NODAT) is one such designation that
type 1 or type 2 diabetes, is associated patients with diabetes or abnormal glu- describes individuals who develop new-
with worse nutritional status, more cose tolerance. Participants all had onset diabetes following transplant.
severe inflammatory lung disease, and weight loss in the year preceding treat- NODAT excludes patients with pretrans-
greater mortality. Insulin insufficiency is ment; however, in the insulin-treated plant diabetes that was undiagnosed as
the primary defect in CFRD. Genetically group, this pattern was reversed, and well as posttransplant hyperglycemia that
determined b-cell function and insulin patients gained 0.39 (± 0.21) BMI units resolves by the time of discharge (143).
resistance associated with infection and (P 5 0.02). The repaglinide-treated Another term, “posttransplantation diabe-
inflammation may also contribute to group had initial weight gain, but it was tes mellitus” (PTDM) (143,144), describes
the development of CFRD. Milder not sustained by 6 months. The placebo the presence of diabetes in the posttrans-
abnormalities of glucose tolerance are group continued to lose weight (139). plant setting irrespective of the timing of
even more common and occur at earlier Insulin remains the most widely used diabetes onset.
ages than CFRD. Whether individuals therapy for CFRD (140). The primary Hyperglycemia is very common during
with IGT should be treated with insulin rationale for the use of insulin in the early posttransplant period, with
replacement has not currently been patients with CFRD is to induce an ana- 90% of kidney allograft recipients
determined. Although screening for dia- bolic state while promoting macronutri- exhibiting hyperglycemia in the first few
betes before the age of 10 years can ent retention and weight gain. weeks following transplant (143–146). In
identify risk for progression to CFRD in Additional resources for the clinical most cases, such stress- or steroid-
those with abnormal glucose tolerance, management of CFRD can be found in induced hyperglycemia resolves by the
no benefit has been established with the position statement “Clinical Care time of discharge (146,147). Although
respect to weight, height, BMI, or lung Guidelines for Cystic Fibrosis–Related the use of immunosuppressive therapies
function. OGTT is the recommended Diabetes: A Position Statement of the is a major contributor to the develop-
screening test; however, recent publica- American Diabetes Association and a ment of PTDM, the risks of transplant
tions suggest that an A1C cut point Clinical Practice Guideline of the Cystic rejection outweigh the risks of PTDM
threshold of 5.5% (5.8% in a second Fibrosis Foundation, Endorsed by the and the role of the diabetes care
study) would detect more than 90% of Pediatric Endocrine Society” (141) and provider is to treat hyperglycemia appro-
cases and reduce patient screening bur- in the International Society for Pediatric priately regardless of the type of immu-
den (131,132). Ongoing studies are and Adolescent Diabetes 2018 clinical nosuppression (143). Risk factors for
underway to validate this approach, and practice consensus guidelines (130). PTDM include both general diabetes
risks (such as age, family history of dia- Drug dose adjustments may be required comprehensive list of causes, see
betes, etc.) as well as transplant-specific because of decreases in the glomerular Genetic Diagnosis of Endocrine Disor-
factors, such as use of immunosuppres- filtration rate, a relatively common com- ders (166).
sant agents (148–150). Whereas post- plication in transplant patients. A small
transplantation hyperglycemia is an short-term pilot study reported that Neonatal Diabetes
important risk factor for subsequent metformin was safe to use in renal Diabetes occurring under 6 months of
PTDM, a formal diagnosis of PTDM is transplant recipients (161), but its safety age is termed “neonatal” or “congenital”
optimally made once the patient is sta- has not been determined in other types diabetes, and about 80–85% of cases
ble on maintenance immunosuppression of organ transplant. Thiazolidinediones can be found to have an underlying
and in the absence of acute infection have been used successfully in patients monogenic cause (8,167–170). Neonatal
(146–148,151). In a recent study of 152 with liver and kidney transplants, but diabetes occurs much less often after 6
heart transplant recipients, 38% had side effects include fluid retention, months of age, whereas autoimmune
PTDM at 1 year. Risk factors for PTDM heart failure, and osteopenia (162,163). type 1 diabetes rarely occurs before 6

