Question 96#

A 54-year-old man with type 2 diabetes mellitus is started on exenatide. Which one of the following statements regarding exenatide is incorrect?

A. Typically results in weight loss

Correct Answer C: Exenatide causes vomiting.

The major adverse effect is nausea and vomiting.

Diabetes mellitus: GLP-1 and the new drugs:
A number of new drugs to treat diabetes mellitus have become available in recent years. Much research has focused around the role of glucagon-like peptide-1 (GLP-1), a hormone released by the small intestine in response to an oral glucose load.

Whilst it is well known that insulin resistance and insufficient B-cell compensation occur other effects are also seen in type 2 diabetes mellitus (T2DM). In normal physiology an oral glucose load results in a greater release of insulin than if the same load is given intravenously - this known as the incretin effect. This effect is largely mediated by GLP-1 and is known to be decreased in T2DM. 

Increasing GLP-1 levels, either by the administration of an analogue or inhibiting its breakdown, is therefore the target of two recent classes of drug.

Glucagon-like peptide-1 (GLP-1) mimetics (e.g. exenatide):

• Increase insulin secretion and inhibit glucagon secretion
• Licensed for use in T2DM
• Must be given by subcutaneous injection within 60 minutes before the morning and evening meals. It should not be given after a meal
• May be combined with metformin, a sulfonylurea or a thiazolidinedione
• Typically results in weight loss
• Major adverse effect is nausea and vomiting

NICE guidelines on the use of exenatide:

• Should be used only when insulin would otherwise be started, obesity is a problem (BMI > 35 kg/m²) and the need for high dose insulin is likely
• Continue only if beneficial response occurs and is maintained (> 1.0 percentage point HbA1c reduction and weight loss > 3% in 6 months)

The Medicines and Healthcare products Regulatory Agency has issued specific warnings on the use of exenatide:

• Increased risk of severe pancreatitis
• Increased risk of renal impairment

Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. Vildagliptin, sitagliptin):

• Oral preparation
• Trials to date show that the drugs are relatively well tolerated with no increased incidence of hypoglycaemia
• Do not cause weight gain

NICE guidelines on DPP-4 inhibitors:

• Continue DPP-4 inhibitor only if there is a reduction of > 0.5 percentage points in HBA1c in 6 months
• NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if further weight gain would cause significant problems, a thiazolidinedione is contraindicated or the person has had a poor response to a thiazolidinedione

Question 97#

A 52-year-old woman who was diagnosed as having primary atrophic hypothyroidism 12 months ago is reviewed following recent thyroid function tests (TFTs): 

She is currently taking 75mcg of levothyroxine once a day.

How should these results be interpreted?

A. Poor compliance with medication

Correct Answer A: 

Thyroid function tests:

The interpretation of thyroid function tests is usually straightforward:

*now referred to as non-thyroidal illness

**TSH may be normal in some cases

Question 98#

A 25-year-old male develops type 2 diabetes mellitus.

Which one of the following genes is most likely to be responsible?

A. Glucokinase

Correct Answer B: 

MODY:

Maturity-onset diabetes of the young (MODY) is characterised by the development of type 2 diabetes mellitus in patients < 25 years old. It is typically inherited as an autosomal dominant condition. Over six different genetic mutations have so far been identified as leading to MODY. Ketosis is not a feature at presentation.

MODY 3:

• 60% of cases
• Due to a defect in the HNF-1 alpha gene

MODY 2:

• 20% of cases
• Due to a defect in the glucokinase gene 

Question 99#

One of your patients is diagnosed with having the metabolic syndrome.

Which one of the following is associated with this condition?

A. Endometriosis

Correct Answer E: 

Metabolic syndrome:
Unfortunately there are a number of competing definitions of the metabolic syndrome around at the present time. It is thought that the key pathophysiological factor is insulin resistance.

SIGN recommend using criteria similar to those from the American Heart Association. The similarity of the International Diabetes Federation criteria should be noted. For a diagnosis of metabolic syndrome at least 3 of the following should be identified:

• Elevated waist circumference: men > 102 cm, women > 88 cm
• Elevated triglycerides: > 1.7 mmol/L
• Reduced HDL: < 1.03 mmol/L in males and < 1.29 mmol/L in females
• Raised blood pressure: > 130/85 mmHg, or active treatment of hypertension
• Raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed type 2 diabetes

The International Diabetes Federation produced a consensus set of diagnostic criteria in 2005, which are now widely in use. These require the presence of central obesity (defined as waist circumference > 94cm for Europid men and > 80cm for Europid women, with ethnicity specific values for other groups) plus any two of the following four factors:

• Raised triglycerides level: > 1.7 mmol/L, or specific treatment for this lipid abnormality
• Reduced HDL cholesterol: < 1.03 mmol/L in males and < 1.29 mmol/L in females, or specific treatment for this lipid abnormality
• Raised blood pressure: > 130/85 mm Hg, or active treatment of hypertension
• Raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed type 2 diabetes 

In 1999 the World Health Organization produced diagnostic criteria which required the presence of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, AND two of the following:

• Blood pressure: > 140/90 mmHg
• Dyslipidaemia: triglycerides: > 1.695 mmol/L and/or high-density lipoprotein cholesterol (HDL-C) < 0.9 mmol/L (male), < 1.0 mmol/L (female)
• Central obesity: waist:hip ratio > 0.90 (male), > 0.85 (female), and/or body mass index > 30 kg/m2
• Microalbuminuria: urinary albumin excretion ratio > 20 mg/min or albumin:creatinine ratio > 30 mg/g

Other associated features include:

• Raised uric acid levels
• Non-alcoholic fatty liver disease
• Polycystic ovarian syndrome

Question 100#

What is the mode of inheritance of haemochromatosis?

A. Autosomal recessive

Correct Answer A: 

Haemochromatosis: features:

Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. It is often asymptomatic in early disease and initial symptoms often non-specific e.g. lethargy and arthralgia.

Epidemiology:

• 1 in 10 people of European descent carry a mutation genes affecting iron metabolism, mainly HFE
• Prevalence in people of European descent = 1 in 200

Presenting features:

• Early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)
• 'bronze' skin pigmentation
• Diabetes mellitus
• Liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition)
• Cardiac failure (2nd to dilated cardiomyopathy)
• Hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)
• Arthritis (especially of the hands)

Questions have previously been asked regarding which features are reversible with treatment:

*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene

**whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not