In 1974, Tattersall and Fajans coined the term mature onset diabetes of the young (MODY).

[1] MODY
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. is the most common form of monogenic diabetes and exhibits autosomal dominant inheritance. Patients
with this form of diabetes can sometimes be mistaken for having either type 1 diabetes (DM1) or type 2
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. diabetes mellitus (DM2). It usually manifests before 25 years of age. This form of diabetes is non-ketotic,
and patients do not have pancreatic autoantibodies. It is due to beta-cell dysfunction. Recognizing and
understanding this syndrome is important in knowing whom to test. It also has implications for patients and
Maturity Onset Diabetes in the Young families given the autosomal dominant inheritance, but also because certain genetic subtypes respond
differently to treatment, have different complication rates and some have other associated extra-pancreatic
abnormalities involving kidneys, liver, intestines, etc.[2] There are 6 widely recognized subtypes, but with
ongoing advances in genetic testing more are being recognized. 
Authors

Laura S. Hoffman1; Tamaryn J. Fox2; Catherine Anastasopoulou3; Ishwarlal Jialal4. Etiology

MODY is caused by defects in pancreatic islet cell development that impairs insulin secretion. It is usually
Affiliations inherited in an autosomal dominant fashion and patients generally have heterozygous mutations. Penetrance
and expressivity can vary immensely, even among family members and the phenotype is largely dependent
1
 California Northstate University on the gene involved.[3] MODY genes affect insulin secretion via impairment of insulin sensing, glucose
2
 Albert Einstein Medical Center metabolism in beta cells, or activation of adenosine triphosphate (ATP)-dependent potassium channels.[4]
3
 Einstein Medical Center
4
 VA MEDICAL CENTER, MATHER , CA
Epidemiology

Last Update: July 24, 2022.
Continuing Education Activity
The most commonly recognized forms of diabetes mellitus include type 1 diabetes, an autoimmune
disorder, and type 2 diabetes, a polygenic disorder influenced by both genetics and environment. Now, it is
understood that more than just 2 forms of diabetes exist, although, hybrid forms occur much less
frequently. Maturity-onset diabetes of the young (MODY) is a type of monogenic diabetes first described
as a mild and asymptomatic form of diabetes that was observed in non-obese children, adolescents, and
young adults. Improvement in blood glucose levels has been observed with sulfonylurea treatment. With
the expansion of genetic technology, many genes linked to MODY have been sequenced and described.
This activity reviews the presentation, evaluation, and management of MODY and stresses the role of an
interprofessional team approach in the care of affected patients.
Objectives:
MODY accounts for less than 5.0% of all patients with diabetes mellitus (DM). It is now thought that
6.5%[5][6] of children with antibody-negative diabetes have a form of MODY. The onset of MODY is
typically between the ages of 10 to 40 years old. Patients with MODY share genotypic features of both type
1 and type 2 diabetes and are often misdiagnosed as having either type 1 diabetes or type 2 diabetes.
Therefore, as the frequency of MODY diagnoses increases, the prevalence may prove to be higher. While
MODY has been described predominantly in Caucasian populations, it has also been reported in other races
such as Asian Indians in South Africa by Jialal et al.[7]
Pathophysiology
Whereas DM1 and DM2 are polygenic, MODY is caused by a single gene mutation that leads to a defect in
beta cell insulin secretion in response to glucose stimulation. Most genetic versions of MODY have
autosomal dominant transmission although, less frequently, autosomal recessive versions may also exist
and could account for neonatal diabetes. Initially, different types of MODY were described numerically
(MODY 1-6). However, they are now classified by their genetic defect.

