Image of molecular strand in body indicating monogenic diabetes.
Patient Resources

Monogenic Diabetes

March 10, 2022

MODY and Neonatal Diabetes

Monogenic diabetes is a rare condition resulting from mutations (changes) in a single gene. In contrast, the most common types of diabetes—type 1 and type 2—are caused by multiple genes (and in type 2 diabetes, lifestyle factors such as obesity). Most cases of monogenic diabetes are inherited from a parent who also has the disorder. It accounts for 2-5 % of all diabetes mellitus. 

Monogenic diabetes appears in several forms and most often affects young people, mostly 25 years or younger. In most forms of the disease, the body is less able to make insulin, a hormone that helps the body use glucose (sugar) for energy. Rarely, the problem is severe insulin resistance, a condition in which the body cannot use insulin properly. The specific form of monogenic diabetes may be called also MODY (formerly, maturity onset diabetes of the young) or neonatal diabetes, depending on when it develops. 

Endocrine Connection 

People typically have two copies of most genes, with one gene inherited from each parent. Genes are instrumental for making proteins within cells. If a gene has mutated, the protein may not function properly, affecting the body’s ability to produce or regulate insulin properly. 

The hormone insulin allows the cells in the muscles, fat and liver to absorb glucose that is in the blood. The glucose serves as energy to these cells, or it can be converted into fat when needed. Insulin also affects other metabolic processes, such as the breakdown of fat or protein. 

Some patients with monogenic diabetes are misdiagnosed as having type 1 or 2 diabetes. The genes control the development, function, and regulation of the insulin-producing (islet, or beta) cells of the pancreas. The monogenic diabetes conditions were previously numbered (see below), related to timing of discovery of the genetic problem, but now are referred to by their genetic mutations. 

The most common mutations are related to genes hepatocyte nuclear factor-1-alpha (HNF1A, MODY3) and glucokinase (GCK, MODY2) genes in 50-60% and 15-30% of people with monogenic diabetes, respectively. 

Some genes causing monogenic diabetes can also cause a more severe form of diabetes, presenting as a baby (neonatal diabetes). The genes are categorized based on whether they cause abnormal insulin production and secretion, islet cell destruction, or abnormal pancreas development. 

A correct diagnosis can help people get the right treatment. For example, some children with monogenic diabetes are misdiagnosed with type 1 diabetes and are given insulin. When correctly diagnosed, some of these children can take diabetes pills instead, with even better glucose control. A correct diagnosis may also benefit family members, who might have monogenic diabetes themselves without knowing it. 

Because monogenic diabetes is rare, this diagnosis is often not considered in people with diabetes. However, certain factors (see below) can make doctors suspect that a diagnosis of type 1 or type 2 diabetes is not correct. A combination of tests and clinical factors help rule out type 1 or type 2 diabetes and identify MODY or neonatal diabetes. 

Blood Tests: Blood glucose and insulin levels help with diagnosis. Doctors might also check for the presence of certain autoimmune antibodies (substances made by the body that work against one’s own healthy tissues), which suggests type 1 diabetes. 

Clinical Factors: Doctors consider factors that may suggest monogenic diabetes: 

  • Being diagnosed in the first six months of life 
  • Having other conditions caused by a specific gene mutation, such as cysts in the kidneys, deafness, or genital abnormalities 
  • Not being overweight or obese with negative autoimmune antibodies for type 1 diabetes mellitus 
  • Having a family history of diabetes, especially when a parent or other first-degree relative (sibling or child) is affected, or when at least 3 generations have diabetes, or when family members with diabetes have normal weights 
  • Belonging to certain ethnic groups (since European Caucasians are less affected by type 2 diabetes) 
  • Having a mild form of diabetes as a child, which does not require insulin  

None of these factors alone mean someone might have monogenic diabetes. Instead, they are considered together, along with blood test results. 

Genetic Testing: A health care provider can best determine whether genetic testing is needed. Testing of the genetic information in a blood sample can determine whether a person has a gene causing MODY or neonatal diabetes. Doctors also can check family members of the person with MODY or neonatal diabetes for the presence or risk of diabetes. These are commercially available. 