included elevated BMI, discharge from Dipeptidyl peptidase 4 inhibitors do not months of age. Neonatal diabetes can
the hospital on insulin, and glucose val- interact with immunosuppressant drugs either be transient or permanent. Tran-
ues in the 24 h prior to hospital dis- and have demonstrated safety in small sient diabetes is most often due to over-
charge (152). In an Iranian cohort, 19% clinical trials (164,165). Well-designed expression of genes on chromosome
had PTDM after heart and lung trans- intervention trials examining the effi- 6q24, is recurrent in about half of cases,
plant (153). The OGTT is considered the cacy and safety of these and other anti- and may be treatable with medications
gold-standard test for the diagnosis of hyperglycemic agents in patients with other than insulin. Permanent neonatal
PTDM (1 year posttransplant) (143,144, PTDM are needed. diabetes is most commonly due to auto-
154,155). Pretransplant elevation in hs- somal dominant mutations in the genes
CRP was associated with PTDM in the encoding the Kir6.2 subunit (KCNJ11)
setting of renal transplant (156,157). MONOGENIC DIABETES and SUR1 subunit (ABCC8) of the b-cell
However, screening patients with fasting SYNDROMES KATP channel. A recent report details a
glucose and/or A1C can identify high-risk de novo mutation in EIF2B1 affecting
Recommendations
patients requiring further assessment eIF2 signaling associated with permanent
and may reduce the number of overall 2.23 Regardless of current age, all
neonatal diabetes and hepatic dysfunc-
OGTTs required. people diagnosed with diabe- tion, similar to Wolcott-Rallison syn-
Few randomized controlled studies tes in the first 6 months of drome but with few severe com-
have reported on the short- and long- life should have immediate orbidities (171). The recent ADA-Euro-
term use of antihyperglycemic agents in genetic testing for neonatal pean Association for the Study of Diabe-
the setting of PTDM (148,158,159). diabetes. A tes type 1 diabetes consensus report
Most studies have reported that trans- 2.24 Children and young adults makes the recommendation that regard-
plant patients with hyperglycemia and who do not have typical char- less of current age, individuals diagnosed
PTDM after transplantation have higher acteristics of type 1 or type 2 under 6 months of age should have
rates of rejection, infection, and reho- diabetes and who often have genetic testing (8). Correct diagnosis has
spitalization (146,148,160). Insulin ther- a family history of diabetes in critical implications because 30–50% of
apy is the agent of choice for the successive generations (sug- people with KATP-related neonatal diabe-
management of hyperglycemia, PTDM, gestive of an autosomal domi- tes will exhibit improved glycemic control
and preexisting diabetes and diabetes in nant pattern of inheritance) when treated with high-dose oral sulfo-
the hospital setting. After discharge, should have genetic testing for nylureas instead of insulin. Insulin
patients with preexisting diabetes could maturity-onset diabetes of the gene (INS) mutations are the second
go back on their pretransplant regimen young. A most common cause of permanent
if they were in good control before 2.25 In both instances, consultation neonatal diabetes, and, while inten-
transplantation. Those with previously with a center specializing in sive insulin management is currently
poor control or with persistent hyper- diabetes genetics is recom- the preferred treatment strategy,
glycemia should continue insulin with mended to understand the sig- there are important genetic counsel-
frequent home self-monitoring of blood nificance of genetic mutations ing considerations, as most of the
glucose to determine when insulin dose and how best to approach fur- mutations that cause diabetes are
reductions may be needed and when it ther evaluation, treatment, dominantly inherited.
may be appropriate to switch to nonin- and genetic counseling. E
sulin agents. Maturity-Onset Diabetes of the
No studies to date have established Young
which noninsulin agents are safest or Monogenic defects that cause b-cell MODY is frequently characterized by onset
most efficacious in PTDM. The choice of dysfunction, such as neonatal diabetes of hyperglycemia at an early age (classi-
agent is usually made based on the side and MODY, represent a small fraction cally before age 25 years, although diag-
effect profile of the medication and of patients with diabetes (<5%). Table nosis may occur at older ages). MODY is
possible interactions with the patient’s 2.6 describes the most common characterized by impaired insulin secretion
immunosuppression regimen (148). causes of monogenic diabetes. For a with minimal or no defects in insulin
Table 2.6—Most common causes of monogenic diabetes (166)

