Ada 2 2023

Diabetes Care Volume 46, Supplement 1, January 2023 S19
2. Classification and Diagnosis of Nuha A. ElSayed, Grazia Aleppo,

Vanita R. Aroda, Raveendhara R. Bannuru,
Diabetes: Standards of Care in Florence M. Brown, Dennis Bruemmer,
Billy S. Collins, Marisa E. Hilliard,
Diabetes—2023 Diana Isaacs, Eric L. Johnson, Scott Kahan,
Kamlesh Khunti, Jose Leon, Sarah K. Lyons,
Diabetes Care 2023;46(Suppl. 1):S19–S40 | https://doi.org/10.2337/dc23-S002 Mary Lou Perry, Priya Prahalad,
Richard E. Pratley, Jane Jeffrie Seley,
Downloaded from http://diabetesjournals.org/care/article-pdf/46/Supplement_1/S19/693597/dc23s002.pdf by guest on 13 December 2022

Robert C. Stanton, and Robert A. Gabbay,
on behalf of the American Diabetes
Association
2. CLASSIFICATION AND DIAGNOSIS OF DIABETES

The American Diabetes Association (ADA) “Standards of Care in Diabetes” in-
cludes the ADA’s current clinical practice recommendations and is intended to
provide the components of diabetes care, general treatment goals and guide-
lines, and tools to evaluate quality of care. Members of the ADA Professional
Practice Committee, a multidisciplinary expert committee, are responsible for up-
dating the Standards of Care annually, or more frequently as warranted. For a de-
tailed description of ADA standards, statements, and reports, as well as the
evidence-grading system for ADA’s clinical practice recommendations and a full
list of Professional Practice Committee members, please refer to Introduction
and Methodology. 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 ab-

solute insulin deficiency, including latent autoimmune diabetes of adulthood)
2. Type 2 diabetes (due to a non-autoimmune progressive loss of adequate
b-cell insulin secretion frequently on the background of insulin resistance and
metabolic syndrome)
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 treat-
ment 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)
Disclosure information for each author is
This section reviews most common forms of diabetes but is not comprehensive. For available at https://doi.org/10.2337/dc23-SDIS.
additional information, see the American Diabetes Association (ADA) position state-
Suggested citation: ElSayed NA, Aleppo G, Aroda
ment “Diagnosis and Classification of Diabetes Mellitus” (1). VR, et al., American Diabetes Association. 2.
Classification and diagnosis of diabetes: Standards
Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical of Care in Diabetes—2023. Diabetes Care 2023;
46(Suppl. 1):S19–S40
presentation and disease progression may vary considerably. Classification is impor-
tant for determining therapy, but some individuals cannot be clearly classified as © 2022 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 1 More information is available at https://www.
diabetes often present with the hallmark symptoms of polyuria/polydipsia, and diabetesjournals.org/journals/pages/license.
S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 46, Supplement 1, January 2023
approximately half present with diabetic combining clinical, pathophysiological, progressive autoimmune b-cell destruc-
ketoacidosis (DKA) (2–4). The onset of and genetic characteristics to more pre- tion (16), thus accelerating insulin initiation
type 1 diabetes may be more variable cisely define the subsets of diabetes that prior to deterioration of glucose manage-
in adults; they may not present with are currently clustered into the type 1 ment or development of DKA (6,17).
the classic symptoms seen in children diabetes versus type 2 diabetes nomen- The paths to b-cell demise and dys-
and may experience temporary remis- clature with the goal of optimizing per- function are less well defined in type 2
sion from the need for insulin (5–7). The sonalized treatment approaches. Many diabetes, but deficient b-cell insulin se-
features most useful in discrimination of of these studies show great promise cretion, frequently in the setting of insulin
type 1 diabetes include younger age at and may soon be incorporated into the resistance, appears to be the common de-
diagnosis (<35 years) with lower BMI diabetes classification system (13). nominator. Type 2 diabetes is associated
(<25 kg/m2), unintentional weight loss, Characterization of the underlying path- with insulin secretory defects related to
ketoacidosis, and glucose >360 mg/dL ophysiology is more precisely developed genetics, inflammation, and metabolic

(20 mmol/L) at presentation (8). Occa- in type 1 diabetes than in type 2 diabe- stress. Future classification schemes for
sionally, people with type 2 diabetes tes. It is now clear from prospective stud- diabetes will likely focus on the patho-
may present with DKA (9,10), particularly ies that the persistent presence of two or physiology of the underlying b-cell dys-
members of ethnic and racial minorities more islet autoantibodies is a near-certain function (12,13,18–20).
(11). It is important for the health care predictor of clinical diabetes (14). The rate
professional to realize that classification of progression is dependent on the age DIAGNOSTIC TESTS FOR DIABETES
of diabetes type is not always straight- at first detection of autoantibody, number
Diabetes may be diagnosed based on
forward at presentation and that mis- of autoantibodies, autoantibody specific-
diagnosis is common (e.g., adults with ity, and autoantibody titer. Glucose and plasma glucose criteria, either the fast-
type 1 diabetes misdiagnosed as having A1C levels rise well before the clinical ing plasma glucose (FPG) value or the
type 2 diabetes, individuals with maturity- onset of diabetes, making diagnosis feasi- 2-h plasma glucose (2-h PG) value during
onset diabetes of the young [MODY] ble well before the onset of DKA. Three a 75-g oral glucose tolerance test (OGTT)
misdiagnosed as having type 1 diabe- distinct stages of type 1 diabetes can or A1C criteria (21) (Table 2.2).
tes). Although difficulties in distinguish- be identified (Table 2.1) and serve as Generally, FPG, 2-h PG during 75-g
ing diabetes type may occur in all age a framework for research and regula- OGTT, and A1C are equally appropriate
groups at onset, the diagnosis becomes tory decision-making (12,15). There is for diagnostic screening. It should be
more obvious over time in people with debate as to whether slowly progressive noted that detection rates of different
b-cell deficiency as the degree of b-cell autoimmune diabetes with an adult on- screening tests vary in both populations
deficiency becomes clear. set should be termed latent autoimmune and individuals. Moreover, the efficacy
In both type 1 and type 2 diabetes, diabetes in adults (LADA) or type 1 dia- of interventions for primary preven-
various genetic and environmental factors betes. The clinical priority with detection tion of type 2 diabetes has mainly been
can result in the progressive loss of b-cell of LADA is awareness that slow auto- demonstrated among individuals who
mass and/or function that manifests clini- immune b-cell destruction can occur in have impaired glucose tolerance (IGT)
cally as hyperglycemia. Once hypergly- adults leading to a long duration of mar- with or without elevated fasting glucose,
cemia occurs, people with all forms of ginal insulin secretory capacity. For the not for individuals with isolated im-
diabetes are at risk for developing the purpose of this classification, all forms paired fasting glucose (IFG) or for those
same chronic complications, although rates of diabetes mediated by autoimmune with prediabetes defined by A1C criteria
of progression may differ. The identification b-cell destruction are included under (22,23).
of individualized therapies for diabetes the rubric of type 1 diabetes. Use of the The same tests may be used to screen
in the future will be informed by better term LADA is common and acceptable for and diagnose diabetes and to detect
characterization of the many paths to in clinical practice and has the practical individuals with prediabetes (Table 2.2 and
b-cell demise or dysfunction (12). Across impact of heightening awareness of Table 2.5) (24). Diabetes may be identified
the globe, many groups are working on a population of adults likely to have anywhere along the spectrum of clinical
Table 2.1—Staging of type 1 diabetes (12,16)

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.
diabetesjournals.org/care Classification and Diagnosis of Diabetes S21
Complications Trial (DCCT) reference as-

Table 2.2—Criteria for the diagnosis of diabetes
say. Point-of-care A1C assays may be
FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*
NGSP certified and cleared by the U.S.
OR Food and Drug Administration (FDA)
2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described for use in monitoring glycemic control
by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose in people with diabetes in both Clinical
dissolved in water.* Laboratory Improvement Amendments
OR (CLIA)-regulated and CLIA-waived settings.
A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method
FDA-approved point-of-care A1C testing
that is NGSP certified and standardized to the DCCT assay.* can be used in laboratories or sites that
are CLIA certified, are inspected, and
OR
meet the CLIA quality standards. These
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random