MODY (formerly Maturity-Onset Diabetes of the Young) 

MODY is the most common form of monogenic diabetes. It usually first occurs in children or teenagers but sometimes is not found until adulthood. MODY can be mild or severe, depending on which gene is involved. Researchers have found at least nine different genes responsible for MODY, and new genetic causes are still being discovered.

Some of the most common are: 

MODY1, hepatocyte nuclear factor-4-alpha (HNF4A): This gene mutation causes decreased insulin secretion in response to glucose in diet which gets progressively worse during adolescence. Patients may initially do well with oral medications (sulfonylureas) but eventually may need insulin, and are at risk for complications of diabetes. 

MODY2, glucokinase (GCK): This gene mutation causes problems converting glucose into a signal for the pancreas to make insulin. Therefore, insulin is not made until higher glucose levels are reached in the blood. Usually, this form of monogenic diabetes is mild, stable, and not associated with complications. It can be controlled with diet, if needed. 

MODY3, hepatocyte nuclear factor-1-alpha (HNF1A): This gene mutation can cause decreased insulin secretion and glucose wasting in the urine. Patients can often be treated with oral medication (sulfonylureas), even if they were previously taking insulin. Patient are at risk for complications of diabetes, including cardiovascular mortality. 

MODY4, insulin promoter factor 1 (IPF1): This gene defect reduces the body’s ability to tell insulin to be made. It can be seen in different ways in individuals, from needing insulin, to having late-onset type 2-like diabetes, to having slightly higher blood glucose levels. Treatment is based on severity in the individual. 

MODY5, hepatocyte nuclear factor-1-beta (HNF1B): This gene defect can cause a multitude of problems besides diabetes, including small pancreas size, abnormal kidney development, slowly progressive kidney disease, low magnesium levels, elevated liver tests, and genital anomalies.  

MODY6, neurogenic differentiation factor 1 (NEUROD1)
: This gene defect causes problems with the development of insulin-producing cells of the pancreas and requires insulin treatment. 

Neonatal Diabetes 

This rare condition occurs in the first 6 months of life. Many infants with neonatal diabetes don’t grow well before birth and are born small for their age. The gene mutations can present in the following ways: 

  • Permanent neonatal diabetes, a lifelong condition 
  • Responsive to oral medication (sulfonylureas), 40% of cases 
  • Requiring lifelong insulin, 10% of cases 
  • Requiring insulin due to a syndrome also having other features (skeletal, liver, eye, hearing, cardiac, kidney, immune, neurologic), 10% of cases 
  • No genetic cause, 20% of cases 
  • Transient neonatal diabetes, 20% of cases: goes away during infancy but can return later in life, especially during puberty or pregnancy, is treated with oral medication or insulin depending on the gene defect 

Treatment depends on the type of MODY. Some people do not need any treatment besides diet and exercise. Others need diabetes medicines. These include injected insulin or a sulfonylurea—a type of diabetes pill that helps the body make more insulin. In one type of MODY, patients also may need treatment for related conditions such as kidney cysts and gout. 

Doctors choose treatment based on the cause. Some types of neonatal diabetes can be treated with a sulfonylurea, but others require insulin. Infants with transient neonatal diabetes may require insulin at first but the condition may disappear at about the age of 12 weeks. If the diabetes returns later in life, insulin might be needed. 

If you or a family member has been diagnosed with type 1 or type 2 diabetes, but you suspect it might be monogenic diabetes, talk with your doctor. Only a specialist, such as an endocrinologist specializing in diabetes, can diagnosis monogenic diabetes. 

  • Does my child (or do I) have a form of monogenic diabetes? 
  • What type of monogenic diabetes does my child (or do I) have? 
  • What are the treatment options? 
  • What are the advantages and disadvantages of each treatment option? 
  • Should I see a diabetes educator? 
  • Should I see an endocrinologist? 
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