Gene Inheritance Clinical features
MODY GCK AD GCK-MODY: higher glucose threshold (set-point) for glucose-stimulated insulin
secretion, causing stable, nonprogressive elevated fasting blood glucose;
typically does not require treatment; microvascular complications are rare; small
rise in 2-h PG level on OGTT (<54 mg/dL [3 mmol/L])
HNF1A AD HNF1A-MODY: progressive insulin secretory defect with presentation in
adolescence or early adulthood; lowered renal threshold for glucosuria; large
rise in 2-h PG level on OGTT (>90 mg/dL [5 mmol/L]); sensitive to sulfonylureas
HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in
adolescence or early adulthood; may have large birth weight and transient
neonatal hypoglycemia; sensitive to sulfonylureas
HNF1B AD HNF1B-MODY: developmental renal disease (typically cystic); genitourinary
abnormalities; atrophy of the pancreas; hyperuricemia; gout

Neonatal diabetes KCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures;
responsive to sulfonylureas
INS AD Permanent: IUGR; insulin requiring
ABCC8 AD Permanent or transient: IUGR; rarely developmental delay; responsive to
sulfonylureas
6q24 (PLAGL1, AD for paternal Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6,
HYMA1) duplications paternal duplication, or maternal methylation defect; may be treatable with
medications other than insulin
GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrine
insufficiency; insulin requiring
EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrine
insufficiency; insulin requiring
EIF2B1 AD Permanent diabetes: can be associated with fluctuating liver function (171)
FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX)
syndrome: autoimmune diabetes, autoimmune thyroid disease, exfoliative
dermatitis; insulin requiring
AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction; OGTT, oral glucose tolerance test; UPD6, uniparental
disomy of chromosome 6; 2-h PG, 2-h plasma glucose.
action (in the absence of coexistent obe- Diagnosis of Monogenic Diabetes (180). Individuals in whom monogenic
sity). It is inherited in an autosomal domi- A diagnosis of one of the three most diabetes is suspected should be referred
nant pattern with abnormalities in at least common forms of MODY, including to a specialist for further evaluation if
13 genes on different chromosomes iden- GCK-MODY, HNF1A-MODY, and HNF4A- available, and consultation can be
tified to date (172). The most commonly MODY, allows for more cost-effective obtained from several centers. Readily
reported forms are GCK-MODY (MODY2), therapy (no therapy for GCK-MODY; sul- available commercial genetic testing fol-
HNF1A-MODY (MODY3), and HNF4A- fonylureas as first-line therapy for lowing the criteria listed below now
MODY (MODY1). HNF1A-MODY and HNF4A-MODY). Addi- enables a cost-effective (181), often
For individuals with MODY, the treat- tionally, diagnosis can lead to identifica- cost-saving, genetic diagnosis that is
ment implications are considerable and tion of other affected family members. increasingly supported by health insur-
warrant genetic testing (173,174). Clini- Genetic screening is increasingly avail- ance. A biomarker screening pathway