 Identify the pathophysiology of mature onset diabetes of the young.
 Summarize the history and physical exam findings typically seen in patients with mature onset
diabetes of the young.
 Describe the management considerations and treatment choices for mature onset diabetes of the
young.
 Explain modalities to improve care coordination among interprofessional team members in
order to improve clinical outcomes for patients affected by mature onset diabetes of the young.
Access free multiple choice questions on this topic.
Introduction
There are now at least 14 different known MODY mutations. They include GCK, HNF1A, HNF4A,
HNF1B, INS,  NEURO1, PDX1, PAX4, ABCC8, KCNJ11, KLF11, CEL, BLK and APPL1. The different
genes vary with respect to age of onset, response to treatment, and the presence of extra-pancreatic
manifestations. The most common gene mutations are the following:
1. Gene mutation in the hepatocyte nuclear factor 1 alpha (HNF1A) accounts for 30% to 60% of
MODY.
2. Gene mutation in the hepatocyte nuclear factor 4 alpha (HNF4A), accounts for 5% to 10% of
MODY cases.
3. Gene mutations in glucokinase (GCK) account for 30% to 60% of the cases of MODY.
4. Gene mutation in hepatocyte nuclear factor 1 beta (HNF1B), accounts for less than 5% of the
cases of MODY.
The difference in the prevalence of the MODY genes varies from country to country which may be, in part,
due to differences in reporting.
HNF1A (MODY 3)
The gene mutation in hepatocyte nuclear factor 1-alpha-HNF1A (MODY 3) acts by inhibiting the key steps
of glucose transport and metabolism as well as mitochondrial metabolism in pancreatic beta
cells. HNF1A is found in the liver, kidney, and intestine as well as pancreatic tissue. There is progressive
beta-cell dysfunction. These patients have a decreased renal threshold for glycosuria. The diagnosis
of HNF1A is typically made between the ages of 21 to 26. The gene defect has high penetrance; 63% of
carriers develop DM by age 25 years old, 79% by 35 years old and 96% by age 35 years old.[8][9]  cases, monitoring of fetal growth during pregnancy and blood glucose levels in neonates can be crucial.
HNF1A is very responsive to sulfonylureas and meglitinides even though beta cells do not respond well to
hyperglycemia with insulin production and release.[10] The mechanism of action involves the binding of
the medication to sulfonylurea receptors on beta-cell membranes. This triggers the influx of calcium, which
leads to the fusion of vesicles containing stored insulin.[11] The use of sulfonylureas can frequently delay
the need for insulin replacement for many years.
GCK (MODY 2)
Glucokinase is an enzyme that enables the pancreatic beta cells and hepatocytes to respond to glucose
levels. In the GCK gene mutation (MODY 2), the glucose threshold for insulin secretion is reset, leading to
a higher fasting glucose level. Oral glucose tolerance testing reveals a mild increase in glucose
concentration. Patients with a GCK mutation typically display mild and nonprogressive hyperglycemia,
which is generally not symptomatic. The HBA1C in these patients is usually less than 8%, and the risk of
microvascular (and possibly macrovascular) complications is low.[12][8]
HNF4A (MODY 1)
The HNF4A mutation (MODY 1) is less common than HNF1A or GCK.  Its presentation is similar
to HNF1A. It should be considered when the patient has features similar to HNF4A, but genetic testing is
negative.  Patients with HNF4A mutation may have decreased HDL-C levels and are therefore more similar
to DM2. Additionally, these patients have a higher birth weight and a higher level of macrosomia. They
may display transient neonatal hypoglycemia.[9] Patients with diabetes and a strong family history of
neonatal hypoglycemia should be suspected for HNF4A. Sulfonylureas work well for the treatment of
hyperglycemia.[13]
Note: HNF1A and HNF4A are both genes that regulate the expression of numerous genes encoding serum
proteins such as clotting factors and apolipoproteins.[14]
HNF1B (MODY 5)
The HNF1B mutation (MODY 5) accounts for less than 5% of MODY. It is associated with a wide
variation in presentations. Half of these patients present with early-onset DM. This mutation can affect
gene regulation in the liver, kidneys, intestines, lungs, or ovaries. Patients can present with abnormalities
such as renal cysts, dysplasia, renal tract malformations, or hypoplastic glomerulocystic kidney
disease. HNF1B MODY is sometimes referred to as RCAD (renal cysts and diabetes syndrome). There can
be a progressive loss of renal function independent of diabetic nephropathy.[15]
 Patients with HNF1B generally are not responsive to oral medications and will require treatment with
insulin. 
PDX1 (MODY 4)
A defect in IPF1 (insulin gene promoter factor 1) causes another form of MODY. PDX1 is a homeobox-
containing transcription factor that affects pancreatic development and insulin gene expression.
NEUROD1 (MODY 6)
NEUROD1 is a mutation in a basic-loop-helix transcription factor that affects pancreatic and neuronal
development. Most patients will require treatment with insulin.[16]
ABCC8 (MODY 12) and KCNJ11 (MODY 13)
