MODY due to hepatocyte nuclear factor 1-alpha mutations
This is one of the two leading causes of MODY, caused by mutations of the hepatocyte nuclear factor 1 homeobox A gene on chromosome 12q, known as HNF1A. This codes for a transcription factor highly expressed in the liver and involved in the regulation of the expression of many liver-specific genes. Its role in insulin secretion is not well defined. The leading characteristics of HNF1A-MODY are: (1) early onset diabetes; (2) diabetes in other family members; (3) low levels of fasting relative to stimulated glucose; (4) a low renal threshold for glucose; and (5) sensitivity to sulphonylurea agents. Diabetes typically develops in the second to fourth decade of life and is generally beta cell antibody negative, C-peptide positive and not associated with features of insulin resistance. The main pathophysiological feature is a failure to augment insulin secretion in response to oral nutrients, which explains the high postprandial glucose levels characteristic of the condition. Metabolic control tends to deteriorate over time in undiagnosed patients despite insulin therapy, and typical late complications of diabetes can develop.
HNF1A mutations are the cause of diabetes in the classic large MODY families recognised in the pre-genomic era. Linkage studies initially localised the gene to chromosome 12q and the gene was identified after the rarer form of MODY due to HNF4A mutations was discovered. In the UK HNF1A-MODY accounts for around 50% of MODY cases. In countries such as France and Spain where more glucokinase mutations are identified (due to glucose testing of asymptomatic young adults), HNF1A mutations account for about 30% of cases.
Mutation carriers have normal glucose tolerance in childhood, but experience a progressive defect of insulin secretion. Diabetes typically presents in the second to fourth decade of life, with a few family members diagnosed at an older age. Pathogenic mutations are highly penetrant (>95%).
Although HNF1A-MODY can be often seem relatively 'mild' and easily controlled at onset, glucose intolerance is progressive, and typical macrovascular and microvascular complications frequently develop. As in type 1 diabetes, good glycaemic control and attention to cardiovascular risk factors are essential features of management.
Diagnosis begins with clinical suspicion. The possibility of monogenic diabetes should be considered in all those with early onset diabetes, even though these may have been given a diagnosis of type 1 or type 2 diabetes.
Clinical features of HNF1A-MODY
- Young-onset diabetes that shows characteristics of not being insulin-dependent (e.g. not developing ketoacidosis in the absence of insulin), good glycaemic control on a small dose of insulin, or detectable C-peptide beyond the expected honeymoon period (3 years) for those who are insulin-treated.
- Family history of young-onset diabetes. This may have been labelled as either type 1 or type 2 diabetes with family members on any form of treatment. Although presence of family history is supportive of MODY, it is not noted in all patients and is also very common in young onset type 2 individuals.
- Typically patients are lean without features of insulin resistance. One study compared HNF1A-MODY patients with young onset type 2 individuals matched for age of diagnosis: this showed the HNF1A-MODY individuals had a lower body mass index (BMI), lower prevalence of hypertension and lower triglycerides than the type 2 individuals but both groups reported a similar prevalence of parental diabetes .
- Those with MODY would not be expected to have positive beta-antibodies and absence of pancreatic antibodies is often part of the selection strategy for genetic testing. A case-control study reported that <1% of 508 patients with a confirmed genetic diagnosis of MODY had positive beta cell antibodies. In contrast, a paediatric survey found that 17% of patients with confirmed MODY mutations had positive antibodies. The differences between the studies probably relates to different laboratories and methods of antibody testing used. in most cases antibody positivity should suggest that the patient has autoimmune diabetes, but where there is a high clinical suspicion of MODY, the presence of pancreatic antibodies should not preclude genetic testing.
- Glycosuria at relatively normal blood glucose levels is often seen as these patients have a low renal threshold due to reduced expression of the high-affinity low-capacity glucose co-transporter 2 (SGLT2), leading to decreased resorption of glucose from the renal tubules.
- Hypoglycaemia on normal doses of sulphonylureas (see section on treatment below).
- Low blood levels of C-reactive protein (CRP). 
Patients with HNF1A gene mutations can initially be treated with diet, although they will have marked postprandial hyperglycaemia following a high carbohydrate load as the beta cell defect results in insufficient increase in insulin secretion with hyperglycaemia. One of the most important reasons for establishing a diagnosis of HNF1A-MODY (and HNF4A-MODY) is the extreme sensitivity to sulphonylurea drugs observed in these forms of diabetes. This was first noted anecdotally and was subsequently confirmed in a randomised controlled cross-over trial that demonstrated a five-fold greater drop in fasting plasma glucose in HNF1A-MODY patients treated with low-dose gliclazide compared with metformin. The effect of metformin was similar to that seen in the type 2 comparison group. Those with HNF4A-MODY showed similar sensitivity to sulphonylureas in a subsequent observational study. On the basis of this, low-dose sulphonylureas are recommended as first-line pharmacological therapy for patients with HNF1A/HNF4A-MODY. A dose of gliclazide 40 mg will typically control diabetes (20 mg is often adequate). If hypogylcaemia occurs, the aim is to reduce the dose rather than discontinuing treatment where possible, as HbA1c may rise with metformin treatment. Much observational evidence suggests that patients treated with insulin from diagnosis can be switched safely to a sulphonylurea. The website of the UK MODY diagnostic centre explains how to do this (Guidance for transferring HNF1A or HNF4A patients from insulin to sulphonylureas). Not surprisingly, patients may require a good deal of reassurance and support through this process, having previously been told they require insulin treatment to stay alive. Not all opt to make the change. A case study of 43 patients reported that 34 changed from insulin to sulphonylureas following diagnosis of HNF1A-MODY, and 24 remained off insulin for 39 months without any deterioration in glycaemic control. Good control may be maintained for many years, although eventually most patients progress to insulin treatment. Nateglinide reduced postprandial glucose excursions acutely in 15 subjects with HNF1A-MODY, suggesting that prandial secretagogues are a useful therapeutic alternative. A recent randomised controlled, double-blind, cross-over trial reported that the GLP-1 agonist liraglutide lowered fasting and postprandial glucose levels with low risk of concurrent hypoglycaemia.  When sulphonylurea drugs begin to fail in HNF1A-MODY, there is no specific evidence base to recommend other treatments. It is reasonable to try other oral agents and metformin probably has a similar efficacy as in type 2 diabetes. Most patients will transfer to insulin after sulphonylurea failure. In theory the addition of basal insulin to sulphonylureas should be effective.
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