cally, patients with GCK-MODY exhibit able and cost-effective (171,174). such as the combination of urinary
mild, stable fasting hyperglycemia and do A diagnosis of MODY should be con- C-peptide/creatinine ratio and antibody
not require antihyperglycemic therapy sidered in individuals who have atypical screening may aid in determining who
except commonly during pregnancy. diabetes and multiple family members should get genetic testing for MODY
Patients with HNF1A- or HNF4A-MODY with diabetes not characteristic of type (182). It is critical to correctly diagnose
usually respond well to low doses of sul- 1 or type 2 diabetes, although admit- one of the monogenic forms of diabetes
fonylureas, which are considered first-line tedly “atypical diabetes” is becoming because these patients may be incor-
therapy; in some instances insulin will be increasingly difficult to precisely define rectly diagnosed with type 1 or type 2
required over time. Mutations or dele- in the absence of a definitive set of diabetes, leading to suboptimal, even
tions in HNF1B are associated with renal tests for either type of diabetes potentially harmful, treatment regimens
cysts and uterine malformations (renal (168–170,173–179). In most cases, the and delays in diagnosing other family
cysts and diabetes [RCAD] syndrome). presence of autoantibodies for type 1 members (183). The correct diagnosis
Other extremely rare forms of MODY diabetes precludes further testing for is especially critical for those with
have been reported to involve other monogenic diabetes, but the presence GCK-MODY mutations, where multiple
transcription factor genes including PDX1 of autoantibodies in patients with studies have shown that no complica-
(IPF1) and NEUROD1. monogenic diabetes has been reported tions ensue in the absence of glucose-
lowering therapy (184). The risks of pancreatitis can lead to PPDM, and the
of gestation in pregnant
microvascular and macrovascular com- risk is highest with recurrent bouts. A
women not previously found
plications with HNFIA- and HNF4A- distinguishing feature is concurrent pan-
to have diabetes or high-risk
MODY are similar to those observed creatic exocrine insufficiency (according
to the monoclonal fecal elastase 1 test abnormal glucose metabolism
in patients with type 1 and type 2 dia-
or direct function tests), pathological detected earlier in the current
betes (185,186). Genetic counseling is
pancreatic imaging (endoscopic ultra- pregnancy. A
recommended to ensure that affected
sound, MRI, computed tomography), 2.28 Screen women with gesta-
individuals understand the patterns of
and absence of type 1 diabetes–associ- tional diabetes mellitus for
inheritance and the importance of a
ated autoimmunity (189–194). There is prediabetes or diabetes at
correct diagnosis and addressing com-
loss of both insulin and glucagon secre- 4–12 weeks postpartum, using
prehensive cardiovascular risk.
tion and often higher-than-expected the 75-g oral glucose tolerance
The diagnosis of monogenic diabetes
insulin requirements. Risk for microvas- test and clinically appropriate
should be considered in children and

