Maturity-Onset Diabetes of the Young:​

Rapid Evidence Review

Ravi Kant, MD;​Amanda Davis, MD;​and Vipin Verma, MD
Medical University of South Carolina, Charleston, South Carolina

Maturity-onset diabetes of the young (MODY) is a non–insulin-dependent form of diabetes mellitus that is usually diagnosed
in young adulthood. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14)
based on the causative genetic mutation. Subtypes 1 to 3 account for 95% of cases. MODY is often misdiagnosed as type 1
or 2 diabetes and should be suspected in nonobese patients who have diabetes that was diagnosed at a young age (younger
than 30 years) and a strong family history of diabetes. Unlike those with type 1 diabetes, patients with MODY have preserved
pancreatic beta-cell function three to five years after diagnosis, as evidenced by detectable serum C-peptide levels with a
serum glucose level greater than 144 mg per dL and no laboratory evidence of pancreatic beta-cell autoimmunity. Patients
with MODY1 and MODY3 have progressive hyperglycemia and vascular complication rates similar to patients with types 1
and 2 diabetes. Lifestyle modification including a low-carbohydrate diet should be the first-line treatment for MODY1 and
MODY3. Sulfonylureas are the preferred pharmacologic therapy based on pathophysiologic reasoning, although clinical
trials are lacking. Patients with MODY2 have mild stable fasting hyperglycemia with low risk of diabetes-related compli-
cations and generally do not require treatment, except in pregnancy. Pregnant patients with MODY may require insulin
therapy and additional fetal monitoring for macrosomia. (Am Fam Physician. 2022;​105(2):​162-167. Copyright © 2022 Amer-
ican Academy of Family Physicians.)

Maturity-onset diabetes of the young •  It is most often an autosomal dominant dis-

(MODY) is an underrecognized type of diabetes ease, with 50% of offspring affected. In the most
mellitus that is usually diagnosed in young adult- common subtype (MODY3), more than 95% of
hood. Advances in genetic testing have led to the people with the mutation will develop diabetes,
discovery of more subtypes of the disease. This most by 25 years of age.2
article provides a summary of the most common • At least 14 genes have been found to cause
subtypes of MODY to help primary care clini- MODY. The glucokinase (GCK), hepatocyte
cians distinguish the condition from types 1 and nuclear factor 1 alpha (HNF1A), and HNF4A
2 diabetes. genes are implicated in approximately 95% of
cases.3 This article focuses on subtypes 1 to 3,
Epidemiology and Genetics which are caused by these mutations (Table 13-8).
•  MODY accounts for approximately 1% to 5% of
diabetes cases.1 Diagnosis
•  Up to 80% of MODY cases are misdiagnosed as
type 1 or 2 diabetes.9
CME This clinical content conforms to AAFP criteria for
• MODY should be considered in nonobese
CME. See CME Quiz on page 124.
patients who have diabetes that was diagnosed at
Author disclosure:​ Dr. Kant does not have a formal rela-
tionship with any commercial company to disclose, but a young age (younger than 30 years), preserved
a public database revealed food and beverage listings for pancreatic beta-cell function, lack of pancreatic
several drugs related to the topic of this manuscript. None beta-cell autoimmunity, and a strong family his-
of these involved cash payments and are not considered a tory of diabetes.1
violation of AFP’s conflict-of-interest policy. Drs. Davis and •  Accurate diagnosis of MODY guides treatment.
Verma have no relevant financial affiliations.
Based on the pathophysiology of the disease, sul-
Patient information:​ A handout on this topic, written by the
fonylureas are thought to be the most effective
authors of this article, is available at https://​w ww.aafp.org/
afp/2022/0200/p162-s1.html. pharmacologic therapy for the most common
subtypes.3,4,10 However, there is no evidence from