standards include specified personnel re-
plasma glucose $200 mg/dL (11.1 mmol/L). quirements (including documented annual
DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glu- competency assessments) and participa-
cose tolerance test; NGSP, National Glycohemoglobin Standardization Program; WHO, World tion three times per year in an approved
Health Organization; 2-h PG, 2-h plasma glucose. *In the absence of unequivocal hyperglyce- proficiency testing program (29–32). As
mia, diagnosis requires two abnormal test results from the same sample or in two separate discussed in Section 6, “Glycemic Targets,”
test samples.
point-of-care A1C assays may be more
generally applied for assessment of glyce-
scenarios—in seemingly low-risk individ- mic stability in the clinic.
Food and Drug Administration–
uals who happen to have glucose testing, A1C has several advantages compared
approved devices at laborato-
in individuals screened based on diabetes with FPG and OGTT, including greater
ries proficient in performing
risk assessment, and in symptomatic pa- convenience (fasting not required), greater
testing of moderate complex- preanalytical stability, and fewer day-to-day
tients. For additional details on the evi-
ity or higher by trained per- perturbations during stress, changes in
dence used to establish the criteria for
sonnel. B nutrition, or illness. However, these ad-
the diagnosis of diabetes, prediabetes,
2.2 Marked discordance between vantages may be offset by the lower
and abnormal glucose tolerance (IFG,
IGT), see the ADA position statement measured A1C and plasma glu- sensitivity of A1C at the designated cut
“Diagnosis and Classification of Diabetes cose levels should raise the point, greater cost, limited availability of
Mellitus” (1) and other reports (21,25,26). possibility of A1C assay interfer- A1C testing in certain regions of the de-
ence and consideration of using veloping world, and the imperfect cor-
Fasting and 2-Hour Plasma Glucose an assay without interference relation between A1C and average
The FPG and 2-h PG may be used to di- or plasma blood glucose criteria glucose in certain individuals. The A1C
agnose diabetes (Table 2.2). The concor- to diagnose diabetes. B test, with a diagnostic threshold of $6.5%
dance between the FPG and 2-h PG tests 2.3 In conditions associated with (48 mmol/mol), diagnoses only 30% of the
is imperfect, as is the concordance be- an altered relationship between diabetes cases identified collectively using
tween A1C and either glucose-based test. A1C and glycemia, such as A1C, FPG, or 2-h PG, according to National
Compared with FPG and A1C cut points, hemoglobinopathies including Health and Nutrition Examination Survey
the 2-h PG value diagnoses more people sickle cell disease, pregnancy (NHANES) data (33). Despite these limi-
with prediabetes and diabetes (27). In (second and third trimesters tations with A1C, in 2009, the Interna-
people in whom there is discordance and the postpartum period), tional Expert Committee added A1C to
between A1C values and glucose values, glucose-6-phosphate dehydro- the diagnostic criteria with the goal of in-
FPG and 2-h PG are more accurate (28). genase deficiency, HIV, hemo- creased screening (21).
dialysis, recent blood loss or When using A1C to diagnose diabetes,
A1C transfusion, or erythropoietin it is important to recognize that A1C is
Recommendations therapy, only plasma blood glu- an indirect measure of average blood
2.1a To avoid misdiagnosis or missed cose criteria should be used to glucose levels and to take other factors
diagnosis, the A1C test should diagnose diabetes. B into consideration that may impact he-
be performed using a method 2.4 Adequate carbohydrate intake moglobin glycation independently of gly-
that is certified by the National (at least 150 g/day) should be cemia, such as hemodialysis, pregnancy,
assured for 3 days prior to HIV treatment (34,35), age, race/ethnicity,
Glycohemoglobin Standardiza-
oral glucose tolerance testing genetic background, and anemia/
tion Program (NGSP) and stan-
as a screen for diabetes. A hemoglobinopathies. (See OTHER CONDI-
dardized to the Diabetes Control
TIONS ALTERING THE RELATIONSHIP OF A 1C AND
and Complications Trial (DCCT)
GLYCEMIA below for more information.)
assay. B
The A1C test should be performed us-
2.1b Point-of-care A1C testing for
ing a method that is certified by the Age
diabetes screening and diagno-
NGSP (ngsp.org) and standardized or The epidemiologic studies that formed
sis should be restricted to U.S.
traceable to the Diabetes Control and the basis for recommending A1C to
diagnose diabetes included only adult measured with continuous glucose on the basis of the confirmatory screen-
populations (33). However, recent ADA monitoring (46). A recent report in ing test. For example, if a patient meets
clinical guidance concluded that A1C, Afro-Caribbean people demonstrated a the diabetes criterion of the A1C (two
FPG, or 2-h PG could be used to test lower A1C than predicted by glucose lev- results $6.5% [48 mmol/mol]) but not
for prediabetes or type 2 diabetes in els (47). Despite these and other reported FPG (<126 mg/dL [7.0 mmol/L]), that
children and adolescents (see SCREENING differences, the association of A1C with person should nevertheless be consid-
AND TESTING FOR PREDIABETES AND TYPE 2 DIABETES risk for complications appears to be ered to have diabetes.
IN CHILDREN AND ADOLESCENTS below for addi- similar in African American and non- Each of the screening tests has prea-
tional information) (36). Hispanic White populations (42,48). nalytic and analytic variability, so it is
In the Taiwanese population, age and possible that a test yielding an abnor-
Race/Ethnicity/Hemoglobinopathies sex have been reported to be associ- mal result (i.e., above the diagnostic
Hemoglobin variants can interfere with ated with increased A1C in men (49); threshold), when repeated, will produce
the clinical implications of this finding

the measurement of A1C, although most a value below the diagnostic cut point.
assays in use in the U.S. are unaffected are unclear at this time. This scenario is likely for FPG and 2-h PG
by the most common variants. Marked if the glucose samples remain at room
discrepancies between measured A1C Other Conditions Altering the Relationship temperature and are not centrifuged
and plasma glucose levels should prompt of A1C and Glycemia promptly. Because of the potential for
consideration that the A1C assay may In conditions associated with increased preanalytic variability, it is critical that
not be reliable for that individual. For red blood cell turnover, such as sickle samples for plasma glucose be spun and
individuals with a hemoglobin variant but cell disease, pregnancy (second and third separated immediately after they are
normal red blood cell turnover, such as trimesters), glucose-6-phosphate dehydro- drawn. If patients have test results near
those with the sickle cell trait, an A1C as- genase deficiency (50,51), hemodialysis, the margins of the diagnostic threshold,
say without interference from hemoglo- recent blood loss or transfusion, or the health care professional should dis-
bin variants should be used. An updated erythropoietin therapy, only plasma blood cuss signs and symptoms with the pa-
list of A1C assays with interferences is glucose criteria should be used to diag- tient and repeat the test in 3–6 months.
available at ngsp.org/interf.asp. nose diabetes (52). A1C is less reliable People should consume a mixed diet
African American individuals heterozy- than blood glucose measurement in other with at least 150 g of carbohydrates on
gous for the common hemoglobin vari- conditions such as the postpartum state the 3 days prior to oral glucose tolerance
ant HbS may have, for any given level of (53–55), HIV treated with certain protease testing (58–60). Fasting and carbohydrate
mean glycemia, lower A1C by about inhibitors (PIs) and nucleoside reverse restriction can falsely elevate glucose level
0.3% compared with those without the transcriptase inhibitors (NRTIs) (34), and with an oral glucose challenge.
trait (37). Another genetic variant, X-linked iron-deficient anemia (56).
glucose-6-phosphate dehydrogenase Diagnosis
G202A, carried by 11% of African Amer- Confirming the Diagnosis In a patient with classic symptoms, mea-
ican individuals, was associated with a Unless there is a clear clinical diagnosis surement of plasma glucose is sufficient
decrease in A1C of about 0.8% in homo- (e.g., patient in a hyperglycemic crisis or to diagnose diabetes (symptoms of hy-
zygous men and 0.7% in homozygous with classic symptoms of hyperglycemia perglycemia or hyperglycemic crisis plus
women compared with those without and a random plasma glucose $200 mg/dL a random plasma glucose $200 mg/dL
the variant (38). For example, in Tanza- [11.1 mmol/L]), diagnosis requires two [11.1 mmol/L]). In these cases, knowing
nia, where there is a high likelihood of abnormal screening test results, either the plasma glucose level is critical because,
hemoglobinopathies in people with HIV, from the same sample (57) or in two in addition to confirming that symptoms
A1C may be lower than expected based separate test samples. If using two sepa- are due to diabetes, it will inform manage-
on glucose, limiting its usefulness for rate test samples, it is recommended that ment decisions. Some health care profes-
screening (39). the second test, which may either be a sionals may also want to know the A1C to
Even in the absence of hemoglobin repeat of the initial test or a different determine the chronicity of the hyper-
variants, A1C levels may vary with race/ test, be performed without delay. For glycemia. The criteria to diagnose diabe-
ethnicity independently of glycemia (40–42). example, if the A1C is 7.0% (53 mmol/mol) tes are listed in Table 2.2.
For example, African American individu- and a repeat result is 6.8% (51 mmol/mol),
als may have higher A1C levels than the diagnosis of diabetes is confirmed. If
TYPE 1 DIABETES
non-Hispanic White individuals with simi- two different tests (such as A1C and FPG)
lar fasting and post–glucose load glucose are both above the diagnostic threshold Recommendations
levels (43). Though conflicting data exist, when analyzed from the same sample or 2.5 Screening for presymptomatic
African American individuals may also in two different test samples, this also type 1 diabetes using screen-
have higher levels of fructosamine and confirms the diagnosis. On the other ing tests that detect autoanti-
glycated albumin and lower levels of hand, if a patient has discordant results bodies to insulin, glutamic acid
1,5-anhydroglucitol, suggesting that their from two different tests, then the test decarboxylase (GAD), islet anti-
glycemic burden (particularly postprandi- result that is above the diagnostic cut gen 2, or zinc transporter 8 is
ally) may be higher (44,45). Similarly, point should be repeated, with careful currently recommended in the
A1C levels may be higher for a given consideration of the possibility of A1C setting of a research study or
mean glucose concentration when assay interference. The diagnosis is made
can be considered an option dependent on insulin for survival and are checkpoint inhibitors (73). To date, the
for first-degree family mem- at risk for DKA (5–7,67,68). At this majority of immune checkpoint inhibitor–
bers of a proband with type 1 later stage of the disease, there is lit- related cases of type 1 diabetes occur in
tle or no insulin secretion, as manifested people with high-risk HLA-DR4 (present in
diabetes. B
by low or undetectable levels of plasma C- 76% of patients), whereas other high-risk
2.6 Development of and persistence
peptide. Immune-mediated diabetes is HLA alleles are not more common than
of multiple islet autoantibodies
the most common form of diabetes in those in the general population (73). To
is a risk factor for clinical di-
childhood and adolescence, but it can date, risk cannot be predicted by family
abetes and may serve as an
occur at any age, even in the 8th and history or autoantibodies, so all health care
indication for intervention in
9th decades of life. professionals administering these medica-
the setting of a clinical trial or Autoimmune destruction of b-cells has tions should be mindful of this adverse ef-
screening for stage 2 type 1 multiple genetic factors and is also re- fect and educate patients appropriately.
diabetes. B