The ABCC8 and KCNJ1 mutations have been associated with a spectrum of disorders including neonatal
diabetes.[9] Neonatal diabetes can be permanent or transient, in which case, it often recurs later in life.
Neonatal diabetes has been associated with mutations in the potassium-ATP channel genes or mutations in
the insulin gene.[5] Additionally, these mutations have been linked to neonatal hypoglycemia due to
elevated insulin levels; this is usually transient, but the patient may develop diabetes later in life. In these
The patients who develop diabetes generally respond well to sulfonylureas.
MODY Genes Associated with Syndromes not Involving DM
MODY mutations have also been noted in several other syndromes.
1. Wolfram Syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic
atrophy, and deafness)
2. Thiamine-responsive megaloblastic anemia syndrome
3. Maternity-inherited diabetes with deafness
History and Physical
History should first include a thorough personal medical history. The diabetes diagnosis characteristic of
MODY occurs in adolescence or early adulthood. Therefore details surrounding their diabetes diagnosis
become of utmost importance. Also, birth history can provide some helpful information if known.
Intrauterine growth retardation (IUGR) is seen in those with HNF1B (MODY 5) in addition to some
congenital abnormalities such as renal and urogenital tract anomalies as well as pancreatic hypoplasia.
Those with the HNF4A (MODY 1) subtype may have a history of a birth weight generally more than 800gr
above normal as well as transient neonatal hyperinsulinemic hypoglycemia. GCK (MODY 2) patients may
have had a history of mild fasting hyperglycemia at birth. Finally, some of those with HFN1A (MODY 3)
may have had transient neonatal hyperinsulinemic hypoglycemia.[17] A further personal medical history
should include a full review of systems and enquire about known medical problems involving other organ
systems as some forms of MODY can be associated with extra-beta cell manifestations including renal,
hepatic, genitourinary, exocrine pancreatic or intestinal effects.
Family history is vital and provides some of the most useful information. Patients with MODY have strong
family history of diabetes spanning at least 3 generations. Details surrounding the diabetes diagnosis for
each family member should include the age of onset, their body habitus at diagnosis, and history of insulin
use. Information of prior genetic testing in the family can be very helpful. [17]
Physical examination does not provide any specific information guiding one to the diagnosis of MODY or a
specific subtype. Even though those with MODY are characteristically of normal weight, obesity in these
patients can coexist. [17] The physical examination, in general, should also include the basics as for any
patient with diabetes, as some forms of MODY do develop complications, therefore testing for retinopathy
and neuropathy should always be included in addition to urine microalbumin and a lipid panel.
Evaluation
In 2008, diagnostic criteria were created in the Practice Guidelines for MODY. The criteria include the age
of onset in a family member of 25 years of age, at least two consecutive generations of patients with
diabetes in the family, no beta-cell autoantibodies, persistent endogenous insulin production in addition to
preservation of pancreatic beta-cell function as evidenced by c-peptide levels >200pmol/L in addition to
lack of necessity for insulin therapy even years after diagnosis.[18]
The evaluation of patients should first start at diagnosis by ruling out DM1 by testing for pancreatic
autoantibodies.  [17]
Particularly in GCK MODY, checking hemoglobin A1C (HbA1C) and fasting plasma glucose levels can be
helpful as they typically fall within specific ranges. For fasting plasma glucose, it generally falls between
99-144mg/dL[18] and the typical range for HbA1C is 5.6-7.3% if less than 40 years of age and 5.9-7.6% if
older than that.[19]
High sensitive CRP (hsCRP) is another surrogate test that can help distinguish HFN1A MODY from other
types of diabetes. This value will be lower in HNF1A MODY (MODY 3) usually less than 0.75mg/L when
compared to other forms of diabetes.[20]
Additionally one can assess for residual beta-cell function. Patients with MODY generally have elevated C-
peptide levels when there is hyperglycemia, usually 0.6mg/dL or higher.[21]
 Who Should be Genetically Tested for MODY?
Genetic testing for MODY should be done in cases where there is a high index of suspicion that the patient
does not have DM1 or DM2. A diagnosis of MODY may change the understanding of the course of the
disease and the optimal treatment (or if treatment is needed at all). Genetic counseling may be beneficial to
family members of MODY patients.  of hypoglycemia).[24]
However, given the time and expense of genetic testing, criteria for narrowing down the patients
appropriate for testing have been sought. Indications for genetic testing include:
 Patients with a strong family history of DM presenting in the second to fifth decade of life
 Leanness
 Autoantibody negative