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 MATURITY-ONSET DIABETES OF THE YOUNG

randomized trials showing that early diagnosis and appro- glutamic acid decarboxylase 65, insulin, tyrosine phospha-
priate therapy improve patient-oriented outcomes. tase IA-2 and IA-2beta, or zinc transporter 8 is diagnostic
•  Commercially available genetic testing can confirm the for type 1 diabetes.11
diagnosis of MODY. Targeted genetic testing is appropriate •  Adding the zinc transporter 8 autoantibody to commer-
because of high cost (Figure 1). Referral to an endocrinolo- cially available beta-cell autoantibody test combinations
gist and/or a clinical genetics consultant should be consid- has increased autoimmunity detection rates for new-onset
ered when clinical suspicion for MODY is high. type 1 diabetes to 96% to 98%.12,13
• Clinicians may consider the cost-saving approach of
TYPE 1 DIABETES VS. MODY checking glutamic acid decarboxylase 65 and tyrosine
•  The pathogenesis of MODY does not involve pancreatic phosphatase IA-2 at the initial assessment and testing for
beta-cell autoimmunity. other autoantibodies only if both are negative.14
• Type 1 diabetes is caused by autoimmune beta-cell •  Repeat autoantibody testing after a few years in patients
destruction, usually leading to absolute insulin deficiency. with autoantibody-negative type 1 diabetes has been shown
A laboratory test confirming autoantibodies to islet cells, to improve detection of beta-cell autoimmunity.15
•  Patients with autoantibody-negative
type 1 diabetes are more likely to have
TABLE 1 clinical characteristics associated with
other diabetes subtypes (e.g., older
Clinical Characteristics of the Common Subtypes age, higher body mass index, family
of Maturity-Onset Diabetes of the Young history of diabetes). A subset of these
Subtype Gene mutation Prominent features patients may have monogenic or type 2
diabetes.16
1 HNF4A Progressive symptomatic diabetes mellitus with •  Levels of C-peptide, a product of the
significant glucose intolerance
insulin prohormone, is used to assess
Prone to diabetes-related vascular complications
pancreatic beta-cell function and insu-
Associated with fetal macrosomia and neonatal lin secretion. In healthy people, fasting
hypoglycemia
C-peptide levels range from 0.9 to 1.8 ng
Treatment:​sensitive to sulfonylureas;​meglitinide and
per mL (0.3 to 0.6 nmol per L) and
glucagon-like peptide 1 agonist may be considered
increase to 3 to 9 ng per mL (1 to 3 nmol
2 GCK Asymptomatic with stable mild fasting hyperglyce- per L) after meals.17 A fasting C-peptide
mia and A1C levels ranging from 5.7% to 7.5% level of less than 0.60 ng per mL (0.20
Low risk of diabetes-related vascular complications nmol per L) represents insulin defi-
Pregnancy:​use of insulin determined by mutation ciency and is associated with type 1
status of mother and fetus and/or evidence of accel- diabetes.17
erated fetal growth on ultrasonography
•  A detectable serum C-peptide level
Treatment:​not required except in pregnancy
with a serum glucose level greater than
3 HNF1A Most common subtype (30% to 50%) 144 mg per dL (8 mmol per L) three
Progressive symptomatic diabetes with significant to five years after diagnosis is unusual
glucose intolerance in a patient with type 1 diabetes and
Prone to diabetes-related vascular complications favors the diagnosis of MODY.4
Postprandial glycosuria develops before the onset of
diabetes TYPE 2 DIABETES VS. MODY
HNF1A mutation in the fetus does not affect birth • The pathophysiology of MODY
weight involves impaired insulin secretion,
Treatment:​sensitive to sulfonylureas;​megli- whereas type 2 diabetes is a heteroge-
tinide and glucagon-like peptide 1 agonist may be neous disease characterized by insu-
considered lin resistance and a progressive loss of
GCK = glucokinase;​HNF1A = hepatocyte nuclear factor 1 alpha;​HNF4A = hepatocyte nuclear beta-cell function.11
factor 4 alpha. • Clues that a patient presumed to
Information from references 3-8. have type 2 diabetes may actually have
MODY include a lack of response to

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 MATURITY-ONSET DIABETES OF THE YOUNG

metformin, a larger drop in serum glucose level

with sulfonylureas, and greater sensitivity to FIGURE 1
insulin.10
Patient with diabetes mellitus
• Although definitive guidelines are lacking, at a young age (< 30 years)
testing for MODY can be considered in a patient
younger than 30 years who has diabetes and:​
∘  Is not obese
Obese?