lated to environmental factors that are
still poorly defined. Although individuals Idiopathic Type 1 Diabetes
Immune-Mediated Diabetes
do not typically have obesity when they Some forms of type 1 diabetes have no
This form, previously called “insulin- present with type 1 diabetes, obesity is known etiologies. These individuals have
dependent diabetes” or “juvenile-onset increasingly common in the general pop- permanent insulinopenia and are prone
diabetes,” accounts for 5–10% of diabetes ulation; as such, obesity should not pre- to DKA but have no evidence of b-cell
and is due to cell-mediated autoimmune clude testing for type 1 diabetes. People autoimmunity. However, only a minority
with type 1 diabetes are also prone to
destruction of the pancreatic b-cells. Au- of people with type 1 diabetes fall into this
other autoimmune disorders such as category. Individuals with autoantibody-
toimmune markers include islet cell auto-
Hashimoto thyroiditis, Graves disease, ce- negative type 1 diabetes of African or
antibodies and autoantibodies to GAD
liac disease, Addison disease, vitiligo, Asian ancestry may suffer from episodic
(glutamic acid decarboxylase, GAD65),
autoimmune hepatitis, myasthenia gra- DKA and exhibit varying degrees of insu-
insulin, the tyrosine phosphatases islet
vis, and pernicious anemia (see Section 4, lin deficiency between episodes (possibly
antigen 2 (IA-2) and IA-2b, and zinc trans-
“Comprehensive Medical Evaluation and
porter 8. Numerous clinical studies are ketosis-prone diabetes) (74). This form of
Assessment of Comorbidities”). Type 1
being conducted to test various methods diabetes is strongly inherited and is not
diabetes can be associated with mono-
of preventing type 1 diabetes in those HLA associated. An absolute requirement
genic polyglandular autoimmune syn-
with evidence of islet autoimmunity for insulin replacement therapy in affected
dromes, including immune dysregulation,
(trialnet.org/our-research/prevention- individuals may be intermittent. Future
polyendocrinopathy, enteropathy, and
studies) (14,17,61–64). Stage 1 of research is needed to determine the
X-linked (IPEX) syndrome, which is an
type 1 diabetes is defined by the cause of b-cell destruction in this rare
early-onset systemic autoimmune, ge-
presence of two or more of these au- clinical scenario.
netic disorder caused by mutation of
toimmune markers. The disease has the forkhead box protein 3 (FOXP3)
strong HLA associations, with linkage gene, and another caused by the auto- Screening for Type 1 Diabetes Risk
to the DQB1 and DRB1 haplotypes, and immune regulator (AIRE) gene mutation The incidence and prevalence of type 1
genetic screening has been used in some (69,70). As indicated by the names, diabetes are increasing (75). People with
research studies to identify high-risk these disorders are associated with type 1 diabetes often present with acute
populations. Specific alleles in these genes other autoimmune and rheumatological symptoms of diabetes and markedly ele-
can be either predisposing or protective diseases. vated blood glucose levels, and 40–60%
(Table 2.1). Introduction of immunotherapy, spe- are diagnosed with life-threatening DKA
The rate of b-cell destruction is quite cifically checkpoint inhibitors, for cancer (2–4). Multiple studies indicate that mea-
variable, being rapid in some individuals treatment has led to unexpected ad- suring islet autoantibodies in relatives of
(particularly but not exclusively in infants verse events, including immune system those with type 1 diabetes (15) or in chil-
and children) and slow in others (mainly activation precipitating autoimmune dis- dren from the general population (76,77)
but not exclusively adults) (65,66). Chil- ease. Fulminant onset of type 1 diabe- can effectively identify those who will de-
dren and adolescents often present with tes can develop, with DKA and low or velop type 1 diabetes. A study reported
DKA as the first manifestation of the undetectable levels of C-peptide as a the risk of progression to type 1 diabetes
disease, and the rates in the U.S. have marker of endogenous b-cell function from the time of seroconversion to auto-
increased dramatically over the past (71,72). Fewer than half of these pa- antibody positivity in three pediatric co-
20 years (2–4). Others have modest tients have autoantibodies that are seen horts from Finland, Germany, and the U.S.
fasting hyperglycemia that can rapidly in type 1 diabetes, supporting alternate Of the 585 children who developed more
change to severe hyperglycemia and/ pathobiology. This immune-related adverse than two autoantibodies, nearly 70% de-
or DKA with infection or other stress. event occurs in just under 1% of check- veloped type 1 diabetes within 10 years
Adults may retain sufficient b-cell func- point inhibitor-treated patients but most and 84% within 15 years (14). These find-
tion to prevent DKA for many years; commonly occurs with agents that block ings are highly significant because while
such individuals may have remission the programmed cell death protein 1/ the German group was recruited from off-
or decreased insulin needs for months programmed cell death ligand 1 pathway spring of parents with type 1 diabetes, the
or years and eventually become alone or in combination with other Finnish and American groups were
recruited from the general popula- 2.8 Testing for prediabetes and/ 2.14 Risk-based screening for predi-
tion. Remarkably, the findings in all or type 2 diabetes in asymp- abetes and/or type 2 diabetes
three groups were the same, suggesting tomatic people should be should be considered after
that the same sequence of events led to considered in adults of any age the onset of puberty or after
clinical disease in both “sporadic” and fa- with overweight or obesity 10 years of age, whichever
milial cases of type 1 diabetes. Indeed, (BMI $25 kg/m2 or $23 kg/m2 occurs earlier, in children and
the risk of type 1 diabetes increases as in Asian American individuals) adolescents with overweight
the number of relevant autoantibodies who have one or more risk (BMI $85th percentile) or
detected increases (63,78,79). In The En- factors (Table 2.3). B obesity (BMI $95th percentile)
vironmental Determinants of Diabetes in 2.9 For all people, screening should
the Young (TEDDY) study, type 1 diabetes and who have one or more
begin at age 35 years. B risk factors for diabetes. (See
developed in 21% of 363 subjects with 2.10 If tests are normal, repeat
at least one autoantibody at 3 years of Table 2.4 for evidence grad-

screening recommended at ing of risk factors.) B
age (80). Such testing, coupled with edu- a minimum of 3-year inter-
cation about diabetes symptoms and close 2.15 People with HIV should be
vals is reasonable, sooner with
follow-up, has been shown to enable ear- screened for diabetes and pre-
symptoms or change in risk
lier diagnosis and prevent DKA (81,82). diabetes with a fasting glucose
(i.e., weight gain). C
While widespread clinical screening test before starting antiretrovi-
2.11 To screen for prediabetes and
of asymptomatic low-risk individuals is ral therapy, at the time of
type 2 diabetes, fasting plasma
not currently recommended due to lack switching antiretroviral therapy,
glucose, 2-h plasma glucose
of approved therapeutic interventions, during 75-g oral glucose toler- and 3–6 months after starting
several innovative research screening pro- ance test, and A1C are each or switching antiretroviral ther-
grams are available in Europe (e.g., Fr1da, appropriate (Table 2.2 and apy. If initial screening results
gppad.org) and the U.S. (trialnet.org, Table 2.5). B are normal, fasting glucose
askhealth.org). Participation should be 2.12 When using oral glucose toler- should be checked annually. E
encouraged to accelerate development ance testing as a screen for di-
of evidence-based clinical guidelines for abetes, adequate carbohydrate
the general population and relatives of Prediabetes
intake (at least 150 g/day) “Prediabetes” is the term used for indi-
those with type 1 diabetes. Individuals should be assured for 3 days
who test positive should be counseled viduals whose glucose levels do not
prior to testing. A
about the risk of developing diabetes, meet the criteria for diabetes yet have
2.13 In people with prediabetes and
diabetes symptoms, and DKA preven- abnormal carbohydrate metabolism (48,85).
type 2 diabetes, identify and
tion. Numerous clinical studies are be- People with prediabetes are defined
treat cardiovascular disease risk
ing conducted to test various methods by the presence of IFG and/or IGT
factors. A
of preventing and treating stage 2 type 1 and/or A1C 5.7–6.4% (39–47 mmol/mol)
diabetes in those with evidence of auto-
immunity with promising results (see
Table 2.3—Criteria for screening for diabetes or prediabetes in asymptomatic
clinicaltrials.gov and trialnet.org). Delay
adults
of overt diabetes development in stage 2
1. Testing should be considered in adults with overweight or obesity (BMI $25 kg/m2 or
type 1 diabetes with the anti-CD3 anti- $23 kg/m2 in Asian American individuals) who have one or more of the following risk factors:
body teplizumab in relatives at risk for First-degree relative with diabetes
type 1 diabetes was reported in 2019, High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian
with an extension of the randomized American, Pacific Islander)
controlled trial in 2021 (83,84). Based on History of CVD
these data, this agent has been submit- Hypertension ($140/90 mmHg or on therapy for hypertension)
HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL
ted to the FDA for the indication of delay
(2.82 mmol/L)
or prevention of clinical type 1 diabetes Individuals with polycystic ovary syndrome
in at-risk individuals. Neither this agent Physical inactivity
nor others in this category are currently Other clinical conditions associated with insulin resistance (e.g., severe obesity,
available for clinical use. acanthosis nigricans)
2. People with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly.
PREDIABETES AND TYPE 2 DIABETES
3. People who were diagnosed with GDM should have lifelong testing at least every 3 years.
Recommendations 4. For all other people, 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
6. People with HIV
or validated risk calculator
should be done in asymptom- CVD, cardiovascular disease; GDM, gestational diabetes mellitus; IFG, impaired fasting glu-
atic adults. B cose; IGT, impaired glucose tolerance.
Hence, it is reasonable to consider an

Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in
asymptomatic children and adolescents in a clinical setting A1C range of 5.7–6.4% (39–47 mmol/mol)
Screening should be considered in youth* who have overweight ($85th percentile) or as identifying individuals with prediabe-
obesity ($95th percentile) A and who have one or more additional risk factors based on tes. Similar to those with IFG and/or IGT,
the strength of their association with diabetes: individuals with A1C of 5.7–6.4% (39–
Maternal history of diabetes or GDM during the child’s gestation A 47 mmol/mol) should be informed of
Family history of type 2 diabetes in first- or second-degree relative A
their increased risk for diabetes and CVD
Race/ethnicity (Native American, African American, Latino, Asian American, Pacific
Islander) A and counseled about effective strategies
Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, to lower their risks (see Section 3,
hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth “Prevention or Delay of Type 2 Diabetes
weight) B and Associated Comorbidities”). Similar
GDM, gestational diabetes mellitus. *After the onset of puberty or after 10 years of age, to glucose measurements, the continuum

