Section 1 – George

George, a 31-year-old chef, comes to the surgery asking to be tested for diabetes. He reports symptoms of thirst and explains that there is a strong family history of diabetes.

How would you proceed from here?

Section 2

Are there any other osmotic symptoms, such as polyuria or weight loss, or a history of recurrent infections, which would support a diagnosis of diabetes?

What about additional symptoms that might point toward diabetic ketoacidosis (DKA): thirst, nausea and vomiting, abdominal pain, breathlessness, confusion, abnormal fatigue? Look for signs of dehydration; is there a fruity breath smell? Next, check a capillary blood glucose reading and, if this is significantly raised, test for blood ketones.

George reports increased micturition but denies weight loss or any symptoms of DKA. A fingerprick capillary blood glucose reading is 13.4 mmol/L. A check for blood ketones is negative.

What else in the history might help to establish the type of diabetes George has?

Section 3

Exploration of the family history of diabetes may help.

George has an elder brother diagnosed with type 1 diabetes in his early twenties; an elder sister who was diagnosed with gestational diabetes in her late twenties and treated with insulin; and a sister without diabetes. His father was diagnosed with diabetes in his forties and, after starting with oral medications, is now taking insulin. George’s father has a brother who also has diabetes. George is uncertain about the diabetes status of his grandparents.

George has a 4-year-old daughter, who is in good health and not known to have diabetes.

George has a BMI of 25.2 kg/m² and a recent blood pressure of 125/81 mmHg. He is a non-smoker who consumes around 12 units of alcohol per week. His past medical history is unremarkable, and he does not take any regular medication. An HbA1c returns later at 66 mmol/mol (8.2%).

So, what are your thoughts on George’s diagnosis?

Section 4

Both type 2 diabetes and, to a lesser extent, type 1 diabetes have a familial tendency. George would be on the young side to have developed type 2 diabetes, and he has only a marginally elevated BMI and nothing specifically to suggest insulin resistance; however, bear in mind it is possible to develop type 2 diabetes with a BMI in the normal range.

George does not have ketosis or significant osmotic symptoms, and he has no personal history of autoimmune disease that might direct towards a diagnosis of type 1 diabetes, but it is important to note that George’s father, brother and sister all have diabetes now managed with insulin.

Another diagnostic possibility would be latent autoimmune disease in adults (LADA). In this situation, individuals (usually over 30 years of age) can often have their hyperglycaemia managed with oral medications for several years but, as the underlying pathology is autoimmune destruction of pancreatic beta-cells, ultimately they will become insulin-dependent as in classical type 1 diabetes (Buzzetti et al, 2020). A personal or family history of autoimmune disease would be supportive of LADA.

Maturity-onset diabetes of the young (MODY) may be suspected with George because of the strong family history of diabetes (irrespective of the type of diabetes his family members may have been labelled with) and because the features are not typical of type 1 or type 2 diabetes (Thanabalasingham and Owen, 2011). It should be noted that a strong family history of diabetes is not in itself a good discriminatory feature distinguishing MODY from type 2 diabetes.

Pancreatogenic diabetes might be considered, but George has no history of pancreatitis or pancreatic damage, and this more commonly occurs in people over the age of 40 years.

What would be your initial management for George?

Section 5

There does not seem to be an immediate requirement for insulin, although you need to be mindful of the possibility of a sudden deterioration in metabolic control that could lead to DKA; accordingly, inform the patient how he might recognise symptoms of this and the need to seek medical help.

George is given a provisional diagnosis of type 2 diabetes, provided with lifestyle advice and commenced on metformin. George’s healthcare professional is, however, concerned that the diagnosis may not be accurate and that he may, in fact, need insulin in the near future. Accordingly, George is referred to secondary care for further investigations to try and clarify the specific type of diabetes.

Both MODY and LADA are considered possible diagnoses in the diabetes outpatient clinic on the basis of George’s age, family history of diabetes and mode of presentation. Further blood tests, including islet cell autoantibodies, are arranged. George is issued with test strips for monitoring capillary blood glucose levels and advised that if these climb significantly or symptoms suggesting DKA arise (which might indicate decompensation and the need for immediate insulin), then he should seek urgent medical assessment (when blood ketones would need to be checked).

What is MODY?

Section 6

MODY is an inherited type of diabetes in which a single gene defect affects beta-cell insulin production. As a monogenic disorder, it contrasts with type 1 and type 2 diabetes, which arise from a complex interaction of multiple genes with environmental factors. MODY has an autosomal dominant inheritance, which means there is a 50% chance of passing on the genetic mutation from parent to child. If the MODY gene is passed on to the next generation then, because of its high penetrance, the child will almost certainly develop MODY (Urakami, 2019).

