Section 1 – Naseem

Naseem is a 37-year-old man of Asian ethnic origin who has made an appointment with the Nurse Practitioner. He reports increased frequency of micturition over a period of weeks, but when asked denies dysuria, abdominal pain, haematuria or fever.

A urine dipstick is performed and this shows an absent reaction for the presence of white cells, nitrite, blood or protein but does reveal glucose +++.

What further immediate test could you perform to help with a diagnosis?

Section 2

A fingerprick blood glucose reading would be useful in establishing the presence of hyperglycaemia and clarifying the likely diagnosis of diabetes.

Naseem’s capillary blood glucose reading is 15.6 mmol/L.

What further symptoms might you ask Naseem about to support the diagnosis of diabetes?

Section 3

Ask about other osmotic symptoms: thirst and weight loss. Has Naseem been feeling unduly tired and has there been any evidence of recurrent or persistent infection – most notably genital thrush or skin eruptions such as boils?

Naseem reports feeling thirsty and tired and thinks he may have lost weight. He has not suffered from any unusual infections recently.

What is the most important type of diabetes to exclude here?

Section 4

You should consider types of diabetes other than type 2 diabetes, especially in a younger person, and most importantly the possibility of type 1 diabetes.

What test would you perform to exclude an acute presentation of type 1 diabetes?

Section 5

You need to check for diabetic ketoacidosis (DKA) by testing for ketones. Blood ketones are a more accurate and contemporaneous measure of ketosis than urinary ketones, so only resort to the latter if blood ketone measurement is not available. Table 1 helps you to interpret ketone levels and direct management (Morris, 2022a).

Naseem’s blood ketone level is 0.2 mmol/L, ruling out DKA  and making type 1 diabetes unlikely.

So what is the most likely form of diabetes that Naseem has? What further information should you seek that would support this diagnosis?

Section 6

Type 2 diabetes seems the most likely diagnosis, and Naseem’s ethnicity would be a clear risk factor for this condition. You should check Naseem’s BMI and ask about family history of type 2 diabetes.

Naseem’s BMI is 28.6 kg/m² which, given his ethnicity, would place him in a similar overweight category as an obese Caucasian with a BMI of 30 kg/m² or more (NICE, 2023a).

Both Naseem’s father and mother have been diagnosed with type 2 diabetes, at around the ages of 50 and 60 years, respectively.

What would you consider to be “early-onset” type 2 diabetes?

Section 7

Early-onset type 2 diabetes is generally accepted as being that which occurs below the age of 40 years (Misra et al, 2023), with a further division often made between children/adolescents (<18 years) and younger adults (18 years or more). Whilst these are somewhat arbitrary cut-offs, there is no doubt that the population distribution of type 2 diabetes has shifted to include those of a younger age.

Early-onset type 2 diabetes is a rapidly developing problem. Why do you think this is the case?

Section 8

The principal driver of the increased incidence of early-onset type 2 diabetes is the epidemic of overweight and obesity.

Can you make a list of the risk factors for early-onset type 2 diabetes?

Section 9

Box 1 lists the key risk factors for developing early-onset type 2 diabetes, which are very similar to those for type 2 diabetes in older adults. Most prominently, they include obesity (in around 90% of cases), family history (again, in nearly 90% of cases, reflecting both genetic predisposition and similar living environment) and ethnicity (Copeland et al, 2011; Wilmot and Idris, 2014).

In the absence of ketosis, what clinical features might make you suspect underlying type 1 diabetes?

Section 10

Rapid progress of osmotic symptoms (thirst, polyuria, weight loss) typically feature in type 1 diabetes. A family history of type 1 diabetes and a personal or family history of other autoimmune conditions (e.g. thyroid disease) increase the likelihood of type 1 diabetes.

If you do clinically suspect type 1 diabetes, how would you manage this situation?

Section 11

As previously indicated, the presence of significant ketosis requires immediate hospital admission. In the absence of ketosis then urgent referral to the specialist diabetes team is indicated for further investigations and consideration of insulin initiation.

In the case of children and young people with new-onset diabetes, it is safer to assume type 1 diabetes (even if there are good reasons to suspect type 2 diabetes) until proven otherwise, and to arrange same-day assessment with the paediatric diabetes team. Insulin can be commenced whilst the outcomes of further investigations are awaited, after which the condition can be safely re-assessed (NICE, 2023b).

Apart from type 1 diabetes, what other types of diabetes could you consider in a younger adult you think has type 2 diabetes?

Section 12

Possibilities include:

• Latent autoimmune disease in adults (LADA, or slowly evolving immune-mediated diabetes).
• Maturity-onset diabetes of the young (MODY).
• Pancreatogenic (type 3c) diabetes.

Can you think of any clinical features that might suggest these alternative diagnoses?

Section 13

LADA, like type 1 diabetes, is an autoimmune condition in which antibodies are directed against pancreatic beta-cells, so review personal and family history of autoimmune disease. However, in contrast to type 1 diabetes, the progression to insulin dependence in LADA can take several years and, initially at least, the condition can be managed with oral glucose-lowering agents; thus, LADA is often initially mislabelled as type 2 diabetes (Naik and Palmer, 2003; Buzzetti et al, 2020).

A strong family history of diabetes across multiple generations is to be expected with MODY, as the inheritance pattern is autosomal dominant (i.e. there is a 50% chance of passing on the condition to the next generation; Thanabalasingham and Owen, 2011). If MODY is initially diagnosed as type 2 diabetes then response to metformin is usually poor, whilst there can be marked sensitivity to sulfonylurea therapy. Referral for genetic testing allows a definitive diagnosis of MODY (University of Exeter, 2022).