whichever occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals of risk is curvilinear, so as A1C rises, the
(or more frequently if BMI is increasing or risk factor profile deteriorating) is recommended. diabetes risk rises disproportionately (86).
Reports of type 2 diabetes before age 10 years exist, and this can be considered with nu-
Aggressive interventions and vigilant
merous risk factors.
follow-up should be pursued for those
considered at very high risk (e.g., those
(Table 2.5). Prediabetes should not be defined by A1C criteria demonstrated a with A1C >6.0% [42 mmol/mol]).
viewed as a clinical entity in its own right strong, continuous association between Table 2.5 summarizes the categories
but rather as a risk factor for progression A1C and subsequent diabetes. In a sys- of prediabetes, and Table 2.3 outlines
to diabetes and cardiovascular disease tematic review of 44,203 individuals from the criteria for screening for prediabe-
(CVD). Criteria for screening for diabetes 16 cohort studies with a follow-up interval tes. The ADA Diabetes Risk Test is an
or prediabetes in asymptomatic adults averaging 5.6 years (range 2.8–12 years), additional option for assessment to
are outlined in Table 2.3. Prediabetes is those with A1C between 5.5% and 6.0% determine the appropriateness of screen-
associated with obesity (especially ab- (between 37 and 42 mmol/mol) had a ing for diabetes or prediabetes in asymp-
dominal or visceral obesity), dyslipidemia substantially increased risk of diabetes tomatic adults (Fig. 2.1) (diabetes.org/
with high triglycerides and/or low HDL (5-year incidence from 9% to 25%). Those socrisktest). For additional background
cholesterol, and hypertension. The pres- with an A1C range of 6.0–6.5% (42–48 regarding risk factors and screening
ence of prediabetes should prompt com- mmol/mol) had a 5-year risk of develop- for prediabetes, see SCREENING AND TESTING
prehensive screening for cardiovascular ing diabetes between 25% and 50% and FOR PREDIABETES AND TYPE 2 DIABETES IN ASYMPTOM-
risk factors. a relative risk 20 times higher compared ATIC ADULTS and also SCREENING AND TESTING FOR
with A1C of 5.0% (31 mmol/mol) (86). In a PREDIABETES AND TYPE 2 DIABETES IN CHILDREN
Diagnosis community-based study of African American AND ADOLESCENTS below. For details re-
IFG is defined as FPG levels from 100 to and non-Hispanic White adults without garding individuals with prediabetes
125 mg/dL (from 5.6 to 6.9 mmol/L) diabetes, baseline A1C was a stronger most likely to benefit from a formal
(82,83) and IGT as 2-h PG levels during predictor of subsequent diabetes and car- behavioral or lifestyle intervention,
75-g OGTT from 140 to 199 mg/dL (from diovascular events than fasting glucose see Section 3, “Prevention or Delay
7.8 to 11.0 mmol/L) (25). It should be (87). Other analyses suggest that A1C of of Type 2 Diabetes and Associated
noted that the World Health Organiza- 5.7% (39 mmol/mol) or higher is associ- Comorbidities.”
tion and numerous other diabetes organ- ated with a diabetes risk similar to that of
izations define the IFG lower limit at the high-risk participants in the Diabetes Type 2 Diabetes
110 mg/dL (6.1 mmol/L). Prevention Program (DPP) (88), and A1C Type 2 diabetes, previously referred to
As with the glucose measures, several at baseline was a strong predictor of the as “non-insulin-dependent diabetes”
prospective studies that used A1C to development of glucose-defined diabetes or “adult-onset diabetes,” accounts for
predict the progression to diabetes as during the DPP and its follow-up (89). 90–95% of all diabetes. This form en-
compasses individuals who have relative
Table 2.5—Criteria defining prediabetes*
(rather than absolute) insulin deficiency
FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG)
and have peripheral insulin resistance.
At least initially, and often throughout
OR
their lifetime, these individuals may not
2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) need insulin treatment to survive.
OR There are various causes of type 2 di-
A1C 5.7–6.4% (39–47 mmol/mol)
abetes. Although the specific etiologies
are not known, autoimmune destruction
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; of b-cells does not occur, and patients
OGTT, oral glucose tolerance test; 2-h PG, 2-h plasma glucose. *For all three tests, risk is
do not have any of the other known
continuous, extending below the lower limit of the range and becoming disproportionately
greater at the higher end of the range. causes of diabetes. Most, but not all,
people with type 2 diabetes have
American
Diabetes
® Association®
Connected for Life
Are you at risk for type 2 diabetes?

WRITE YOUR SCORE
Diabetes Risk Test: IN THE BOX.
Height Weight (lbs.)

1. How old are you? ................................................... 4’ 10” 119–142 143–190 191+
Less than 40 years (0 points)
4’ 11” 124–147 148–197 198+
40–49 years (1 point)
5’ 0” 128–152 153–203 204+
50–59 years (2 points)
5’ 1” 132–157 158–210 211+
60 years or older (3 points)
5’ 2” 136–163 164–217 218+
2. Are you a man or a woman? ................................. 5’ 3” 141–168 169–224 225+
Man (1 point) Woman (0 points) 5’ 4” 145–173 174–231 232+
5’ 5” 150–179 180–239 240+
3. If you are a woman, have you ever been
5’ 6” 155–185 186–246 247+
diagnosed with gestational diabetes?..................
5’ 7” 159–190 191–254 255+
Yes (1 point) No (0 points)
5’ 8” 164–196 197–261 262+
4. Do you have a mother, father, sister or brother 5’ 9” 169–202 203–269 270+
with diabetes? ........................................................ 5’ 10” 174–208 209–277 278+
Yes (1 point) No (0 points) 5’ 11” 179–214 215–285 286+
5. Have you ever been diagnosed with high 6’ 0” 184–220 221–293 294+
blood pressure? ..................................................... 6’ 1” 189–226 227–301 302+
Yes (1 point) No (0 points) 6’ 2” 194–232 233–310 311+
6’ 3” 200–239 240–318 319+
6. Are you physically active? ....................................
6’ 4” 205–245 246–327 328+
Yes (0 points) No (1 point)
1 point 2 points 3 points
7. What is your weight category? ............................. If you weigh less than the amount in
See chart at right. the left column: 0 points
Adapted from Bang et al., Ann Intern Med

ADD UP 151:775–783, 2009 • Original algorithm was validated
without gestational diabetes as part of the model.
YOUR SCORE.
If you scored 5 or higher:
You are at increased risk for having type 2 diabetes.
However, only your doctor can tell for sure if you do
Lower Your Risk
have type 2 diabetes or prediabetes, a condition in The good news is you can manage your
Diabetes Risk Test | American Diabetes Association®
which blood glucose levels are higher than normal risk for type 2 diabetes. Small steps make
but not yet high enough to be diagnosed as diabetes. a big difference in helping you live a longer,
Talk to your doctor to see if additional testing is needed. healthier life.
If you are at high risk, your first step is to
Type 2 diabetes is more common in African Americans, visit your doctor to see if additional testing
Hispanics/Latinos, Native Americans, Asian Americans, is needed.
and Native Hawaiians and Pacific Islanders.
Visit diabetes.org or call 1-800-DIABETES
Higher body weight increases diabetes risk for everyone. (800-342-2383) for information, tips on
Asian Americans are at increased diabetes risk at lower getting started, and ideas for simple, small
body weight than the rest of the general public (about 15 steps you can take to help lower your risk.
pounds lower).
Learn more at diabetes.org/risktest | 1-800-DIABETES (800-342-2383)
Figure 2.1—ADA risk test (diabetes.org/socrisktest).
overweight or obesity. Excess weight it- percentage of body fat distributed pre- illness such as infection or myocardial infarc-
self causes some degree of insulin re- dominantly in the abdominal region. tion or with the use of certain drugs (e.g.,
sistance. Individuals who do not have DKA seldom occurs spontaneously in corticosteroids, atypical antipsychotics, and
obesity or overweight by traditional type 2 diabetes; when seen, it usually arises sodium–glucose cotransporter 2 inhibitors)
weight criteria may have an increased in association with the stress of another (90,91). Type 2 diabetes frequently goes
undiagnosed for many years because guide health care professionals on (109). Employing a probabilistic model,
hyperglycemia develops gradually and, whether performing a diagnostic test Peterson et al. (110) demonstrated cost
at earlier stages, is often not severe (Table 2.2) is appropriate. Prediabetes and health benefits of preconception
enough for the patient to notice the and type 2 diabetes meet criteria for screening.
classic diabetes symptoms caused by hy- conditions in which early detection via A large European randomized con-
perglycemia, such as dehydration or un- screening is appropriate. Both conditions trolled trial compared the impact of
intentional weight loss. Nevertheless, are common and impose significant clin- screening for diabetes and intensive
even undiagnosed people with diabetes ical and public health burdens. There is multifactorial intervention with that of
are at increased risk of developing macro- often a long presymptomatic phase be- screening and routine care (111). Gen-
vascular and microvascular complications. fore the diagnosis of type 2 diabetes. eral practice patients between the ages
People with type 2 diabetes may have Simple tests to detect preclinical disease of 40 and 69 years were screened for
insulin levels that appear normal or ele- are readily available (101). The duration diabetes and randomly assigned by prac-