cular complications appears to be similar nonpregnancy diagnostic crite-
adults diagnosed with diabetes in early
to other forms of diabetes. In the con- ria. B
adulthood with the following findings:
text of pancreatectomy, islet autotrans- 2.29 Women with a history of ges-
plantation can be done to retain insulin tational diabetes mellitus
• Diabetes diagnosed within the first 6
secretion (195,196). In some cases, auto- should have lifelong screen-
months of life (with occasional cases
transplant can lead to insulin indepen- ing for the development of
presenting later, mostly INS and
dence. In others, it may decrease insulin diabetes or prediabetes at
ABCC8 mutations) (167,187)
requirements (197). least every 3 years. B
• Diabetes without typical features of
2.30 Women with a history of ges-
type 1 or type 2 diabetes (negative
GESTATIONAL DIABETES tational diabetes mellitus found
diabetes-associated autoantibodies,
MELLITUS to have prediabetes should
no obesity, lacking other metabolic
features, especially with strong fam- receive intensive lifestyle inter-
Recommendations
ily history of diabetes) ventions and/or metformin to
2.26a In women who are planning prevent diabetes. A
• Stable, mild fasting hyperglycemia pregnancy, screen those with
(100–150 mg/dL [5.5–8.5 mmol/L]), risk factors B and consider
stable A1C between 5.6% and 7.6% testing all women for undiag- Definition
(between 38 and 60 mmol/mol), nosed diabetes. E For many years, GDM was defined as any
especially if no obesity 2.26b Before 15 weeks of gestation, degree of glucose intolerance that was
test women with risk factors first recognized during pregnancy (84),
PANCREATIC DIABETES OR B and consider testing all regardless of the degree of hyperglyce-
DIABETES IN THE CONTEXT OF women E for undiagnosed mia. This definition facilitated a uniform
DISEASE OF THE EXOCRINE diabetes at the first prenatal strategy for detection and classification of
PANCREAS visit using standard diagnos- GDM, but this definition has serious limi-
Pancreatic diabetes includes both struc- tic criteria, if not screened tations (198). First, the best available evi-
tural and functional loss of glucose-nor- preconception. dence reveals that many cases of GDM
malizing insulin secretion in the context 2.26c Women identified as having represent preexisting hyperglycemia that
of exocrine pancreatic dysfunction and is diabetes should be treated as is detected by routine screening in preg-
commonly misdiagnosed as type 2 diabe- such. A nancy, as routine screening is not widely
tes. Hyperglycemia due to general pan- 2.26d Before 15 weeks of gestation, performed in nonpregnant women of
creatic dysfunction has been called “type screen for abnormal glucose reproductive age. It is the severity of
3c diabetes” and, more recently, diabe- metabolism to identify women hyperglycemia that is clinically important
tes in the context of disease of the exo- who are at higher risk of with regard to both short- and long-term
crine pancreas has been termed adverse pregnancy and neona- maternal and fetal risks.
pancreoprivic diabetes (1). The diverse tal outcomes, are more likely The ongoing epidemic of obesity
set of etiologies includes pancreatitis to need insulin, and are at and diabetes has led to more type 2
(acute and chronic), trauma or pancrea- high risk of a later gestational diabetes in women of reproductive age,
tectomy, neoplasia, cystic fibrosis diabetes mellitus diagnosis. B with an increase in the number of preg-
(addressed elsewhere in this chapter), Treatment may provide some nant women with undiagnosed type 2
hemochromatosis, fibrocalculous pan- benefit. E
diabetes in early pregnancy (199–201).
creatopathy, rare genetic disorders (188), 2.26e Screen for early abnormal glu-
Ideally, undiagnosed diabetes should
cose metabolism using fasting
and idiopathic forms (1); as such, pancre- be identified preconception in women
glucose of 110–125 mg/dL
atic diabetes is the preferred umbrella with risk factors or in high-risk popula-
(6.1 mmol/L) or A1C 5.9–6.4%
terminology. tions (202–207), as the preconception
(41–47 mmol/mol). B
Pancreatitis, even a single bout, can lead care of women with preexisting diabe-
2.27 Screen for gestational diabe-
to postpancreatitis diabetes mellitus tes results in lower A1C and reduced
tes mellitus at 24–28 weeks
(PPDM). Both acute and chronic risk of birth defects, preterm delivery,
perinatal mortality, small-for-gesta- early abnormal glucose metabolism reduce diabetes risk and for type 2 dia-
tional-age births, and neonatal inten- remain uncertain. Nutrition counseling betes to allow treatment at the earliest
sive care unit admission (208). If and periodic “block” testing of glucose possible time (225).
women are not screened prior to preg- levels weekly to identify women with
nancy, universal early screening at high glucose levels are suggested. Test- Diagnosis
<15 weeks of gestation for undiag- ing frequency may proceed to daily, and GDM carries risks for the mother, fetus,
nosed diabetes may be considered treatment may be intensified, if the and neonate. The Hyperglycemia and
over selective screening (Table 2.3), fasting glucose is predominantly >110 Adverse Pregnancy Outcome (HAPO)
particularly in populations with high mg/dL, prior to 18 weeks of gestation. study (226), a large-scale multinational
prevalence of risk factors and undiag- Both the fasting glucose and A1C are cohort study completed by more than
nosed diabetes in women of childbear- low-cost tests. An advantage of the A1C 23,000 pregnant women, demonstrated
ing age. Strong racial and ethnic is its convenience, as it can be added to that risk of adverse maternal, fetal,
disparities exist in the prevalence of the prenatal laboratories and does not and neonatal outcomes continuously

