HNF1A and HNF4A (Transcription factor MODY)
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 281-283
2025-12-21
40
Transcription factors are proteins that bind to DNA and form part of a complex regulatory network controlling gene expression. The majority of people with MODY have a heterozygous variant in a transcription factor gene, by far the commonest being variants in the hepatic nuclear factors 1A and 4A (HNF1A and HNF4A). Diabetes resulting from variants in other transcription factor encoding genes including HNF1B and insulin promoter factor 1 (IPF- 1) are discussed elsewhere in this chapter.
Transcription factor variants alter insulin secretion in the mature β cell as well as altering β- cell development, proliferation, and cell death. Variants in the hepatic nuclear factors alter levels of proteins critical in metabolism, including the glucose transporter GLUT 2 and key enzymes in the mitochondrial metabolism of glucose. Reduced β- cell proliferation and preserved or increased apoptosis could explain the progressive deterioration in β- cell function seen in these individuals. Variants in HNF1A account for up to 70 % of cases of MODY, with over 500 different variants reported. In the UK, variants in HNF4A account for approximately 10 % of MODY cases.
Clinical features
Heterozygous transcription factor variants cause autosomal dominant diabetes presenting in adolescence or early adulthood resulting from progressive failure of insulin secretion. While diabetes is similar in HNF1A and HNF4A variant carriers, as a result of a common pattern of β- cell dysfunction, several differences in extra- pancreatic features occur (Table 1).
Table1. Extra- pancreatic features assisting in the differential diagnosis of transcription factor maturity- onset diabetes of the young (MODY).
Diabetes
People with transcription factor MODY are usually born with nor mal glucose tolerance and then show progressive β- cell dysfunction until they develop diabetes, usually aged 10–30 years. Of HNF1A carriers, 63% are diagnosed with diabetes by the age of 25 years and 79% by the age of 35 years. The age of diagnosis is partly related to the location of the underlying variant within the gene. The age of diagnosis is earlier in people with HNF1A than HNF4A. Those who show deteriorating glycaemia with age require pharmacological treatment. In the oral glucose tolerance test in those with HNF1A MODY, in contrast to people with glucokinase variants, the fasting glucose is often normal initially, but there is marked elevation of glycaemia at two hours and consequently a large two- hour increment (>5.0 mmol/l; 90 mg/dl). This occurs because insulin secretion rates in early HNF1A MODY remain appropriate, with blood glucose values <8.0 mmol/l (145 mg/dl); however, when blood glucose levels rise above 8.0 mmol/l, the insulin secretion rates are reduced significantly in comparison to non- variant carriers without diabetes and result in a rise in blood glucose levels. Microvascular complications are frequent particularly when hyperglycaemia is inadequately treated. People with transcription factor MODY tend to be lean and insulin sensitive; obesity occurs at similar levels to the nor mal population.
Extra- pancreatic clinical features
These are summarized in Table 1 and discussed in more detail in the following.
HNF1A
People with HNF1A variants have elevated levels of high- density lipoprotein (HDL) cholesterol, which contrasts with the reduced HDL levels seen in type 2 diabetes. Despite this, they have a greater risk of coronary heart disease than people with type 1 diabetes. Frequency of microvascular complications is similar to that seen in type 1 and type 2 diabetes and relates to glycaemic levels. HNF1A variants are associated with a reduced renal threshold for glucose. Variant carriers without diabetes may develop glycosuria after a glucose challenge even if glycaemia remains within normal limits. Individuals with HNF1A variants have a greater risk of liver adenomatosis and its complications, including acute intra- abdominal haemorrhage. Screening for liver adenomas, in people with HNF1A variants with no clinical features suggesting adenomas, needs to be considered carefully, as there is no treatment that can be offered at present.
HNF4A
HNF4A variants are associated with an 800 g increase in birth weight compared with non- variant- carrying siblings. This means that the offspring of HNF4A variant- carrying fathers, as well as the off spring of HNF4A mothers, are at risk of macrosomia. There is also an increased risk of hypoglycaemia in affected neonates. These features relate to increased insulin secretion in utero and in early infancy, which evolves into reduced insulin secretion and diabetes in later life. Recently, cffDNA testing has become available to determine fetal genotype and aid the management of HNF4A pregnancies. HNF4A variant carriers have reduced levels of HDL (and lipoprotein A1 and A2) and frequently have raised LDL cholesterol, while triglyceride levels are similar to population norms.
Differentiating from type 1 diabetes
Individuals with HNF1A or HNF4A MODY are frequently misdiagnosed as having type 1 diabetes as they have symptomatic diabetes presenting in adolescence or young adulthood. We recommend genetic testing by targeted next- generation sequencing to detect variants in HNF1A/HNF4A in any young adult with apparent type 1 diabetes, who is antibody negative to at least GAD and IA2 at diagnosis and also has a parent with diabetes. HNF4A should be suspected where there is increased birth weight and/or neonatal hypoglycaemia. Evidence of non- insulin dependence increases the likelihood of a positive result, shown by a non- fasting random C- peptide >200 pmol/l 3–5 years after diagnosis (i.e. outside the honeymoon period).
