US Pharm. 2013;38(10)(Diabetes suppl):3-6.

ABSTRACT: Monogenic diabetes is a form of diabetes caused by gene mutations. Dozens of genes that cause monogenic diabetes have been identified. Monogenic diabetes is classified into neonatal diabetes and familial diabetes (also called maturity-onset diabetes of the young). Neonatal diabetes is usually diagnosed in the first 6 months of life, and familial diabetes is typically diagnosed in late childhood through early adulthood. Patients with monogenic diabetes may be misdiagnosed with type 1 or type 2 diabetes. Clinical presentation and treatment vary depending upon which gene mutation is present. Proper diagnosis is important for initiation of appropriate treatment and testing of family members, if necessary. Research is ongoing to expand knowledge of monogenic diabetes in order to accurately diagnose and treat patients.

The term monogenic diabetes describes a group of single-gene genetic disorders. Researchers have been uncovering the various gene mutations responsible for monogenic diabetes since the 1990s.1 Appropriate treatment is based on the type of monogenic diabetes diagnosed. The medications used to treat monogenic diabetes are the same as those used to treat type 1 and type 2 diabetes mellitus (DM1 and DM2, respectively).


Monogenic diabetes is a form of diabetes caused by a mutation in one of several genes. It is often misdiagnosed as DM1 or DM2. Accurate diagnosis is essential for determining appropriate treatment. Patients with monogenic diabetes have varying signs, symptoms, and clinical courses depending upon which type of diabetes is present.2

The two categories of monogenic diabetes are neonatal and familial (also known as maturity-onset diabetes of the young [MODY]). At least 10 genes have been linked to familial diabetes, and more than 20 genes may cause neonatal diabetes.3 TABLE 1 lists genes that have been linked to neonatal diabetes, and TABLE 2 describes the variations of familial diabetes.2,4-7

Mutations in genes encoding transcription factors are most common in MODY. When these genes are altered, beta cells may exhibit impaired growth, differentiation, and renewal.1


Monogenic diabetes is an autosomal-dominant disease. Therefore, first-degree relatives (i.e., parents, siblings, offspring) of an affected person have a 50% chance of carrying the gene alteration. Additionally, more than 95% of individuals with the gene mutation develop familial diabetes.3 Several years ago, the University of Chicago created the Monogenic Diabetes Registry (see SIDEBAR); by July 2011, more than 700 patients had been catalogued. Although the overall prevalence of monogenic diabetes is unclear, the disease is estimated to account for 1% to 2% of all diabetes cases.8

Clinical Characteristics

In both neonatal and familial diabetes, the clinical presentation is related to which gene contains a mutation.

Neonatal Diabetes: Usually diagnosed within the first 6 months of life, neonatal diabetes can be transient (TNDM) or permanent (PNDM). TNDM is most commonly caused by changes to the ZAC and HYAMI genes.4 TNDM usually resolves at age 3 to 6 months, although it can continue to age 12 to 18 months, and 50% of cases relapse.3 PNDM affects the patient for life.4 The patient may exhibit macroglossia (enlarged tongue), a nonpancreatic symptom.2

Thirty percent of PNDM cases are caused by a mutation in KCNJ11.3 Patients with this mutation present with features of insulin dependence. Thirty percent will have ketoacidosis and a nondetectable C-peptide level. Twenty percent of patients will have neurologic features in addition to diabetes. In the severest cases, patients may have DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome.2 Twenty percent of cases involve a mutation in ABCC8 (SUR1).3 Other, even rarer, forms of neonatal diabetes exist.

Familial Diabetes (MODY): The development of familial diabetes commonly occurs from late childhood through early adulthood, although it has been diagnosed in adults in their 50s.7 The most common form of familial diabetes is MODY3. Clinically, these patients generally have a family history of diabetes, are non–insulin-dependent, and have a low renal threshold for glucose. A patient with a low renal threshold for glucose will renally excrete glucose when his or her blood glucose level is close to normal or slightly elevated. In comparison, a person with a normal renal threshold for glucose would not renally excrete glucose until the blood glucose level reached 160 to 180 mg/dL. Oral glucose tolerance tests (OGTTs) show a large glucose increment, often >90 mg/dL.4

The presentation of MODY1 mutations is clinically similar to that of MODY3. The main differences are that these patients do not have a low renal threshold and usually are older at diagnosis. One case study has associated MODY1 with an expansive regulatory network in the pancreatic beta cells, liver, and kidneys.9