vated, yet the failure to normalize blood of glycemic burden is a strong predictor tice to intensive treatment of multiple
glucose reflects a relative defect in glu- of adverse outcomes. There are effective risk factors or routine diabetes care.
cose-stimulated insulin secretion. Thus, interventions that prevent progression After 5.3 years of follow-up, CVD risk
insulin secretion is defective in these from prediabetes to diabetes. It is im- factors were modestly but significantly
individuals and insufficient to compensate portant to individualize risk/benefit of improved with intensive treatment com-
for insulin resistance. Insulin resistance formal intervention for people with pre- pared with routine care, but the inci-
may improve with weight reduction, diabetes and consider patient-centered dence of first CVD events or mortality
physical activity, and/or pharmacologic goals. Risk models have explored the was not significantly different between
treatment of hyperglycemia but is sel- benefit, in general finding higher ben- the groups (26). The excellent care pro-
dom restored to normal. Recent inter- efit of intervention in those at highest vided to patients in the routine care
ventions with intensive diet and exercise risk (102) (see Section 3, “Prevention or group and the lack of an unscreened
or surgical weight loss have led to diabe- Delay of Type 2 Diabetes and Associated control arm limited the authors’ ability
tes remission (92–98) (see Section 8, to determine whether screening and
Comorbidities”) and reduce the risk
“Obesity and Weight Management for of diabetes complications (103) (see
early treatment improved outcomes com-
the Prevention and Treatment of Type 2 pared with no screening and later treat-
Section 10, “Cardiovascular Disease and
Diabetes”). ment after clinical diagnoses. Computer
Risk Management,” Section 11, “Chronic
The risk of developing type 2 diabetes simulation modeling studies suggest that
Kidney Disease and Risk Management,”
increases with age, obesity, and lack of major benefits are likely to accrue from
and Section 12, “Retinopathy, Neuropathy,
physical activity (99,100). It occurs more the early diagnosis and treatment of
and Foot Care”). In the most recent Na-
frequently in individuals with prior gesta- hyperglycemia and cardiovascular risk
tional Institutes of Health (NIH) Diabetes
tional diabetes mellitus (GDM) or poly- factors in type 2 diabetes (112); more-
Prevention Program Outcomes Study over, screening, beginning at age 30 or
cystic ovary syndrome. It is also more
(DPPOS) report, prevention of progres- 45 years and independent of risk factors,
common in people with hypertension or
sion from prediabetes to diabetes (104) may be cost-effective (<$11,000 per
dyslipidemia and in certain racial/ethnic
resulted in lower rates of developing ret- quality-adjusted life year gained—2010
subgroups (African American, Native
American, Hispanic/Latino, and Asian inopathy and nephropathy (105). Similar modeling data) (113). Cost-effectiveness
American). It is often associated with impact on diabetes complications was of screening has been reinforced in co-
a strong genetic predisposition or family reported with screening, diagnosis, and hort studies (114,115).
history in first-degree relatives (more so comprehensive risk factor management Additional considerations regarding
than type 1 diabetes). However, the ge- in the U.K. Clinical Practice Research testing for type 2 diabetes and predia-
netics of type 2 diabetes are poorly un- Datalink database (103). In that report, betes in asymptomatic individuals in-
derstood and under intense investigation progression from prediabetes to diabetes clude the following.
in this era of precision medicine (18). In augmented risk of complications.
adults without traditional risk factors for Approximately one-quarter of people Age
type 2 diabetes and/or of younger age, with diabetes in the U.S. and nearly half Age is a major risk factor for diabetes.
consider islet autoantibody testing (e.g., of Asian and Hispanic American people Testing should begin at no later than age
GAD65 autoantibodies) to exclude the with diabetes are undiagnosed (106,107). 35 years for all people (116). Screening
diagnosis of type 1 diabetes (8). Although screening of asymptomatic indi- should be considered in adults of any
viduals to identify those with prediabetes age with overweight or obesity and one
Screening and Testing for Prediabetes or diabetes might seem reasonable, rigor- or more risk factors for diabetes.
and Type 2 Diabetes in Asymptomatic ous clinical trials to prove the effective-
Adults ness of such screening have not been BMI and Ethnicity
Screening for prediabetes and type 2 di- conducted and are unlikely to occur. In general, BMI $25 kg/m2 is a risk fac-
abetes risk through an informal assess- Clinical conditions, such as hyperten- tor for diabetes. However, data suggest
ment of risk factors (Table 2.3) or with sion, hypertensive pregnancy, and obe- that the BMI cut point should be lower
an assessment tool, such as the ADA sity, enhance risk (108). Based on a for the Asian American population
risk test (Fig. 2.1) (online at diabetes. population estimate, diabetes in people (117,118). The BMI cut points fall con-
org/socrisktest), is recommended to of childbearing age is underdiagnosed sistently between 23 and 24 kg/m2
(sensitivity of 80%) for nearly all Asian pancreatic b-cells. NRTIs also affect fat and 14.60% meeting criteria for pre-
American subgroups (with levels slightly distribution (both lipohypertrophy and diabetes and diabetes, respectively,
lower for Japanese American individ- lipoatrophy), which is associated with using random blood glucose. Further
uals). This makes a rounded cut point insulin resistance. For people with HIV research is needed to demonstrate
of 23 kg/m2 practical. An argument can and ARV-associated hyperglycemia, it may the feasibility, effectiveness, and cost-
be made to push the BMI cut point to be appropriate to consider discontinuing effectiveness of screening in this setting.
lower than 23 kg/m2 in favor of in- the problematic ARV agents if safe and
creased sensitivity; however, this would effective alternatives are available (124). Screening and Testing for Prediabetes
lead to an unacceptably low specificity Before making ARV substitutions, care- and Type 2 Diabetes in Children and
(13.1%). Data from the World Health fully consider the possible effect on Adolescents
Organization also suggest that a BMI of HIV virological control and the poten- In the last decade, the incidence and
$23 kg/m2 should be used to define in- tial adverse effects of new ARV agents. prevalence of type 2 diabetes in chil-
dren and adolescents has increased dra-

creased risk in Asian American individu- In some cases, antihyperglycemic agents
als (119). The finding that one-third to may still be necessary. matically, especially in racial and ethnic
one-half of diabetes in Asian American minority populations (75). See Table 2.4
people is undiagnosed suggests that Testing Interval for recommendations on risk-based
testing is not occurring at lower BMI The appropriate interval between screen- screening for type 2 diabetes or pre-
thresholds (99,120). ing tests is not known (125). The rationale diabetes in asymptomatic children and
Evidence also suggests that other pop- for the 3-year interval is that with this in- adolescents in a clinical setting (36). See
ulations may benefit from lower BMI cut terval, the number of false-positive tests Table 2.2 and Table 2.5 for the criteria
points. For example, in a large multiethnic that require confirmatory testing will for the diagnosis of diabetes and pre-
cohort study, for an equivalent incidence be reduced, and individuals with false- diabetes, respectively, that apply to
rate of diabetes, a BMI of 30 kg/m2 in negative tests will be retested before children, adolescents, and adults. See
non-Hispanic White individuals was equiv- substantial time elapses and complica- Section 14, “Children and Adolescents,”
alent to a BMI of 26 kg/m2 in African tions develop (125). In especially high- for additional information on type 2 dia-
American individuals (121). risk individuals, particularly with weight betes in children and adolescents.
gain, shorter intervals between screen- Some studies question the validity of
Medications ing may be useful. A1C in the pediatric population, espe-
Certain medications, such as glucocorti- cially among certain ethnicities, and
coids, thiazide diuretics, some HIV medi- Community Screening suggest OGTT or FPG as more suitable
cations (34), and atypical antipsychotics Ideally, screening should be carried out diagnostic tests (131). However, many
(92), are known to increase the risk of within a health care setting because of of these studies do not recognize that
diabetes and should be considered when the need for follow-up and treatment. diabetes diagnostic criteria are based
deciding whether to screen. Community screening outside a health on long-term health outcomes, and vali-
care setting is generally not recommended dations are not currently available in
HIV because people with positive tests may the pediatric population (132). The ADA
Individuals with HIV are at higher risk not seek, or have access to, appropriate acknowledges the limited data support-
for developing prediabetes and diabetes follow-up testing and care. However, in ing A1C for diagnosing type 2 diabetes
on antiretroviral (ARV) therapies; a specific situations where an adequate re- in children and adolescents. Although
screening protocol is therefore recom- ferral system is established beforehand A1C is not recommended for diagnosis
mended (122). The A1C test may underes- for positive tests, community screening of diabetes in children with cystic fibro-
timate glycemia in people with HIV; it is may be considered. Community screen- sis or symptoms suggestive of acute on-
not recommended for diagnosis and may ing may also be poorly targeted; i.e., it set of type 1 diabetes, and only A1C
present challenges for monitoring (35). In may fail to reach the groups most at risk assays without interference are appro-
those with prediabetes, weight loss through and inappropriately test those at very priate for children with hemoglobinopa-
healthy nutrition and physical activity may low risk or even those who have already
thies, the ADA continues to recommend
reduce the progression toward diabe- been diagnosed (126).
A1C and the criteria in Table 2.2 for di-
tes. Among people with HIV and dia-
agnosis of type 2 diabetes in this cohort
betes, preventive health care using an Screening in Dental Practices
to decrease barriers to screening (133,134).
approach used in people without HIV Because periodontal disease is associ-
is critical to reduce the risks of micro- ated with diabetes, the utility of screen-
vascular and macrovascular complica- ing in a dental setting and referral to CYSTIC FIBROSIS–RELATED
tions. Diabetes risk is increased with primary care as a means to improve the DIABETES
certain PIs and NRTIs. New-onset diabe- diagnosis of prediabetes and diabetes Recommendations
tes is estimated to occur in more than has been explored (127–129), with one 2.16 Annual screening for cystic
5% of individuals infected with HIV on study estimating that 30% of patients fibrosis–related diabetes with
PIs, whereas more than 15% may have $30 years of age seen in general dental an oral glucose tolerance test
prediabetes (123). practices had dysglycemia (129,130). A should begin by age 10 years in
PIs are associated with insulin resis- similar study in 1,150 dental patients all people with cystic fibrosis
tance and may also lead to apoptosis of >40 years old in India reported 20.69%
not previously diagnosed associated with preservation of lung diabetes mellitus is best made
with cystic fibrosis–related dia- function. The European Cystic Fibrosis once the individual is stable on
betes. B Society Patient Registry reported an in- an immunosuppressive regi-
2.17 A1C is not recommended as crease in CFRD with age (increased 10% men and in the absence of
per decade), genotype, decreased lung
a screening test for cystic an acute infection. B
function, and female sex (140,141). Con-
fibrosis–related diabetes. B 2.21 The oral glucose tolerance test
tinuous glucose monitoring or HOMA of
2.18 People with cystic fibrosis– is the preferred test to make a
b-cell function (142) may be more sensi-
related diabetes should be diagnosis of posttransplanta-
tive than OGTT to detect risk for progres-
treated with insulin to attain in- tion diabetes mellitus. B
sion to CFRD; however, evidence linking
dividualized glycemic goals. A 2.22 Immunosuppressive regimens
these results to long-term outcomes is
2.19 Beginning 5 years after the shown to provide the best out-
lacking, and these tests are not recom-
diagnosis of cystic fibrosis– comes for patient and graft