undiagnosed diabetes. Therefore, early require an early-morning fasting appoint- increased as a function of maternal glyce-
screening provides an initial step to ment. Disadvantages include inaccuracies mia at 24–28 weeks of gestation, even
identify these health disparities so in the presence of increased red blood within ranges previously considered nor-
that they can begin to be addressed cell turnover and hemoglobinopathies mal for pregnancy. For most complica-
(204–207). Standard diagnostic criteria (usually reads lower), and higher values tions, there was no threshold for risk.
for identifying undiagnosed diabetes in with anemia and reduced red blood cell These results have led to careful recon-
early pregnancy are the same as those turnover (219). A1C is not reliable to sideration of the diagnostic criteria for
used in the nonpregnant population screen for GDM or for preexisting diabe- GDM.
(see Table 2.2). Women found to have tes at 15 weeks of gestation or later. See GDM diagnosis (Table 2.7) can be
diabetes by the standard diagnostic Recommendation 2.3 above. accomplished with either of two
criteria used outside of pregnancy GDM is often indicative of underlying strategies:
should be classified as having diabetes b-cell dysfunction (220), which confers
complicating pregnancy (most often marked increased risk for later develop- 1. The “one-step” 75-g OGTT derived
type 2 diabetes, rarely type 1 diabetes ment of diabetes, generally but not from the IADPSG criteria, or
or monogenic diabetes) and managed always type 2 diabetes, in the mother 2. The older “two-step” approach with a
accordingly. after delivery (221,222). As effective 50-g (nonfasting) screen followed by a
Early abnormal glucose metabolism, prevention interventions are available 100-g OGTT for those who screen
defined as fasting glucose threshold of (223,224), women diagnosed with GDM positive, based on the work of Car-
110 mg/dL (6.1 mmol/L) or an A1C of should receive lifelong screening for penter and Coustan’s interpretation of
5.9% (39 mmol/mol) may identify prediabetes to allow interventions to the older O’Sullivan (227) criteria.
women who are at higher risk of adverse
pregnancy and neonatal outcomes (pre-
eclampsia, macrosomia, shoulder dysto- Table 2.7—Screening for and diagnosis of GDM
cia, perinatal death), are more likely to
One-step strategy
need insulin treatment, and are at high Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1
risk of a later GDM diagnosis (209–215). and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with diabetes.
An A1C threshold of 5.7% has not been The OGTT should be performed in the morning after an overnight fast of at least 8 h.
shown to be associated with adverse The diagnosis of GDM is made when any of the following plasma glucose values are met or
perinatal outcomes (216,217). exceeded:
Fasting: 92 mg/dL (5.1 mmol/L)
If early screening is negative, women