 Features inconsistent with DM1 or DM2 such as:
 In most countries, metformin and insulin are approved for use in the youth. Certain countries have
o Low renal threshold
o A large increase in blood sugar in OGTT
o Lower than expected CRP levels
 Lower than expected HDL-C
 High insulin sensitivity (although as noted above insulin resistance has been observed in a small
number of MODY gene defects)
 Children diagnosed with DM1 who are antibody-negative and exhibit elevated C peptide levels
Molecular genetic testing helps to identify which mutation is involved. The type of testing performed
depends on the clinician's pretest probability of knowing which particular gene is involved. Should a patient
have particular characteristics of a specific subtype such as typical associated extra-pancreatic features,
single-gene testing or serial single-gene testing can be performed. If a patient's phenotype cannot be
differentiated from other subtypes, one may opt to perform a MODY multigene panel which tests for 14
known genes to be associated with MODY. Finally, if the patient has clinically suggestive features but the
mutation cannot be found utilizing conventional testing, one can consider comprehensive genomic testing.
Treatment / Management
The optimal treatment for diabetes associated with MODY varies on the gene mutation. Thus knowing the
genetic subtype is important in understanding the treatment and prognosis in these patients.
In MODY 2 (GCK), patients tend to have elevated fasting blood glucose but do not usually develop
postprandial hyperglycemia as they have sufficient insulin secretion in response to elevated glucose. These
patients generally need lifestyle and dietary modification alone.[22]
For MODY 1 (HNF1A) and MODY 3 (HNF4A) patients can generally be managed with dietary changes
alone in the beginning. These patients do experience postprandial hyperglycemia after carbohydrate-rich
food.[23] Progressively over time, they may get deterioration of their beta cells and may require treatment.
These patients tend to respond well to sulfonylureas. An alternative treatment option is a glucagon-like
peptide 1 agonist (GLP-1RA). A randomized control trial that compared GLP1RA to Glimepiride in the
treatment of MODY 3 patients, it found that these drugs were comparable in lowering blood glucose
(although glimepiride had slightly greater glucose-lowering effect but in conjunction with an increased risk
Patients with MODY 5 (HNF1B) generally do not respond well to sulfonylureas. This may in part be
explained by concurrent pancreatic hypoplasia in addition to a degree of hepatic insulin resistance.
[25] Thus these patients will usually require insulin to control their hyperglycemia. This subset of MODY
patients has been described as having a propensity for microvascular complications. In particular, their
renal function needs to be monitored closely as most of these patients will develop renal dysfunction by age
45 and can progress to end-stage kidney disease.[26]
In general, guidelines do not exist for many of the subtypes due to the paucity of cases and how rare they
are.
Management of MODY in the Youth
approved the use of sulfonylureas in the adolescent population. Otherwise, no other category of oral
antidiabetic agents has been approved in those less than 18 years of age.[27]
Management in Pregnancy [28]
As mentioned above, GCK MODY generally does not require treatment except during pregnancy.
Determining which GCK MODY patients need treatment is determined by the fetal genotype. This is not
genetically determined but assessed by the abdominal circumference of the fetus measured during the
second trimester. Should this value exceed 75%, this infers that the fetus does not carry the GCK mutation
and thus these mothers should be treated with insulin during pregnancy to help prevent macrosomia. If the
fetus has an abdominal circumference less than 75%, this infers the fetus does not carry the gene as they
will have the same glucose setpoint as the mother which is increased, and thus maternal hyperglycemia will
be sensed by the fetus as normal and therefore growth will be normal and maternal treatment with insulin is
not indicated and it can even result in growth restriction.[28]
Differential Diagnosis
  Type 1 Diabetes Mellitus MODY 3 (HNF1A): It carries a high risk of microvascular and macrovascular complications, similar to
DM1 and DM2.[9] The HDL-C is typically elevated, which can help distinguish it from DM2.
Additionally, hsCRP levels are typically lower in HNF1A than in other forms of DM, thereby making it a
 Type 2 Diabetes Mellitus
potential biomarker. This is despite the fact that these patients having high HDL-C and low hsCRP levels,
they are particularly prone to cardiovascular disease. Thus it is imperative to start a statin in these patients
 Chronic pancreatitis by the time they are 40 years old. Pancreatic exocrine dysfunction has also been reported in this genetic
subtype.[32]
 Cystic fibrosis
MODY 4 (PDX1): This rare defect has been associated with pancreatic agenesis, neonatal DM, and
 Diabetic Ketoacidosis (DKA) pancreatic exocrine dysfunction.[33]