The age at diagnosis of MODY can vary from the second to the fifth decade of life but frequently will be under 30 years of age. MODY may present with classic symptoms of diabetes but these are often mild, and diagnosis may be a chance finding from routine testing. Characteristic features of type 2 diabetes (obesity, hypertension, hyperlipidaemia, acanthosis nigricans) and type 1 diabetes (severe osmotic symptoms, DKA) are often absent, and there is usually no immediate requirement for insulin. If there is a positive family history of MODY then it is highly likely that the cause of new-onset diabetes in an individual will be MODY (Urakami, 2019).

MODY is thought to be responsible for approximately 1–2% of cases of diabetes, although this may be an underestimate as diagnosis is often delayed or not made at all (Urakami, 2019). Distinguishing MODY from type 1 or type 2 diabetes is not easy using clinical features alone. Around 80–90% of cases that turn out to be MODY are initially diagnosed as type 1 (typically if younger and not obese) or type 2 diabetes (typically if older and overweight) (Shields et al, 2010).

The diagnostic criteria for MODY are as follows (Hattersley et al, 2018):

• Onset before 25 years of age in one family member.
• Diabetes in two consecutive generations.
• Absence of beta-cell autoantibodies.
• Sustained endogenous insulin secretion.

Why is it important for George to have a definite diagnosis of MODY?

Section 7

Having an accurate diagnosis of MODY would allow George to receive the most effective treatment and to receive advice as to how his diabetes is likely to develop. If MODY is confirmed, it will need to be explained that his children have a 50% chance of inheriting the condition and that it is quite likely those members of his family already diagnosed with diabetes also have MODY (Urakami, 2019).

Section 8 – Investigations supporting the diagnosis of MODY

The majority of individuals with type 1 diabetes or LADA will test positive for pancreatic autoantibodies, whereas the majority of those with MODY will not. One study found that anti-GAD or anti-IA-2 antibodies were present in 82% of people with type 1 diabetes but <1% in those with MODY (the same as a control population) (McDonald et al, 2011).

A further means of helping differentiate MODY from type 1 diabetes is the measurement of levels of C-peptide. C-peptide is secreted from the pancreatic beta-cell in a 1:1 ratio with insulin and, thus, is a convenient surrogate marker for endogenous insulin secretion. C-peptide levels would be expected to be markedly reduced in type 1 diabetes (and to a lesser extent with LADA), whereas significant levels of C-peptide (>200 pmol/L), indicating sustained beta-cell function, would be expected with MODY (Hattersley et al, 2018).

Section 9 – George’s results

George’s tests for pancreatic islet cell autoantibodies (GAD, IA-2 and ZnT8 autoantibodies) come back negative and his C-peptide levels are within “normal” range. These results strengthen the likelihood of MODY as the cause of George’s diabetes.

George had samples sent to the molecular genetic testing laboratory at Exeter, and subsequently HNF1A MODY, or MODY type 3, was diagnosed. The HNF1A (hepatocyte nuclear factor-1 alpha) mutation accounts for around half of MODY cases in the UK and leads to beta-cell dysfunction. Normoglycaemia is usually maintained in early childhood but, as insulin production gradually declines, diabetes arises in the second to fifth decades.

Are you aware of any of the different subtypes of MODY?

Section 10 – Different types of MODY

At least 14 genetic mutations that cause MODY have now been identified, of which the four most frequently found in the UK are listed in the Table below (Kavvoura and Owen, 2012).

Specific criteria need to be met to justify genetic testing, which is expensive, but knowledge of the genetic subtype of MODY allows optimal treatment and advice on prognosis (Hattersley et al, 2018).

Section 11 – How is MODY managed?

In the case of the HNF4A and HNF1A subtypes (MODY 1 and MODY 3), post-prandial rises in blood glucose after eating carbohydrate-rich foods are seen, so dietary advice is important. Beyond dietary control, first-line therapy is a sulfonylurea, to which these conditions are highly sensitive (Diabetes Genes, 2024a; 2024b). When these conditions are definitively diagnosed, individuals established on insulin (with a presumptive diagnosis of type 1 diabetes) and those on other oral agents including metformin (with a presumptive diagnosis of type 2 diabetes) may be switched to sulfonylurea therapy, often at a low dose (Shepherd et al, 2003). Treatment with sulfonylureas may successfully control blood glucose levels for many years, although ultimately insulin is likely to be required. The meglitinides (e.g. repaglinide), as insulin secretagogues, are also effective in these types of MODY and may reduce the risk of hypoglycaemia compared to sulfonylureas (Tuomi et al, 2006).

There is also evidence supporting the effectiveness of GLP-1 receptor agonists and DPP-4 inhibitors in HNF1A and HNF4A, and these treatments avoid the risk of hypoglycaemia and weight gain experienced with sulfonylureas (Urakami, 2018).

In the case of the GCK subtype (MODY 2), dietary advice alone is usually sufficient, with post-prandial hyperglycaemia not a significant issue (Hattersley et al, 2018).