MODY2 is the second most common type of familial diabetes.6 MODY2 causes a mild fasting hyperglycemia in which glucose is regulated at a higher set point. This hyperglycemia does not progress quickly.2 The following characteristics are common: 1) fasting hyperglycemia is persistent and stable over months to years; 2) glycosylated hemoglobin is 5.5% to 5.7% (upper limit of normal); 3) OGTT shows a small increment, generally <63 mg/dL; and 4) one parent has a mildly high fasting blood glucose level. Treatment may not be required, and microvascular and macrovascular complications are uncommon.4

In addition to diabetes, MODY5 can cause nondiabetic renal disease. The renal disease, which often can be diagnosed in utero, precedes the presentation of diabetes.2

Comorbid Genetic Syndromes: Diabetes may manifest in combination with other genetic syndromes. Monogenic diabetes should be considered in these patients. In the autosomal-recessive Wolfram syndrome, the diabetes is nonautoimmune and presents at an average age of 6 years. These patients also have optic atrophy, bilateral sensorineural deafness, diabetes insipidus, dilated renal tracts, and truncal ataxia (loss of coordinated muscle movements for maintaining normal posture of the trunk). Roger’s syndrome is a rare, recessive syndrome involving early-onset megaloblastic anemia and sensorineural deafness, as well as diabetes.2

Mitochondrial Diabetes: This form of diabetes, also known as maternally inherited diabetes with deafness, is the result of transmission of mutated or deleted mitochondrial DNA. Mitochondrial diabetes, which is associated with nonautoimmune beta-cell failure, is progressive. Patients commonly present with short stature and sensorineural deafness.2


Monogenic Diabetes: A definitive diagnosis of monogenic diabetes is made through genetic testing, results of which take weeks to months to acquire.3 Genetic testing is expensive and is not recommended for all patients. A diagnosis of monogenic diabetes should be considered in patients with one of the following clinical presentations: neonatal diabetes or diabetes diagnosed in the first 6 months of life; nonobesity; family history of diabetes affecting a parent; mild fasting hyperglycemia (99-153 mg/dL); and extrapancreatic features in conjunction with diabetes.2

Several laboratory measures can support a suspicion of monogenic diabetes. These include a normal C-peptide level and the absence of pancreatic autoantibodies.2 Pancreatic autoantibodies are also absent in 5% to 20% of patients newly diagnosed with DM1. Therefore, a negative autoantibody finding does not exclude a diagnosis of DM1. In DM1 patients, the autoantibodies may be missing prior to diagnosis or may be lost as the disease progresses.10

In the diagnosis of neonatal diabetes, a few tests may be useful before molecular genetic screening is performed. These include scanning the pancreas, checking for exocrine pancreatic function, and testing for pancreatic antibodies. The pancreas scan may show atrophy or absence of the organ in some forms of neonatal diabetes.2

Misdiagnosis of DM1: A misdiagnosis of DM1 may be considered when the patient meets several of the following criteria: diabetes diagnosed before age 6 months; family history of diabetes affecting a parent; insulin production after 3 years of diabetes, with a C-peptide >200 mmol/L when glucose is >144 mg/dL; and absence of pancreatic autoantibodies, especially at diagnosis.2

Misdiagnosis of DM2: A misdiagnosis of DM2 may be considered when the patient meets several of the following criteria: nonobesity, or diabetic family members of normal weight; absence of acanthosis nigricans (dark discoloration of the neck, armpits, and groin); low prevalence of DM2 in patient’s ethnic background; and fasting C-peptide in normal range and no insulin resistance.2


Treatment for monogenic diabetes depends upon the type of mutation diagnosed in the patient. Extensive guidelines and treatment algorithms have not been published. However, experts suggest which medications are likely to be most effective in several of the more common gene mutations. TABLE 3 gives the most common treatments for the various forms of monogenic diabetes.1,3,4,11,12

Neonatal Diabetes: Patients with KCNJ11-related PNDM do not require insulin therapy despite clinical features suggesting otherwise. Patients may be treated with sulfonylureas.2 The sulfonylureas close the activated potassium channel of the beta cells, thereby correcting the underlying pathologic mechanism.1 Starting doses are high and may be up to three times the maximum dosage used in DM2.13 Often, the dosage can be reduced over time, maintaining good glycemic control without an increased risk of hypoglycemia.2 For administration, tablets may be made into a suspension, or else crushed and given with food.13 Patients with INS and EIF2AK3 mutations need insulin therapy to control their diabetes.1