MODY 5 (HNF1B): These patients in addition to MODY, develop congenital urogenital anomalies.

 Diabetic Nephropathy [34] The HNF1B mutation has also been associated with genital abnormalities including a bicornate uterus,
Rokitanski syndrome, agenesis of the vas deferens, and hypospadias.[9] Additionally, it has been associated
 Disorders of target tissues with hypomagnesemia due to renal wasting, hyperuricemic nephropathy with gout, and primary
hyperparathyroidism.[9] These patients can also develop pancreatic atrophy, genital tract abnormalities,
 Endocrine disorders abnormal liver enzyme levels, and neuropsychiatric abnormalities including intellectual disability and
autism. Patients with HNFIB can have low birth rates due to decreased insulin secretion in utero.
 Glucocorticoids Interestingly, these patients may demonstrate insulin resistance in some cases and microvascular
complications can also be common.
 Insulin Resistance MODY 6 (NEUROD1): Heterozygotes cause diabetes in children, neurological abnormalities, and learning
disabilities.[16]
 Lead Nephropathy

 Nondiabetic glycosuria Deterrence and Patient Education

 Renal glycosuria
 Secondary hyperglycemia
Prognosis
MODY 2 (GCK) patients generally have a good prognosis as a result of the relatively mild hyperglycemia
and low complication rates.[29]
MODY 3 (HNF1A) patients haver similar complication rates and prognosis to type 1 and type 2 diabetes
mellitus. This is the case with most subtypes of MODY with the exception of MODY 2 which has the best
prognosis.[29]
MODY 5 (HNF1B) patients have a propensity of developing end-stage kidney disease requiring renal
replacement therapy independent of diabetic nephropathy. This is because the affected gene is involved in
the organogenesis of multiple organs including the kidneys.[29]
Complications
Complications are dependent on the genetic subtype of MODY.
MODY 1 (HNF4A): These patients can have vascular complications. In addition, given the fact that
HNF4A is also expressed in the liver, the elevation of serum lipids and metabolic syndrome can occur.[30]
As discussed above, MODY is an autosomal dominant condition and different genetic subtypes behave
differently. Patient education is important in terms of teaching them that it runs in families and thus genetic
counselling becomes vital. Knowing that this condition runs in families can allow for adequate screening
and implementation of treatment, if necessary, early to avoid complications. They must understand the
disease and the need to follow up. Even though certain subtypes may only require dietary intervention, the
disease may progress to the point of necessitating pharmacologic intervention. Certain subtypes have a
higher propensity of developing complications and therefore counseling patients on regular appropriate
screenings and subspecialist follow ups is important. Women with MODY and the GCK mutation need to
be made aware that they may require insulin treatment during pregnancy depending on the fetus genotype,
and they should be monitored closely by a specialist during their pregnancies. 
Enhancing Healthcare Team Outcomes
MODY is caused by defects in pancreatic islet cell development and insulin secretion. It is usually inherited
in an autosomal dominant fashion and the patients generally have heterozygote mutations. Penetrance and
expressivity can vary immensely, even among family members. MODY genes affect insulin secretion via
impairment of insulin sensing, glucose metabolism in beta cells, or activation of adenosine triphosphate
(ATP)-dependent potassium channels. The disorder is best managed by an interprofessional team that
consists of a diabetic nurse, endocrinologist, internist, geneticist, dietitian, ophthalmologist, nephrologist,
occasionally gynecologist (MODY 5) and a cardiologist. These patients are prone to the same
complications as other diabetics except for patients with the GCK mutation and early referral to a specialist
is highly recommended. (Level V)

MODY 2 (GCK): This subtype is rarely associated with diabetes-associated complications such as

microvascular and macrovascular complications.[31]