mended for screening outside of the re-
related diabetes, annual mon- search setting (143). survival should be used, irre-
itoring for complications of di- CFRD mortality has significantly de- spective of posttransplantation
abetes is recommended. E creased over time, and the gap in mor- diabetes mellitus risk. E
tality between people with cystic fibrosis
Cystic fibrosis–related diabetes (CFRD) is with and without diabetes has consider- Several terms are used in the literature
the most common comorbidity in people ably narrowed (144). There are limited to describe the presence of diabetes
with cystic fibrosis, occurring in about clinical trial data on therapy for CFRD. following organ transplantation (147).
The largest study compared three regi-
20% of adolescents and 40–50% of adults “New-onset diabetes after transplantation”
mens: premeal insulin aspart, repagli-
(135). Diabetes in this population, com- (NODAT) is one such designation that
nide, or oral placebo in people with cystic
pared with individuals with type 1 or describes individuals who develop new-
fibrosis and diabetes or abnormal glucose
type 2 diabetes, is associated with worse onset diabetes following transplant.
tolerance. Participants all had weight loss
nutritional status, more severe inflamma- NODAT excludes people with pretrans-
in the year preceding treatment; however,
tory lung disease, and greater mortality. In- plant diabetes that was undiagnosed as
in the insulin-treated group, this pattern
sulin insufficiency is the primary defect in well as posttransplant hyperglycemia
was reversed, and participants gained 0.39
CFRD. Genetically determined b-cell func- that resolves by the time of discharge
(± 0.21) BMI units (P = 0.02). The repagli-
tion and insulin resistance associated with (148). Another term, “posttransplantation
nide-treated group had initial weight
infection and inflammation may also diabetes mellitus” (PTDM) (148,149), de-
gain, but it was not sustained by 6
contribute to the development of CFRD. scribes the presence of diabetes in the
months. The placebo group continued to
Milder abnormalities of glucose toler- lose weight (144). Insulin remains the posttransplant setting irrespective of the
ance are even more common and occur most widely used therapy for CFRD (145). timing of diabetes onset.
at earlier ages than CFRD. Whether indi- The primary rationale for the use of insu- Hyperglycemia is very common dur-
viduals with IGT should be treated with lin in people with CFRD is to induce an ana- ing the early posttransplant period, with
insulin replacement has not currently bolic state while promoting macronutrient 90% of kidney allograft recipients ex-
been determined. Although screening retention and weight gain. hibiting hyperglycemia in the first few
for diabetes before the age of 10 years Additional resources for the clinical weeks following transplant (148–151).
can identify risk for progression to CFRD management of CFRD can be found in In most cases, such stress- or steroid-
in those with abnormal glucose toler- the position statement “Clinical Care induced hyperglycemia resolves by the
ance, no benefit has been established Guidelines for Cystic Fibrosis–Related time of discharge (151,152). Although
with respect to weight, height, BMI, or Diabetes: A Position Statement of the the use of immunosuppressive thera-
lung function. OGTT is the recommended American Diabetes Association and a pies is a major contributor to the devel-
screening test; however, recent publica- Clinical Practice Guideline of the Cystic opment of PTDM, the risks of transplant
tions suggest that an A1C cut point Fibrosis Foundation, Endorsed by the rejection outweigh the risks of PTDM,
threshold of 5.5% (5.8% in a second Pediatric Endocrine Society” (146) and and the role of the diabetes care health
study) would detect more than 90% of in the International Society for Pediatric care professional is to treat hyperglyce-
cases and reduce patient screening bur- and Adolescent Diabetes 2018 clinical mia appropriately regardless of the type
den (136,137). Ongoing studies are un- practice consensus guidelines (135). of immunosuppression (148). Risk fac-
derway to validate this approach, and tors for PTDM include both general dia-
A1C is not recommended for screening betes risks (such as age, family history
POSTTRANSPLANTATION
(138). Regardless of age, weight loss or of diabetes, etc.) as well as transplant-
DIABETES MELLITUS
failure of expected weight gain is a risk specific factors, such as use of immuno-
for CFRD and should prompt screening Recommendations suppressant agents (153–155). Whereas
(136,137). The Cystic Fibrosis Foundation 2.20 After organ transplantation, posttransplantation hyperglycemia is an
Patient Registry (139) evaluated 3,553 screening for hyperglycemia important risk factor for subsequent
people with cystic fibrosis and diag- should be done. A formal di- PTDM, a formal diagnosis of PTDM is op-
nosed 445 (13%) with CFRD. Early diagnosis of posttransplantation timally made once the patient is stable
agnosis and treatment of CFRD was on maintenance mmunosuppression and
in the absence of acute infection people with liver and kidney transplants, 6 months of age. Neonatal diabetes can
(151–153,156). In a recent study of 152 but side effects include fluid retention, either be transient or permanent. Tran-
heart transplant recipients, 38% had heart failure, and osteopenia (167,168). sient diabetes is most often due to over-
PTDM at 1 year. Risk factors for PTDM Dipeptidyl peptidase 4 inhibitors do not expression of genes on chromosome
included elevated BMI, discharge from interact with immunosuppressant drugs 6q24, is recurrent in about half of cases,
the hospital on insulin, and glucose val- and have demonstrated safety in small and may be treatable with medications
ues in the 24 h prior to hospital dis- clinical trials (169,170). Well-designed inter- other than insulin. Permanent neonatal
charge (157). In an Iranian cohort, 19% vention trials examining the efficacy and diabetes is most commonly due to auto-
had PTDM after heart and lung trans- safety of these and other antihyperglyce- somal dominant mutations in the genes
plant (158). The OGTT is considered mic agents in people with PTDM are encoding the Kir6.2 subunit (KCNJ11)
the gold-standard test for the diagnosis needed. and SUR1 subunit (ABCC8) of the b-cell
of PTDM (1 year posttransplant) (148, KATP channel. A recent report details a

149,159,160). Pretransplant elevation MONOGENIC DIABETES SYNDROMES de novo mutation in EIF2B1 affecting
in hs-CRP was associated with PTDM in eIF2 signaling associated with permanent
the setting of renal transplant (161,162). Recommendations neonatal diabetes and hepatic dys-
However, screening people with fasting 2.23 Regardless of current age, all function, similar to Wolcott-Rallison
glucose and/or A1C can identify high- people diagnosed with diabe- syndrome but with few severe comor-
risk individuals requiring further assess- tes in the first 6 months of bidities (176). The recent ADA-European
ment and may reduce the number of life should have immediate Association for the Study of Diabetes
overall OGTTs required. genetic testing for neonatal type 1 diabetes consensus report recom-
Few randomized controlled studies diabetes. A mends that regardless of current age, in-
have reported on the short- and long- 2.24 Children and young adults who dividuals diagnosed under 6 months of
term use of antihyperglycemic agents do not have typical characteris- age should have genetic testing (8). Cor-
in the setting of PTDM (153,163,164). tics of type 1 or type 2 diabetes rect diagnosis has critical implications be-
Most studies have reported that trans- and who often have a family cause 30–50% of people with KATP-related
plant patients with hyperglycemia and history of diabetes in successive neonatal diabetes will exhibit improved
PTDM after transplantation have higher
generations (suggestive of an blood glucose levels when treated with
rates of rejection, infection, and rehospi-
autosomal dominant pattern high-dose oral sulfonylureas instead of in-
talization (151,153,165). Insulin therapy
of inheritance) should have sulin. Insulin gene (INS) mutations are the
is the agent of choice for the manage-
genetic testing for maturity- second most common cause of perma-
ment of hyperglycemia, PTDM, and pre-
onset diabetes of the young. A nent neonatal diabetes, and while inten-
existing diabetes and diabetes in the
2.25 In both instances, consultation sive insulin management is currently the
hospital setting. After discharge, people
with a center specializing in preferred treatment strategy, there are
with preexisting diabetes could go back
on their pretransplant regimen if they diabetes genetics is recom- important genetic counseling considera-
were in good control before transplanta- mended to understand the tions, as most of the mutations that cause
tion. Those with previously poor glycemic significance of genetic muta- diabetes are dominantly inherited.
stability or with persistent hyperglycemia tions and how best to approach
should continue insulin with frequent further evaluation, treatment, Maturity-Onset Diabetes of the Young
home glucose monitoring to determine and genetic counseling. E MODY is frequently characterized by on-
when insulin dose reductions may be set of hyperglycemia at an early age
needed and when it may be appropriate (classically before age 25 years, although
Monogenic defects that cause b-cell diagnosis may occur at older ages).
to switch to noninsulin agents.
dysfunction, such as neonatal diabetes MODY is characterized by impaired insu-
No studies to date have established
which noninsulin agents are safest or and MODY, represent a small fraction of lin secretion with minimal or no defects
most efficacious in PTDM. The choice of people with diabetes (<5%). Table 2.6 in insulin action (in the absence of coex-
agent is usually made based on the side describes the most common causes of istent obesity). It is inherited in an autoso-
effect profile of the medication and monogenic diabetes. For a comprehen- mal dominant pattern with abnormalities
possible interactions with the patient’s sive list of causes, see Genetic Diagnosis in at least 13 genes on different chromo-
immunosuppression regimen (153). Drug of Endocrine Disorders (171). somes identified to date (177). The most
dose adjustments may be required be- commonly reported forms are GCK-MODY
cause of decreases in the glomerular Neonatal Diabetes (MODY2), HNF1A-MODY (MODY3), and
filtration rate, a relatively common Diabetes occurring under 6 months of HNF4A-MODY (MODY1).
complication in transplant patients. A age is termed “neonatal” or “congenital” For individuals with MODY, the treat-
small short-term pilot study reported diabetes, and about 80–85% of cases ment implications are considerable and
that metformin was safe to use in re- can be found to have an underlying warrant genetic testing (178,179). Clini-
nal transplant recipients (166), but its monogenic cause (8,172–175). Neonatal cally, people with GCK-MODY exhibit
safety has not been determined in diabetes occurs much less often after mild, stable fasting hyperglycemia and
other types of organ transplant. Thiazolidi- 6 months of age, whereas autoimmune do not require antihyperglycemic ther-
nediones have been used successfully in type 1 diabetes rarely occurs before apy except commonly during pregnancy.
Table 2.6—Most common causes of monogenic diabetes (171)