TNDM related to ZAC and HYAMI is initially treated with high doses of insulin. Insulin requirements will reduce over time. Disease in patients who relapse may be controlled with diet until progression requires insulin.2 Additionally, patients with TNDM from ABCC8 or KCNJ11 mutations may be managed with low doses of sulfonylureas.13

Familial Diabetes (MODY): Patients with MODY3 show a good response to sulfonylureas. This was confirmed in a double-blind, randomized, clinical study comparing the efficacy of metformin and gliclazide—a sulfonylurea not available in the United States—in patients with MODY3.1 The gene for MODY3 is responsible for glucose uptake, glycolysis, and mitochondrial metabolism. Sulfonylureas work at a point in the process of beta-cell function that is past the defective steps.1 The sulfonylurea dose should be started low to avoid hypoglycemia. One-fourth the normal dose is a recommended starting point.2 Additionally, patients with MODY1 are often sensitive to sulfonylureas. A diabetic diet works well for the majority of patients with MODY2. These patients do not need oral medications or insulin.2 Patients with MODY5 are not sensitive to sulfonylureas and tend to require insulin treatment.4

Genetic Syndromes: Patients with Wolfram syndrome require insulin treatment from the time of diagnosis.4 The diabetes associated with Roger’s syndrome is sometimes responsive to high doses of thiamine, but often requires insulin in the long term.2

Mitochondrial Diabetes: The most effective treatment for mitochondrial diabetes is not yet known. In some cases, insulin is required from diagnosis. In other cases, secretagogues (drugs, such as sulfonylureas and glinides, that stimulate the pancreas to release insulin) or diet alone may be an effective treatment option. Metformin is generally avoided owing to the potential risk of lactic acidosis.1

Pharmacist Intervention

Pharmacists should be aware of the clinical characteristics of monogenic diabetes. If a patient meets the diagnostic criteria for one of the types, a conversation between the pharmacist, the patient or parents, and the physician can ensure that the proper diagnosis was made. Although the goals for monogenic diabetes are generally the same as for DM1 and DM2, treatment options may differ in some cases. However, pharmacists can continue to counsel patients about their diabetes, healthy lifestyle behaviors, and the use of insulin and/or oral medications (see SIDEBAR). Little is known about the long-term progression of monogenic diabetes, as well as long-term treatment outcomes.1 In any event, pharmacists have an exciting and important role to play in the management of diabetes of all types.


The recognition of diabetes cases that may be misdiagnosed is important. The treatment of monogenic diabetes differs based upon the gene mutation. Once diagnosed, the patient can receive appropriate treatment and family members can be tested for diagnosis, if necessary. Continued research is needed to identify types of monogenic diabetes and appropriate treatment. Several studies are ongoing in and beyond the U.S. Hopefully, measures will be taken to make genetic testing more affordable and available for patients and to make diagnosis easier.


1. Klupa T, Skupien J, Malecki MT. Monogenic models: what have the single gene disorders taught us? Curr Diab Rep. 2012;12:659-666.
2. Hattersley A, Bruining J, Shield J, et al. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2009;10(suppl 12):33-42.
3. The University of Chicago Kovler Diabetes Center. Testing for neonatal diabetes and MODY. Accessed April 17, 2013.
4. Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence. Brussels, Belgium: International Diabetes Federation; 2011:32-36.
5. The University of Chicago Kovler Diabetes Center. Types of neonatal diabetes. Accessed April 17, 2013.
6. The University of Chicago Kovler Diabetes Center. Types of MODY. Accessed April 17, 2013.
7. Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev. 2008;29:254-264.
8. Greeley SA, Naylor RN, Cook LS, et. al. Creation of the Web-based University of Chicago Monogenic Diabetes Registry: using technology to facilitate longitudinal study of rare subtypes of diabetes. J Diabetes Sci Technol. 2011;5:879-886.
9. Stanescu DE, Hughes N, Kaplan B, et al. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012;97:e2026-e2030.
10. Rubio-Cabezas O, Edghill EL, Argente J, Hattersley AT. Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes. Diabet Med. 2009;26:1070-1074.
11. The University of Chicago Kovler Diabetes Center. Treatment for neonatal diabetes. Accessed April 17, 2013.
12. Oishi K, Diaz GA. Thiamine-responsive megaloblastic anemia syndrome. GeneReviews [Internet]. October 24, 2003 [updated September 20, 2012]. Accessed April 29, 2013.
13. Hattersley A. Transferring patients who have a mutation in KCNJ11 or ABCC8. Accessed August 18, 2013.

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