Chapter 1

Jim is a 47-year-old electrician diagnosed with type 2 diabetes four years ago. Maintenance treatments are metformin 1 g twice daily, alogliptin 25 mg once daily and atorvastatin 20 mg once daily for cardiovascular protection. There is no family history of diabetes and no ongoing diabetes complications.

Blood test results ahead of his diabetes review appointment in primary care revealed: HbA1c 89 mmol/mol (6 months previously HbA1c was 59 mmol/mol); eGFR 74 mL/min/1.73 m2; normal liver blood tests, thyroid function tests; total cholesterol 3.7 mmol/L, non-HDL cholesterol 2.3 mmol/L.

What questions might be helpful in understanding the sudden deterioration in glycaemic control?

Chapter 2

Has there been any alteration in lifestyle? Establish whether there has been any significant change in dietary or exercise habits.

Has Jim been taking his medications regularly? Are there any significant side-effects? Most notably, have gastrointestinal side-effects with metformin been problematic?

Is Jim suffering any osmotic symptoms of diabetes, such as thirst, polyuria or weight loss?

At review with the Practice Diabetes Nurse, Jim could not identify any lifestyle change to account for the worsening diabetes control and confirmed he had been taking his medications regularly.

Clinic measurements: fingerprick blood glucose reading 15.3 mmol/L; negative blood ketone testing; blood pressure 132/75 mmHg; weight 71 kg; BMI 23.7 kg/m2 (similar to previous clinic measurements).

How would you interpret Jim’s diagnosis of type 2 diabetes in the context of a normal BMI?

Chapter 3

A minority of individuals with type 2 diabetes will have a normal BMI, estimated to be around 12% (1). However, this feature does suggest that Jim may be insulin deficient rather than insulin resistant. The sudden deterioration in glycaemic control should make you think that oral hypoglycaemic agents are insufficient to maintain glycaemic control and that there may be a need for insulin. Indeed, these observations throw open the question as to whether Jim really does have type 2 diabetes.

What might you try next to improve glycaemic control?

Chapter 4

A sulfonylurea might be tried and could be viewed as a pragmatic test of Jim’s insulin reserve. The mode of action of sulfonylureas is to stimulate insulin secretion from beta-cells and, if Jim’s endogenous insulin supply is running out, they will be ineffective.

Pioglitazone remains an option, though the side-effect profile may deter use. An SGLT2 inhibitor would represent a higher risk option under the circumstances of possible low insulin reserve because they can predispose to diabetic ketoacidosis (DKA). A GLP-1 receptor agonist would not usually be employed in an individual with normal BMI. Insulin is likely to work well and, with a normal BMI, Jim may require only a relatively low dose. However, insulin use does increase the risk of hypoglycaemia and there would be a need for blood glucose monitoring along with a requirement for a detailed education package.

Following discussion between the Practice Nurse and GP, gliclazide (a sulfonlyurea) was added to Jim’s regimen.

How would you safety net the use of a sulphonylurea in this situation?

Chapter 5

It is important that Jim monitors his blood glucose readings. If blood glucose readings continue to rise, then he will need to report this as it is likely to signal an immediate need for insulin.

In this context, it would also be useful for Jim to have the facility to check blood ketone levels (should there be persistently high blood glucose readings or symptoms of DKA), as there is a definite risk of decompensation (leading to DKA). On the other hand, if gliclazide was effective, then it would be useful for Jim to identify any hypoglycaemia and he should be instructed on how to deal with this. It may be prudent to start at a less-than-maximum dose of sulfonylurea.

Gliclazide 80 mg twice daily was commenced. He was provided with a meter and strips to record fingerprick blood glucose readings and, if necessary, blood ketones.

Despite the addition of gliclazide, Jim’s blood glucose readings remained elevated, between 10 and 18 mmol/L.

What action would you now take?

Chapter 6

Options are now very limited. The need for insulin treatment seems inevitable.

At this stage Jim was referred urgently to secondary care, querying his diabetes classification and the need for insulin therapy.

How might you now revise Jim’s original diagnosis of type 2 diabetes?