A caveat to all the above advice would be that in children and young people, even if MODY is considered a likely diagnosis, the safer course of action would be to assume type 1 diabetes and treat with insulin until a definitive diagnosis is reached (Thanabalasingham and Owen, 2011).

What other management aspects do you need to think about in MODY apart from glycaemic control?

Section 12

The majority of MODY classifications carry the risk of both macrovascular (coronary heart disease, cerebrovascular disease, peripheral vascular disease) and microvascular (retinopathy, nephropathy, neuropathy) complications, the exception being the GCK subtype. Thus, individuals with MODY should undergo usual diabetes screening procedures and receive treatment for hypertension and dyslipidaemia, as well as for hyperglycaemia, to the usual recommended targets for diabetes (Thanabalasingham and Owen, 2011).

So when should you suspect MODY?

Section 13

Consider MODY as a diagnosis when there is a strong family history of diabetes and the clinical features do not fit well with type 1 or type 2 diabetes (see previous sections), including those individuals in whom a different classification of diabetes has already been assigned (Juszczak et al, 2016).

So, this might be a person labelled with type 1 diabetes who remains on an unexpectedly low dose of insulin (<0.5 units/kg/day) several years after diagnosis, when endogenous insulin supply would be expected to have deteriorated. Persisting levels of C-peptide and absent pancreatic autoantibodies would be expected in MODY, but not in type 1 diabetes.

Alternatively, MODY may be considered in the younger individual who has been diagnosed with type 2 diabetes who is not overweight and lacks features of metabolic syndrome. In either situation, referral to the diabetes specialist would be appropriate and, if necessary, onward referral for genetic testing could be made.

Section 14 – George’s management

George is prescribed gliclazide 40 mg twice daily, and is given appropriate warnings over possible hypoglycaemia (particularly in relation to driving), as standard doses of gliclazide would run a high risk of hypoglycaemia. His target capillary blood glucose readings are set at 5–8 mmol/L pre-meals and 7–10 mmol/L pre-bedtime.

George’s cardiovascular risk was assessed. Factoring in his lipid profile – total cholesterol 4.9 mmol/L, non-HDL cholesterol 3.7 mmol/L – and his normal blood pressure generated a QRISK3 score of well under 10%, and it was decided not to proceed with statin therapy at this stage. Renal function tests were normal. 

George was offered advice on diet and exercise and referred to the local lifestyle programme for people with diabetes. A urinary albumin:creatinine ratio test was requested and George was referred for diabetes eye and foot screening.

This case study ends here.

Section 15 – Nadia

Nadia, 27 years old, has, amongst a set of otherwise normal routine blood investigations, a mildly elevated fasting blood glucose level, confirmed on repeat testing, and is diagnosed as having diabetes. She is well and asymptomatic (no osmotic symptoms or ketosis), is careful with her diet and exercises regularly. There are no symptoms to suggest past or present pancreatic disease (e.g. vomiting, abdominal pain, fatty stools, weight loss).

Nadia’s BMI is 23.2 kg/m² and her HbA_1c is 49 mmol/mol (6.6%). She has no relevant past medical history and her only medication is the combined contraceptive pill. Her father was diagnosed with type 2 diabetes at the age of 43, and this is controlled by diet.

What type of diabetes might you suspect?

Section 16

This does not look typical of either type 1 or type 2 diabetes, and there is nothing in Nadia’s history to suggest pancreatogenic diabetes. LADA might be possible (though Nadia would be very young for this), but certainly MODY should be considered given that her father has diabetes requiring neither oral medication nor insulin.

Further investigations in secondary care (including negative pancreatic autoantibodies and maintained C-peptide levels) subsequently led to genetic testing for MODY, and this proved positive for the glucokinase (GCK) mutation.

Since diagnosis, Nadia’s HbA_1c has remained very stable, at around 50 mmol/mol, without pharmacological treatment.

Section 17 – GCK MODY

Glucokinase is an enzyme that recognises and responds to raised blood glucose levels in the body, triggering insulin response. With the glucokinase (GCK) mutation, the plasma glucose level at which this happens is higher than normal. However, the rise in blood glucose levels is usually mild and usually does not require treatment (Urakami, 2018). Often individuals are asymptomatic and the condition is discovered in routine examination, for example in pregnancy as a cause of gestational diabetes (Rudland et al, 2016).

Microvascular complications of the diabetes associated with the GCK mutation appear to be avoided, and cardiovascular risk does not seem to be elevated (Steele et al, 2014). Lifelong mild, stable fasting hyperglycaemia (5.5–8.0 mmol/L) with an HbA_1c usually under 58 mmol/mol is typical (Urakami, 2018; Diabetes Genes, 2024c).

So how can we advise Nadia?

Section 18

Nadia can be reassured that the type of diabetes she has does not lead to significant complications and that medication is unlikely to be needed. The exception to this might be in pregnancy, as the issue of fetal macrosomia arises. If necessary, insulin may be given to suppress blood glucose levels.