∘ Lacks signs of insulin resistance such as

acanthosis nigricans, skin tags, androgenic No Yes
alopecia, or markers of metabolic syndrome
∘ Lacks pancreatic beta-cell autoantibodies
  Signs of insulin resistance

∘ Has a fasting C-peptide level greater than

(acanthosis nigricans, skin
tags [acrochordons], andro-
0.60 ng per mL genic alopecia, markers of
∘ Has a family history of diabetes in young,
  metabolic syndrome)?
nonobese family members10
No Yes
FEATURES OF MODY1 AND MODY3
•  MODY1 and MODY3 are caused by mutations Pancreatic beta-cell Likely type 2
in transcription factors (HNF4A and HNF1A, autoimmunity testing* diabetes
respectively). This results in impaired insulin
secretion from defective beta-cell signaling in
response to glucose.5 These patients have glucose
Positive findings Negative findings
intolerance and may have normal fasting serum
glucose levels in the early stages of the disease.
• Patients with MODY3 usually develop post- Type 1 diabetes Fasting C-peptide
prandial glycosuria before the onset of diabetes.6 level < 0.60 ng per mL
(0.20 nmol per L)?
• Like patients with types 1 and 2 diabetes,
patients with MODY1 and MODY3 are thought
to develop associated micro- and macrovascular No Yes
complications caused by suboptimal glycemic
Family history of diabetes?† Type 1 diabetes
control.3

FEATURES OF MODY2 No Yes

• MODY2 is caused by mutations in the GCK
gene, resulting in a higher glucose set point for Preserved beta-cell function Suspect MODY
(detectable C-peptide level with
insulin secretion.5 In contrast to those with other a serum glucose level > 144 mg
subtypes, patients with MODY2 regulate insulin per dL [8 mmol per L]) three to
secretion adequately, but higher serum glucose five years after the initial diabe-
tes diagnosis
levels are needed to induce insulin secretion.4,11
•  Patients with MODY2 are typically asymptom-
atic and may have stable mild fasting hypergly- Suspect MODY if Consider genetic testing
cemia (100 to 145 mg per dL [5.55 to 8.05 mmol patient is not obese Consider referral to an
per L]) for years, with A1C levels ranging from endocrinologist and/or a
clinical genetics consultant
5.7% to 7.5%.18,19
•  Unlike in MODY1 and MODY3, patients with MODY = maturity-onset diabetes of the young.
*—Autoantibodies to islet cell, glutamic acid decarboxylase 65, insulin, tyrosine
MODY2 usually do not have significant post- phosphatase IA-2 and IA-2beta, or zinc transporter 8.
prandial hyperglycemia.18 †—Suspicion of MODY is higher in patients with a family history of diabetes in
•  MODY2 is not associated with a higher inci- young, nonobese individuals.
dence of vascular complications.3,20
• Patients with MODY2 are at risk of devel- Algorithm for targeted genetic testing for MODY.
oping concurrent type 2 diabetes later in life,

164  American Family Physician www.aafp.org/afp Volume 105, Number 2 ◆ February 2022
 MATURITY-ONSET DIABETES OF THE YOUNG