Differentiating from type 2 diabetes
HNF1A/HNF4A should be suspected and targeted next- generation sequencing performed in people otherwise suspected to have type 2 diabetes where the following features are present:
• Young- onset diabetes: typically diagnosed before 25 years of age in at least one family member.
• Family history of diabetes: in at least two generations and ideally two individuals diagnosed in their 20s or 30s, particularly where affected individuals do not have obesity.
• Absence of obesity, acanthosis nigricans, or other evidence of insulin resistance.
In addition, marked sensitivity to sulfonylureas (hypoglycaemia on low doses) and a lipid profile showing normal or raised HDL cholesterol and normal or low triglycerides (atypical for type 2 diabetes) would all be supportive of a diagnosis of HNF1A rather than type 2 diabetes. Individuals with HNF4A variants have a nor mal renal threshold for glucose, but frequently have a personal and/ or family history of high birth weight and/or neonatal hypoglycaemia.
Management
People with both HNF1A and HNF4A variants are sensitive to sulfonylurea therapy, which is recommended as first- line treatment. Better glycaemic levels are often seen with sulfonylureas than with insulin and the fasting glucose–lowering effect is four times greater than that seen in type 2 diabetes. Transfer to sulfonylurea treatment is successful in the majority of people, although insulin therapy may be required as the duration of diabetes progresses. Even very low doses of sulfonylurea may cause hypo glycaemia in individuals with HNF1A/HNF4A MODY. The starting dose of sulfonylurea should therefore be low, typically an initial dose of 20–40 mg/day gliclazide or 2.5 mg/day glibenclamide in adults. If there is hypoglycaemia with low doses of standard agents, a short- acting agent such as nateglinide may be appropriate. Recent data from the UK UNITED study indicate that individuals with HNF1A/HNF4A MODY who were more likely to be successfully managed on sulfonylurea therapy alone had a shorter diabetes duration, lower HbA1c, and lower BMI at the time of genetic testing. However, individuals with HNF1A/HNF4A MODY with a longer duration of diabetes (>11 years), especially in those with overweight or obesity and who had a high HbA1c at the time of genetic diagnosis, were more likely to require insulin treatment in addition to a sulfonylurea. Glucagon- like peptide 1 (GLP- 1) receptor agonists are also effective at reducing glycaemia [. When sulfonylureas are not controlling hyperglycaemia, sodium- glucose cotransporter- 2 (SGLT- 2) inhibitors can improve glycaemic levels, but may result in marked hypovolaemia due to excessive urinary glucose loss. More research is required to assess the safety and efficacy of SGLT- 2 inhibitors in individuals with HNF1A MODY, who have a low renal threshold for glucose due to reduced SGLT2 activity. Recently, the DPP- 4 inhibitor linagliptin was shown to be an effective add- on treatment to the sulfonylurea glimepiride in individuals with HNF1A variants by improving glycaemic variability and HbA1c, without increasing the risk of hypoglycaemia. Due to the increased risk of cardiovascular disease in HNF1A, statin therapy should be recommended for those aged over 40 years.
Management in pregnancy
Evidence to support management strategies for HNF1A and HNF4A in pregnancy is limited, but there is a 50% chance that the fetus of an affected parent will inherit the variant. The sulfonylurea glibenclamide has been widely used for treatment of gestational diabetes; however, glibenclamide crosses the placenta and stimulates fetal insulin secretion, resulting in an increased risk of macrosomia and neonatal hypoglycaemia. Due to the risk of stimulating fetal insulin secretion, women with HNF1A/HNF4A variants treated with sulfonylurea prior to conception with good glycaemic levels should either transfer to insulin before conception, at the risk of a brief increase in glycaemic levels, or continue with glibenclamide treatment in the first trimester and transfer to insulin in the second trimester. In women with HNF1A/HNF4A MODY, glibenclamide should be avoided during the third trimester to avoid increased fetal weight gain.
Special considerations in HNF4A pregnancies
If a fetus carries the affected HNF4A gene, the risk of macrosomia and neonatal hypoglycaemia is extremely high whether the variant is inherited from the mother or father, as it will add >800 g to the birth weight, which may result in considerable obstetric complications. Early delivery should be considered when the fetus inherits a HNF4A variant from either parent. In women with HNF4A, there is an additional contribution to fetal birth weight from maternal glycaemia and it is very important to avoid adding to this further by refraining from sulfonylurea (glibenclamide) treatment from the second trimester onwards.
Recent developments in non- invasive prenatal testing to detect cffDNA in maternal blood will enable personalized management of pregnancies based on the fetal genotype and identify pregnancies at increased risk of macrosomia [51] due to HNF4A variants. Further guidelines for the management of pregnancy in individuals with HNF4A variants are available at www.diabetesgenes.org.
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