Gene Inheritance Clinical features
MODY 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
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])
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, paternal
HYMA1) duplications 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 (172)
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.
Individuals with HNF1A- or HNF4A-MODY with diabetes not characteristic of type 1 be incorrectly diagnosed with type 1
usually respond well to low doses of sul- or type 2 diabetes, although admit- or type 2 diabetes, leading to subopti-
fonylureas, which are considered first-line tedly, “atypical diabetes” is becoming mal, even potentially harmful, treatment
therapy; in some instances, insulin will increasingly difficult to precisely define plans and delays in diagnosing other
be required over time. Mutations or de- in the absence of a definitive set of tests family members (188). The correct diag-
letions in HNF1B are associated with re- for either type of diabetes (173–175, nosis is especially critical for those with
nal cysts and uterine malformations (renal 178–184). In most cases, the presence GCK-MODY mutations, where multiple
cysts and diabetes [RCAD] syndrome). of autoantibodies for type 1 diabetes studies have shown that no complications
Other extremely rare forms of MODY precludes further testing for mono- ensue in the absence of glucose-lowering
have been reported to involve other genic diabetes, but the presence of auto- therapy (189). The risks of microvascular
antibodies in people with monogenic and macrovascular complications with
transcription factor genes, including PDX1
diabetes has been reported (185). Indi-
(IPF1) and NEUROD1. HNFIA- and HNF4A-MODY are similar
viduals in whom monogenic diabetes is
to those observed in people with type 1
suspected should be referred to a spe-
Diagnosis of Monogenic Diabetes and type 2 diabetes (190,191). Genetic
cialist for further evaluation if available,
A diagnosis of one of the three most counseling is recommended to ensure
and consultation can be obtained from
common forms of MODY, including HFN1A- that affected individuals understand the
several centers. Readily available com-
MODY, GCK-MODY, and HNF4A-MODY, patterns of inheritance and the impor-
mercial genetic testing following the
allows for more cost-effective therapy criteria listed below now enables a tance of a correct diagnosis and address-
(no therapy for GCK-MODY; sulfonylureas cost-effective (186), often cost-saving, ge- ing comprehensive cardiovascular risk.
as first-line therapy for HNF1A-MODY netic diagnosis that is increasingly sup- The diagnosis of monogenic diabetes
and HNF4A-MODY). Additionally, diag- ported by health insurance. A biomarker should be considered in children and
nosis can lead to identification of other screening pathway, such as the combina- adults diagnosed with diabetes in early
affected family members. Genetic screen- tion of urinary C-peptide/creatinine ratio adulthood with the following findings:
ing is increasingly available and cost- and antibody screening, may aid in deter-
effective (176,178). mining who should get genetic testing for • Diabetes diagnosed within the first
A diagnosis of MODY should be con- MODY (187). It is critical to correctly diag- 6 months of life (with occasional cases
sidered in individuals who have atypical nose one of the monogenic forms of di- presenting later, mostly INS and ABCC8
diabetes and multiple family members abetes because these individuals may mutations) (172,192)
• Diabetes without typical features of GESTATIONAL DIABETES MELLITUS found to have prediabetes
type 1 or type 2 diabetes (negative should receive intensive life-
Recommendations
diabetes-associated autoantibodies, no style interventions and/or met-
2.26a In individuals who are plan-
obesity, lacking other metabolic fea- formin to prevent diabetes. A
ning pregnancy, screen those
tures, especially with strong family
with risk factors B and con-
history of diabetes)
sider testing all individuals of
• Stable, mild fasting hyperglycemia Definition
childbearing potential for un-
(100–150 mg/dL [5.5–8.5 mmol/L]), For many years, GDM was defined as
diagnosed diabetes. E
stable A1C between 5.6% and 7.6% any degree of glucose intolerance that
2.26b Before 15 weeks of gestation,
(between 38 and 60 mmol/mol), es-
test individuals with risk factors was first recognized during pregnancy
pecially if no obesity (86), regardless of the degree of hyper-
B and consider testing all indi-
viduals E for undiagnosed dia- glycemia. This definition facilitated a

PANCREATIC DIABETES OR DIABETES betes at the first prenatal uniform strategy for detection and clas-
IN THE CONTEXT OF DISEASE OF visit using standard diagnos- sification of GDM, but this definition
THE EXOCRINE PANCREAS tic criteria if not screened has serious limitations (203). First, the
Pancreatic diabetes includes both struc- preconception. best available evidence reveals that many
tural and functional loss of glucose- 2.26c Individuals of childbearing cases of GDM represent preexisting
normalizing insulin secretion in the con- potential identified as having hyperglycemia that is detected by rou-
text of exocrine pancreatic dysfunction diabetes should be treated tine screening in pregnancy, as routine
and is commonly misdiagnosed as type 2 as such. A screening is not widely performed in
diabetes. Hyperglycemia due to general 2.26d Before 15 weeks of gestation, nonpregnant individuals of reproduc-
pancreatic dysfunction has been called screen for abnormal glucose tive age. It is the severity of hypergly-
“type 3c diabetes,” and, more recently, metabolism to identify individu- cemia that is clinically important with
diabetes in the context of disease of als who are at higher risk of regard to both short- and long-term
the exocrine 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 and
set of etiologies includes pancreatitis to need insulin, and are at diabetes has led to more type 2 diabe-
(acute and chronic), trauma or pancrea- high risk of a later gestational tes in people of reproductive age, with
tectomy, neoplasia, cystic fibrosis (ad- diabetes mellitus diagnosis. B an increase in the number of pregnant
dressed elsewhere in this chapter), Treatment may provide some individuals with undiagnosed type 2 dia-
hemochromatosis, fibrocalculous pan- benefit. E betes in early pregnancy (204–206). Ide-
creatopathy, rare genetic disorders (193), 2.26e Screen for early abnormal glu- ally, undiagnosed diabetes should be
and idiopathic forms (1); as such, pancre- cose metabolism using fasting identified preconception in individuals
atic diabetes is the preferred umbrella glucose of 110–125 mg/dL with risk factors or in high-risk popula-
terminology. (6.1 mmol/L) or A1C 5.9–6.4% tions (207–212), as the preconception
Pancreatitis, even a single bout, can (41–47 mmol/mol). B care of people with preexisting diabetes
lead to postpancreatitis diabetes melli- 2.27 Screen for gestational diabe- results in lower A1C and reduced risk of
tus (PPDM). Both acute and chronic pan- tes mellitus at 24–28 weeks birth defects, preterm delivery, perinatal
creatitis can lead to PPDM, and the risk of gestation in pregnant individ- mortality, small-for-gestational-age birth
is highest with recurrent bouts. A distin- uals not previously found to weight, and neonatal intensive care unit
guishing feature is concurrent pancreatic have diabetes or high-risk ab- admission (213). If individuals are not
exocrine insufficiency (according to the normal glucose metabolism screened prior to pregnancy, universal
monoclonal fecal elastase 1 test or direct detected earlier in the current early screening at <15 weeks of gestation
function tests), pathological pancreatic pregnancy. A for undiagnosed diabetes may be consid-
imaging (endoscopic ultrasound, MRI, 2.28 Screen individuals with gesta- ered over selective screening (Table
computed tomography), and absence tional diabetes mellitus for pre- 2.3), particularly in populations with
of type 1 diabetes-associated autoim- diabetes or diabetes at 4–12 high prevalence of risk factors and un-
munity (194–199). There is loss of both weeks postpartum, using the diagnosed diabetes in people of child-
insulin and glucagon secretion and often 75-g oral glucose tolerance test bearing age. Strong racial and ethnic
higher-than-expected insulin requirements. and clinically appropriate non- disparities exist in the prevalence of un-
Risk for microvascular complications ap- pregnancy diagnostic criteria. B diagnosed diabetes. Therefore, early
2.29 Individuals with a history of screening provides an initial step to
pears to be similar to that of other
gestational diabetes mellitus identify these health disparities so that
forms of diabetes. In the context of pan-
should have lifelong screening
createctomy, islet autotransplantation can they can begin to be addressed
for the development of diabe-
be done to retain insulin secretion (209–212). Standard diagnostic criteria
tes or prediabetes at least ev-
(200,201). In some cases, autotransplant for identifying undiagnosed diabetes in
ery 3 years. B
can lead to insulin independence. In early pregnancy are the same as those
2.30 Individuals with a history of
others, it may decrease insulin require- used in the nonpregnant population
gestational diabetes mellitus
ments (202). (Table 2.2). Individuals found to have
diabetes by the standard diagnostic crite- gestation or later. See Recommendation GDM diagnosis (Table 2.7) can be ac-
ria used outside of pregnancy should be 2.3 above. complished with either of two strategies:
classified as having diabetes complicat- GDM is often indicative of underlying
ing pregnancy (most often type 2 diabe- b-cell dysfunction (225), which confers 1. The “one-step” 75-g OGTT derived
tes, rarely type 1 diabetes or monogenic marked increased risk for later develop- from the IADPSG criteria, or
diabetes) and managed accordingly. ment of diabetes, generally but not al- 2. The older “two-step” approach with
Early abnormal glucose metabolism, ways type 2 diabetes, in the mother after a 50-g (nonfasting) screen followed
defined as fasting glucose threshold of delivery (226,227). As effective prevention by a 100-g OGTT for those who
110 mg/dL (6.1 mmol/L) or an A1C of interventions are available (228,229), screen positive based on the work
5.9% (39 mmol/mol), may identify in- individuals diagnosed with GDM should of Carpenter-Coustan’s interpretation
dividuals who are at higher risk of ad- receive lifelong screening for prediabetes of the older O’Sullivan and Mahan
verse pregnancy and neonatal outcomes to allow interventions to reduce diabetes (232) criteria.