A further possibility is pancreatogenic diabetes. A past history of pancreatitis (responsible for 75% of cases) may be suggestive of this diagnosis, although if this is the pathology then diabetes usually occurs over the age of 40 years. You could seek a history of upper abdominal pain and establish alcohol consumption.

Pancreatogenic diabetes can, however, occur at a younger age with genetic conditions such as cystic fibrosis. Look out for gastrointestinal symptoms such as upper abdominal pain, steatorrhoea and weight loss, which could indicate malabsorption secondary to pancreatic enzyme insufficiency, which usually precedes the onset of diabetes (Duggan and Conlon, 2017; ElSayed et al, 2023).

Characteristics of these different types of diabetes are summarised in Table 2 (Morris, 2022b).

Referral to secondary care is indicated to establish these diagnoses.

It looks like Naseem has type 2 diabetes. How would you confirm this diagnosis?

Section 14

We need just one HbA_1c reading of 48 mmol/mol or more to confirm the diagnosis of diabetes because Naseem is symptomatic.

Naseem is given dietary advice and asked to monitor fingerprick blood glucose readings. A baseline set of blood tests are arranged.

Naseem’s HbA_1c comes back at 73 mmol/mol, confirming the diagnosis of diabetes. Urea and electrolytes, eGFR, liver function tests, thyroid function tests and full blood counts are all within the normal range; however, there is an adverse lipid profile. Fingerprick glucose readings have been in the range of 10–18 mmol/L.

How would you initially manage Naseem’s hyperglycaemia?

Section 15

In line with NICE (2022) NG28 guidance, start metformin at low dose with plans for gradual dose uptitration.

It would also be reasonable to offer low-dose gliclazide (say, 40 mg twice daily) to achieve immediate lowering of blood glucose and provide relief of osmotic symptoms of diabetes. Once glucose control has been established and stabilised with metformin, consideration could be given to withdrawing the gliclazide and, if necessary, adding in a more suitable agent for hyperglycaemia, such as an SGLT2 inhibitor, which will facilitate weight loss and carry a lower risk of hypoglycaemia.

Naseem is commenced on low doses of metformin and gliclazide and given advice on avoiding simple sugars in his diet and restricting starchy carbohydrate intake. He is referred to be seen in the practice diabetes clinic the following week.

What needs to be covered in Naseem’s first diabetes clinic appointment?

Section 16

Firstly, reinforce the importance of lifestyle issues – diet, exercise and weight loss – and offer Naseem referral to a diabetes educational programme (NICE, 2022).

You should also give due consideration to Naseem’s cardiovascular risk factors, controlling his blood pressure to 140/90 mmHg and introducing a statin if indicated by QRISK assessment.

Naseem needs to be enrolled for retinopathy and podiatry screening, and a urine sample should be sent for albuminuria screening.

How aggressive a condition do you think early-onset type 2 diabetes is in comparison to type 2 diabetes developing at a later age?

Section 17

Early-onset type 2 diabetes is regarded as a more aggressive disease than later-onset type 2 diabetes. This is in part due to longer exposure to hyperglycaemia; however, the early-onset form is also thought to be a more rapidly progressive condition in itself. People with early-onset type 2 diabetes are vulnerable to microvascular and macrovascular complications at an earlier age (Al-Saeed et al, 2016; Lascar et al, 2018).

For these reasons, and also if there is any doubt over the correct diagnosis of type 2 diabetes, you should have a low threshold for referring those with early-onset type 2 diabetes to specialist care.

Section 18 – Tamsin

Tamsin is a 29-year-old lady of Caucasian ethnicity without significant past medical history. She sees her GP with thirst, weight loss and recurrent genital thrush and is found to have a raised fingerprick glucose level of 12.7 mmol/L but no indication of ketosis.

Tamsin has a BMI of 25.7 kg/m². She is physically active, has no history of autoimmune disease, has not been diagnosed with polycystic ovarian syndrome and has never been pregnant. There is no history of pancreatitis, recurrent abdominal pain, loose offensive stools or excessive alcohol consumption. Tamsin’s father receives treatment for type 2 diabetes and her deceased paternal grandmother also suffered from diabetes, although Tamsin is uncertain of the details. She has no siblings.

Blood tests are performed and an HbA_1c comes back at 67 mmol/mol.

What are you thinking diagnostically for Tamsin?

Section 19

This may represent early-onset type 2 diabetes, considering Tamsin’s family history, but she is only marginally overweight, not from an ethnic group at high risk of type 2 diabetes and is unusually young to develop type 2 diabetes. You should, therefore, consider other possible types of diabetes that could affect someone of this age.

The absence of ketosis argues against type 1 diabetes, and there are no pointers towards pancreatogenic diabetes. The family history could suggest MODY (three generations affected and always the possibility that her father may have been mislabelled as having type 2 diabetes). LADA is certainly a possibility.

How would you manage Tamsin’s situation?

Section 20

It would be wise to refer Tamsin to the specialist diabetes team to clarify this diagnosis. Pancreatic autoantibodies and C-peptide levels would be helpful in these circumstances.

In the meantime, it is reasonable to start treatment for type 2 diabetes, as discussed in Sections 15 and 16. There is always the possibility of decompensation to DKA if the underlying diagnosis is type 1 diabetes or LADA, so Tamsin should be warned of danger symptoms suggesting DKA and asked to monitor her fingerprick glucose readings regularly for any sudden rise. Should these occur, she should seek immediate medical review and be tested for ketones.