Chapter 7

A likely diagnosis for Jim is LADA (latent autoimmune diabetes in adults). He has now reached the point of requiring exogenous insulin to achieve glycaemic control. The diagnosis of LADA, rather than type 2 diabetes, may be suspected in the younger individual (but usually over 30 years of age) who is not overweight (2,3). Be aware, however, that LADA can present in the elderly and obesity does not exclude the diagnosis. There may be an absence of comorbidities that are commonly associated with type 2 diabetes, such as hypertension and hyperlipidaemia (features of metabolic syndrome). As the stage of decompensation approaches, then osmotic symptoms (thirst, polyuria, weight loss) may be present and, indeed, progression to DKA may occur.

Can you think of any linked autoimmune conditions that might support a diagnosis of LADA or any blood tests that might help point towards this specific diagnosis?

Chapter 8

LADA is characterised by the autoimmune destruction of beta-cells. A personal or family history of autoimmune disease strengthens the possibility of this diagnosis (see below).
Autoimmune diseases that may be linked to LADA

• Thyroid autoimmune disease (Grave’s disease, Hashimoto’s disease)
• Pernicious anaemia
• Addison’s disease
• Coeliac disease
• Vitiligo
• Myasthenia gravis
• Autoimmune hepatitis

Biochemically, the finding of pancreatic cell autoantibodies is supportive of the diagnosis of LADA. The presence of anti-GAD and IA2 antibodies strongly predicts the future need for insulin in individuals initially labelled as having type 2 diabetes (4,5). Multiple antibodies correlate with a more rapid progression to insulin dependence.
Pragmatically, LADA is best regarded as a slowly developing variant of type 1 diabetes (3).
It was noted that although there was no family history of diabetes, Jim’s mother suffered from hypothyroidism and was on maintenance vitamin B12 injections for presumed pernicious anaemia.
Lantus (insulin glargine), a basal insulin, was commenced and the gliclazide discontinued. Testing for islet cell autoantibodies and for C-peptide level were requested.

What would be your future plan for medical treatment be if the these blood tests support the diagnosis of LADA?

Chapter 9

This initiation of insulin glargine led to an immediate improvement in blood glucose levels. In the meantime, anti-GAD and IA2 antibody results came back elevated, along with a low post-meal C-peptide level.

Jim’s low C-peptide response indicated poor insulin reserve. C-peptide is secreted in a 1:1 molecular ratio with insulin and is more easily measured than insulin. Thus, it represents a good surrogate marker for insulin reserve (2).

At follow-up, Jim was converted to a basal–bolus insulin regimen and metformin was discontinued. Subsequently, blood glucose readings fell to within the range 5–10 mmol/L and HbA1c improved to 55 mmol/mol.

Key take-away

This case illustrates the need to keep an open mind diagnostically as to the type of diabetes an individual might have. Because Jim’s initial presentation was not with DKA and there was no immediate requirement for insulin, the initial diagnostic label was type 2 diabetes and treatment was based on lifestyle change and oral hypoglycaemics. In the case of LADA, it may take several years before an absolute need for insulin develops, although, as this case illustrates, there can be a relatively rapid deterioration in glycaemic control heralding this requirement (2,3).

Provided glycaemic control remains satisfactory in LADA, then dietary measures and oral hypoglycaemic agents can be continued. However, patients must be aware of the danger of rapid decompensation and risk of DKA. Many individuals would prefer to defer insulin treatment for social and occupational reasons. Alternatively, there is the option of commencing insulin ahead of decompensation, thus averting the risk of DKA. The initial intensity of the insulin regimen can be adapted to individual circumstances. Possible starting regimens include a basal insulin or a twice-daily biphasic insulin, although ultimately a basal–bolus regimen may offer the best option for glycaemic control in the individual with LADA, as it does for the individual with type 1 diabetes.

It is good practice for individuals with suspected LADA to monitor fingerprick blood glucose readings. A sudden rise in blood glucose levels should prompt blood ketone measurement and, if ketones are present in a significant concentration, urgent medical review should follow with a view to commencing insulin therapy.

Once the decision to commence insulin has been made, then the individual with LADA will need the same educational support as a person with type 1 diabetes. They will also require the same attention to the control of hypertension, hyperlipidaemia and glycaemia as others with diabetes to minimise the risk of macrovascular and microvascular complications.