1 h: 180 mg/dL (10.0 mmol/L)
should be rescreened for GDM between 2 h: 153 mg/dL (8.5 mmol/L)
24 and 28 weeks of gestation (see Sec-
Two-step strategy
tion 15, “Management of Diabetes in
Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at
Pregnancy,” https://doi.org/10.2337/
24–28 weeks of gestation in women not previously diagnosed with diabetes.
dc22-S015). The International Associa- If the plasma glucose level measured 1 h after the load is $130, 135, or 140 mg/dL (7.2,
tion of the Diabetes and Pregnancy 7.5, or 7.8 mmol/L, respectively), proceed to a 100-g OGTT.
Study Groups (IADPSG) GDM diagnostic Step 2: The 100-g OGTT should be performed when the patient is fasting.
criteria for the 75-g OGTT as well as the The diagnosis of GDM is made when at least two* of the following four plasma glucose
GDM screening and diagnostic criteria levels (measured fasting and at 1, 2, and 3 h during OGTT) are met or exceeded
(Carpenter-Coustan criteria [244]):
used in the two-step approach were not
Fasting: 95 mg/dL (5.3 mmol/L)
derived from data in the first half of 1 h: 180 mg/dL (10.0 mmol/L)
pregnancy and should not be used for 2 h: 155 mg/dL (8.6 mmol/L)
early screening (218). To date, most ran- 3 h: 140 mg/dL (7.8 mmol/L)
domized controlled trials of treatment
GDM, gestational diabetes mellitus; GLT, glucose load test; OGTT, oral glucose tolerance
of early abnormal glucose metabolism test. *American College of Obstetricians and Gynecologists notes that one elevated value
have been underpowered for outcomes. can be used for diagnosis (240).
Therefore, the benefits of treatment for
Different diagnostic criteria will iden- trials found modest benefits including Additional well-designed clinical studies
tify different degrees of maternal hyper- reduced rates of large-for-gestational- are needed to determine the optimal
glycemia and maternal/fetal risk, leading age births and preeclampsia (232,233). intensity of monitoring and treatment of
some experts to debate, and disagree It is important to note that 80–90% of women with GDM diagnosed by the one-
on, optimal strategies for the diagnosis women being treated for mild GDM in step strategy (237,238).
of GDM. these two randomized controlled trials
could be managed with lifestyle therapy Two-Step Strategy
One-Step Strategy alone. The OGTT glucose cutoffs in In 2013, the NIH convened a consensus
The IADPSG defined diagnostic cut these two trials overlapped with the development conference to consider
points for GDM as the average fasting, thresholds recommended by the diagnostic criteria for diagnosing GDM
1-h, and 2-h PG values during a 75-g IADPSG, and in one trial (233), the 2-h (239). The 15-member panel had
OGTT in women at 24–28 weeks of ges- PG threshold (140 mg/dL [7.8 mmol/L]) representatives from obstetrics and
tation who participated in the HAPO was lower than the cutoff recom- gynecology, maternal-fetal medicine,