(preeclampsia, macrosomia, shoulder dys- risk and for type 2 diabetes to allow
tocia, perinatal death), are more likely to treatment at the earliest possible time Different diagnostic criteria will identify dif-
need insulin treatment, and are at high (230). ferent degrees of maternal hyperglycemia
risk of a later GDM diagnosis (214–220). and maternal/fetal risk, leading some ex-
An A1C threshold of 5.7% has not been Diagnosis perts to debate, and disagree on, opti-
shown to be associated with adverse peri- GDM carries risks for the mother, fetus, mal strategies for the diagnosis of GDM.
natal outcomes (221,222). and neonate. The Hyperglycemia and
If early screening is negative, individ- Adverse Pregnancy Outcome (HAPO) One-Step Strategy
uals should be rescreened for GDM be- study (231), a large-scale multinational The IADPSG defined diagnostic cut points
tween 24 and 28 weeks of gestation cohort study completed by more than for GDM as the average fasting, 1-h, and
(see Section 15, “Management of 23,000 pregnant individuals, demon- 2-h PG values during a 75-g OGTT in in-
Diabetes in Pregnancy”). The Interna- strated that risk of adverse maternal, fe- dividuals at 24–28 weeks of gestation
tional Association of the Diabetes and tal, and neonatal outcomes continuously who participated in the HAPO study at
Pregnancy Study Groups (IADPSG) GDM increased as a function of maternal gly- which odds for adverse outcomes
diagnostic criteria for the 75-g OGTT, as cemia at 24–28 weeks of gestation, reached 1.75 times the estimated odds
well as the GDM screening and diagnos- even within ranges previously consid- of these outcomes at the mean fasting,
tic criteria used in the two-step ap- ered normal for pregnancy. For most 1-h, and 2-h PG levels of the study pop-
proach, were not derived from data in complications, there was no threshold ulation. This one-step strategy was
the first half of pregnancy and should for risk. These results have led to careful anticipated to significantly increase the inci-
not be used for early screening (223). To reconsideration of the diagnostic criteria dence of GDM (from 5–6% to 15–20%),
date, most randomized controlled trials for GDM. primarily because only one abnormal value,
of treatment of early abnormal glucose
metabolism have been underpowered
for outcomes. Therefore, the benefits of Table 2.7—Screening for and diagnosis of GDM
treatment for early abnormal glucose One-step strategy
Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and
metabolism remain uncertain. Nutrition
2 h, at 24–28 weeks of gestation in individuals not previously diagnosed with diabetes.
counseling and periodic “block” testing The OGTT should be performed in the morning after an overnight fast of at least 8 h.
of glucose levels weekly to identify indi- The diagnosis of GDM is made when any of the following plasma glucose values are met or
viduals with high glucose levels are sug- exceeded:
gested. Testing frequency may proceed Fasting: 92 mg/dL (5.1 mmol/L)
to daily, and treatment may be intensi- 1 h: 180 mg/dL (10.0 mmol/L)
2 h: 153 mg/dL (8.5 mmol/L)
fied, if the fasting glucose is predomi-
nantly >110 mg/dL prior to 18 weeks of Two-step strategy
gestation. Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at
24–28 weeks of gestation in individuals not previously diagnosed with diabetes.
Both the fasting glucose and A1C are
If the plasma glucose level measured 1 h after the load is $130, 135, or 140 mg/dL
low-cost tests. An advantage of the A1C (7.2, 7.5, or 7.8 mmol/L, respectively), proceed to a 100-g OGTT.
is its convenience, as it can be added to Step 2: The 100-g OGTT should be performed when the patient is fasting.
the prenatal laboratories and does not The diagnosis of GDM is made when at least two* of the following four plasma glucose levels
require an early-morning fasting ap- (measured fasting and at 1, 2, and 3 h during OGTT) are met or exceeded (Carpenter-Coustan
pointment. Disadvantages include inac- criteria [251]):
Fasting: 95 mg/dL (5.3 mmol/L)
curacies in the presence of increased
1 h: 180 mg/dL (10.0 mmol/L)
red blood cell turnover and hemoglo- 2 h: 155 mg/dL (8.6 mmol/L)
binopathies (usually reads lower) and 3 h: 140 mg/dL (7.8 mmol/L)
higher values with anemia and reduced
GDM, gestational diabetes mellitus; GLT, glucose load test; OGTT, oral glucose tolerance
red blood cell turnover (224). A1C is test. *American College of Obstetricians and Gynecologists notes that one elevated value
not reliable to screen for GDM or for can be used for diagnosis (247).
preexisting diabetes at 15 weeks of
not two, became sufficient to make the one-step method using IADPSG criteria ver- Two-Step Strategy
diagnosis (233). Many regional studies sus the two-step method using a 1-h 50-g In 2013, the NIH convened a consensus
have investigated the impact of adopting glucose loading test (GLT) and, if posi- development conference to consider
the IADPSG criteria on prevalence and tive, a 3-h OGTT by Carpenter-Coustan diagnostic criteria for diagnosing GDM
have seen a roughly one- to threefold in- criteria identified twice as many individu- (246). The 15-member panel had repre-
crease (234). The anticipated increase als with GDM using the one-step method sentatives from obstetrics and gynecol-
in the incidence of GDM could have a compared with the two-step method. ogy, maternal-fetal medicine, pediatrics,
substantial impact on costs and medical Despite treating more individuals for diabetes research, biostatistics, and other
infrastructure needs and has the po- related fields. The panel recommended a
GDM using the one-step method, there
tential to “medicalize” pregnancies pre- was no difference in pregnancy and peri-
two-step approach to screening that used
viously categorized as normal. A recent a 1-h 50-g GLT followed by a 3-h 100-g
natal complications (239). However, con-
follow-up study of individuals participating OGTT for those who screened positive.
cerns have been raised about sample
The American College of Obstetricians

in a blinded study of pregnancy OGTTs
size estimates and unanticipated sub-
found that 11 years after their pregnan- and Gynecologists (ACOG) recommends
optimal engagement with the protocol any of the commonly used thresholds
cies, individuals who would have been
with regard to screening and treatment. of 130, 135, or 140 mg/dL for the 1-h
diagnosed with GDM by the one-step
For example, in the two-step group, 165 50-g GLT (247). Updated from 2014, a
approach, as compared with those
participants who did not get counted as 2021 U.S. Preventive Services Task Force
without, were at 3.4-fold higher risk of
developing prediabetes and type 2 di- having GDM were treated for isolated el- systematic review continues to conclude
abetes and had children with a higher evated fasting glucose >95 mg/dL (240). that one-step versus two-step screening
risk of obesity and increased body fat, The high prevalence of prediabetes in is associated with increased likelihood of
suggesting that the larger group of indi- people of childbearing age may sup- GDM (11.5% vs. 4.9%) but without im-
viduals identified by the one-step ap- port the more inclusive IADPSG criteria. proved health outcomes. It reports that
proach would benefit from the increased NHANES data demonstrate a 21.5% preva- the oral glucose challenge test using 140
screening for diabetes and prediabetes lence of prediabetes in people of reproduc- or 135 mg/dL thresholds had sensitivities
that would accompany a history of tive age 20–44 years, which is comparable of 82% and 93% and specificities of 82%
GDM (235,236). The ADA recommends to or higher than the prevalence of GDM di- and 79%, respectively, against Carpenter-
the IADPSG diagnostic criteria with the agnosed by the one-step method (241). Coustan criteria. Fasting plasma glucose
intent of optimizing gestational outcomes The one-step method identifies the cutoffs of 85 mg/dL or 90 mg/dL had
because these criteria are the only ones long-term risks of maternal prediabetes sensitivities of 88% and 81% and specif-
based on pregnancy outcomes rather and diabetes and offspring abnormal glu- icities of 73% and 82%, respectively,
than end points such as prediction of cose metabolism and adiposity. Post hoc against Carpenter-Coustan criteria (248).
subsequent maternal diabetes. GDM in individuals diagnosed by the one- The use of A1C at 24–28 weeks of gesta-
The expected benefits of using IADPSG step method in the HAPO cohort was as- tion as a screening test for GDM does
criteria to the offspring are inferred from sociated with higher prevalence of IGT; not function as well as the GLT (249).
intervention trials that focused on individ- higher 30-min, 1-h, and 2-h glucoses dur- Key factors cited by the NIH panel in
uals with lower levels of hyperglycemia ing the OGTT; and reduced insulin sensi- their decision-making process were the
than identified using older GDM diag- tivity and oral disposition index in their lack of clinical trial data demonstrating
nostic criteria. Those trials found mod- offspring at 10–14 years of age compared the benefits of the one-step strategy
est benefits including reduced rates of with offspring of mothers without GDM. and the potential negative consequences
large-for-gestational-age births and pre- of identifying a large group of individu-
Associations of mother’s fasting, 1-h, and
eclampsia (237,238). It is important to als with GDM, including medicalization
2-h values on the 75-g OGTT were contin-
note that 80–90% of participants being of pregnancy with increased health care
uous with a comprehensive panel of off-
treated for mild GDM in these two ran- utilization and costs. Moreover, screen-
spring metabolic outcomes (236,242). In
domized controlled trials could be ing with a 50-g GLT does not require
addition, HAPO Follow-up Study (HAPO
managed with lifestyle therapy alone. fasting and therefore is easier to accom-
FUS) data demonstrate that neonatal adi- plish for many individuals. Treatment
The OGTT glucose cutoffs in these two
trials overlapped the thresholds recom- posity and fetal hyperinsulinemia (cord of higher-threshold maternal hyper-
mended by the IADPSG, and in one trial C-peptide), both higher across the contin- glycemia, as identified by the two-step
(238), the 2-h PG threshold (140 mg/dL uum of maternal hyperglycemia, are me- approach, reduces rates of neonatal mac-
[7.8 mmol/L]) was lower than the diators of childhood body fat (243). rosomia, large-for-gestational-age births
cutoff recommended by the IADPSG Data are lacking on how the treatment (250), and shoulder dystocia without
(153 mg/dL [8.5 mmol/L]). of mother’s hyperglycemia in pregnancy increasing small-for-gestational-age births.
No randomized controlled trials of affects her offspring’s risk for obesity, dia- ACOG currently supports the two-step ap-
treating versus not treating GDM diag- betes, and other metabolic disorders. Ad- proach but notes that one elevated value,
nosed by the IADPSG criteria but not ditional well-designed clinical studies are as opposed to two, may be used for the
the Carpenter-Coustan criteria have been needed to determine the optimal in- diagnosis of GDM (247). If this approach
published to date. However, a recent tensity of monitoring and treatment of is implemented, the incidence of GDM
randomized trial of testing for GDM individuals with GDM diagnosed by the by the two-step strategy will likely
at 24–28 weeks of gestation by the one-step strategy (244,245). increase markedly. ACOG recommends
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Diabetes Care Volume 46, Supplement 1, January 2023 S19

2. Classification and Diagnosis of Nuha A. ElSayed, Grazia Aleppo,

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2. CLASSIFICATION AND DIAGNOSIS OF DIABETES

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

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Table 2.1—Staging of type 1 diabetes (12,16)

Complications Trial (DCCT) reference as-

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Hence, it is reasonable to consider an

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Connected for Life

Are you at risk for type 2 diabetes?

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Adapted from Bang et al., Ann Intern Med

Learn more at diabetes.org/risktest | 1-800-DIABETES (800-342-2383)

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

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Table 2.6—Most common causes of monogenic diabetes (171)

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