with prevalence similar to that in the general

population.21 SORT:​KEY RECOMMENDATIONS FOR PRACTICE

Treatment Evidence
MODY1 AND MODY3 Clinical recommendation rating Comments
•  There are limited data on what A1C goals are MODY should be considered in non- C Consensus,
associated with the best outcomes for patients obese patients who have diabetes expert opinion
with MODY1 and MODY3. Because these mellitus that was diagnosed at a young
patients are thought to be susceptible to micro- age (younger than 30 years), preserved
pancreatic beta-cell function, lack of
and macrovascular complications, it is reason- pancreatic beta-cell autoimmunity, and
able to individualize A1C goals based on patient a strong family history of diabetes.1
characteristics (e.g., comorbidities, life expec-
Sulfonylureas are the preferred phar- C Consensus,
tancy, risks associated with hypoglycemia), as
macologic therapy for hyperglycemia in expert opinion
recommended by American Diabetes Associ- MODY1 and MODY3.3,4
ation guidelines for patients with types 1 and 2
diabetes.22 Pharmacologic treatment of hyper- C Consensus,
glycemia is not required for MODY2 expert opinion
•  Lifestyle modification including a low-carbo- because the risk of vascular com-
hydrate diet should be first-line therapy because plications is low and patients are
MODY1 and MODY3 are predominantly associ- asymptomatic. 3,4
ated with glucose intolerance.
MODY = maturity-onset diabetes of the young.
• If glycemic control worsens, sulfonylureas
A = consistent, good-quality patient-oriented evidence;​B = inconsistent or limit-
are the recommended pharmacologic ther- ed-quality patient-oriented evidence;​C = consensus, disease-oriented evidence,
apy because these drugs bypass the defective usual practice, expert opinion, or case series. For information about the SORT
glucose-mediated insulin secretion associated evidence rating system, go to https://​w ww.aafp.org/afpsort.

with HNF1A and HNF4A mutations. 3,4

• Patients with MODY3 are four times more

responsive to sulfonylureas than patients with type 2 dia- MODY2
betes and are therefore at higher risk of hypoglycemia when •  Pharmacologic treatment of hyperglycemia is not required
using these drugs.10 for MODY2, except in pregnancy, because the risk of vascu-
•  Sulfonylureas should be started at one-fourth of the typi- lar complications is low and patients are asymptomatic.3,4
cal starting dose to avoid hypoglycemia, then slowly titrated • Treatment with oral hypoglycemic agents and insulin
to achieve optimal glycemic control.3,4 may not be effective in decreasing A1C.19
•  Although glucose-induced insulin secretion may decline
over time, most patients remain responsive to sulfonylureas Special Considerations for Pregnant Patients
for decades.23 •  MODY may be first discovered when screening for ges-
•  Meglitinides may be considered instead of sulfonylureas tational diabetes during pregnancy. The prevalence of
to treat postprandial hyperglycemia if sulfonylurea use is MODY in patients with gestational diabetes is estimated
complicated by frequent hypoglycemic events.7 at 1% to 6%.26,27
•  A small double-blind, randomized, crossover trial com- • There are no guidelines to assist in determining which
pared liraglutide (Victoza), a glucagon-like peptide 1 ago- patients with gestational diabetes should be tested for MODY.
nist, with glimepiride (Amaryl), a sulfonylurea. Patients •  A diagnosis of MODY may be considered in pregnant
taking liraglutide had similar glycemic control as those tak- patients younger than 25 years with a normal prepreg-
ing glimepiride but much lower risk of hypoglycemia. Lira- nancy body mass index;​a history of previous gestational
glutide may be considered in patients who are obese or with diabetes;​and a family history of diabetes, gestational dia-
high rates of hypoglycemia.8 betes, or fasting hyperglycemia greater than 99 mg per dL
•  Limited data suggest that dipeptidyl-peptidase 4 inhib- (5.5 mmol per L).28,29
itors and sodium-glucose cotransporter 2 inhibitors may •  There is a lack of high-quality evidence to guide MODY
also be effective, but additional studies are needed.24,25 treatment in pregnancy.
•  Because MODY is associated with impaired insulin secre- • Glyburide is the only sulfonylurea recommended for
tion and minimal or no defects in insulin action, metformin use during pregnancy because it has been studied most
is not a preferred pharmacologic agent. extensively.30

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 MATURITY-ONSET DIABETES OF THE YOUNG

•  However, glyburide use in patients with gestational dia- 3100, Anderson, SC 29621 (email:​kant.ravi.md@​gmail.com).
betes is associated with more than a twofold increased risk Reprints are not available from the authors.
of macrosomia and neonatal hypoglycemia compared with
insulin use. Insulin is therefore the preferred agent in preg-
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