study at which odds for adverse out- mended by the IADPSG (153 mg/dL pediatrics, diabetes research, biostatis-
comes reached 1.75 times the estimated [8.5 mmol/L]). No randomized con- tics, and other related fields. The panel
odds of these outcomes at the mean trolled trials of treating versus not recommended a two-step approach to
fasting, 1-h, and 2-h PG levels of the treating GDM diagnosed by the IADPSG screening that used a 1-h 50-g GLT fol-
study population. This one-step strategy criteria but not the Carpenter-Coustan lowed by a 3-h 100-g OGTT for those
was anticipated to significantly increase criteria have been published to date. who screened positive. The American
the incidence of GDM (from 5–6% to However, a recent randomized trial of College of Obstetricians and Gynecolo-
15–20%), primarily because only one testing for GDM at 24–28 weeks of gists (ACOG) recommends any of the
abnormal value, not two, became suffi- gestation by the one-step method commonly used thresholds of 130,
cient to make the diagnosis (228). Many using IADPSG criteria versus the two- 135, or 140 mg/dL for the 1-h 50-g
regional studies have investigated the step method using a 1-h 50-g glucose GLT (240). A systematic review for the
impact of adopting the IADPSG criteria loading test (GLT) and, if positive, a 3-h U.S. Preventive Services Task Force
on prevalence and have seen a roughly OGTT by Carpenter-Coustan criteria compared GLT cutoffs of 130 mg/dL
one- to threefold increase (229). The identified twice as many women with (7.2 mmol/L) and 140 mg/dL (7.8
anticipated increase in the incidence of GDM using the one step-method com- mmol/L) (241). The higher cutoff
GDM could have a substantial impact on pared with the two-step. Despite treat- yielded sensitivity of 70–88% and spe-
costs and medical infrastructure needs ing more women for GDM using the cificity of 69–89%, while the lower cut-
and has the potential to “medicalize” one-step method, there was no differ- off was 88–99% sensitive and 66–77%
pregnancies previously categorized as ence in pregnancy and perinatal com- specific. Data regarding a cutoff of 135
normal. A recent follow-up study of plications (234). mg/dL are limited. As for other screen-
women participating in a blinded study The one-step method identifies the ing tests, choice of a cutoff is based
of pregnancy OGTTs found that 11 years long-term risks of maternal prediabetes upon the trade-off between sensitivity
after their pregnancies, women who and diabetes and offspring abnormal and specificity. The use of A1C at
would have been diagnosed with GDM glucose metabolism and adiposity. Post 24–28 weeks of gestation as a screen-
by the one-step approach, as compared hoc GDM in women diagnosed by the ing test for GDM does not function as
with those without, were at 3.4-fold one-step method in the HAPO cohort well as the GLT (242).
higher risk of developing prediabetes and was associated with higher prevalence Key factors cited by the NIH panel in
type 2 diabetes and had children with a of IGT; higher 30-min, 1-h, and 2-h glu- their decision-making process were the
higher risk of obesity and increased body coses during the OGTT; and reduced lack of clinical trial data demonstrating
fat, suggesting that the larger group of insulin sensitivity and oral disposition the benefits of the one-step strategy
women identified by the one-step index in their offspring at 10–14 years and the potential negative consequen-
approach would benefit from the of age compared with offspring of ces of identifying a large group of
increased screening for diabetes and pre- mothers without GDM. Associations of women with GDM, including medicaliza-
diabetes that would accompany a history mother’s fasting, 1-h, and 2-h values on tion of pregnancy with increased health
of GDM (230,231). The ADA recommends the 75-g OGTT were continuous with a care utilization and costs. Moreover,
the IADPSG diagnostic criteria with the comprehensive panel of offspring meta- screening with a 50-g GLT does not
intent of optimizing gestational outcomes bolic outcomes (231,235). In addition, require fasting and is therefore easier to
because these criteria are the only ones HAPO Follow-up Study (HAPO FUS) data accomplish for many women. Treatment
based on pregnancy outcomes rather demonstrate that neonatal adiposity of higher-threshold maternal hypergly-
than end points such as prediction of and fetal hyperinsulinemia (cord C-pep- cemia, as identified by the two-step
subsequent maternal diabetes. tide), both higher across the continuum approach, reduces rates of neonatal
The expected benefits of using of maternal hyperglycemia, are media- macrosomia, large-for-gestational-age
IADPSG criteria to the offspring are tors of childhood body fat (236). births (243), and shoulder dystocia with-
inferred from intervention trials that Data are lacking on how the treatment out increasing small-for-gestational-age
focused on women with lower levels of of mother’s hyperglycemia in pregnancy births. ACOG currently supports the
hyperglycemia than identified using affects her offspring’s risk for obesity, dia- two-step approach but notes that one
older GDM diagnostic criteria. Those betes, and other metabolic disorders. elevated value, as opposed to two, may
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ADA Classification and Diagnosis of Diabetes

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Diabetes Care Volume 45, Supplement 1, January 2022 S17

2. Classification and Diagnosis of American Diabetes Association

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1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to abso-

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Table 2.1—Staging of type 1 diabetes (12,15)

people with diabetes in both Clinical

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clinical disease in both “sporadic” and

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Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in

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Figure 2.1—ADA risk test (diabetes.org/socrisktest).

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CYSTIC FIBROSIS–RELATED A1C is not recommended for screening POSTTRANSPLANTATION

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Table 2.6—Most common causes of monogenic diabetes (166)

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211. Ma~ ne L, Flores-Le Roux JA, G

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