Diabetes (T1 & T2)

Question 1

Diabetes complications - KNIVES

Answer 1

Kidney – nephropathy

Neuromuscular – peripheral neuropathy, mononeuritis, amyotrophy

Infective – UTIs, TB

Vascular – coronary/cerebrovascular/peripheral artery disease

Eye – cataracts, retinopathy

Skin – lipohypertrophy/lipoatrophy, necrobiosis lipoidica

Question 2

Diabetes mellitus is a chronic, multi-system disease, with profound biochemical and structural sequelae. It can be classified into four main groups:

Answer 2

Type 1 diabetes mellitus: characterised by an inability to produce/secrete insulin due to autoimmune destruction of the beta-cells (production site of insulin) in the pancreatic islets of Langerhan.
Type 2 diabetes mellitus: characterised by a combination of peripheral insulin resistance and inadequate secretion of insulin. It is strongly associated with obesity and the metabolic syndrome.
Gestational diabetes mellitus: new onset of diabetes in pregnancy. It is associated with both maternal and foetal complications and as such patients are managed as part of a multi-disciplinary team in both antenatal and diabetic clinics. Patients with GDM have a higher risk of developing both GDM in future pregnancies and overt diabetes mellitus.
Other: These can be divided into genetic and acquired disease. Genetic causes refer to monogenic diabetes (i.e caused by mutation to a single gene). They are rare and collectively termed ‘mature-onset diabetes of the young’ (MODY). Acquired causes may be secondary to medications or pathological conditions. Common causes include corticosteroids, pancreatitis and pancreatic tumours.

Question 3

T1DM

Answer 3

Type 1 diabetes is a condition caused by an inability to produce or secrete insulin. It is characterised by an absolute insulin deficiency, state of persistent hyperglycaemia with abnormalities in carbohydrate, fat and protein metabolism.

It accounts for 90-95% of diabetes in children, classically presenting with polyuria, polydipsia and weight loss. Insulin is central to management as is monitoring for and treating complications.

Question 4

T1DM

Answer 4

The condition can develop at any age. It is estimated that over 370,000 adults are affected with T1DM within the UK and this is thought to represent about 10% of adults who suffer from diabetes. The incidence of T1DM is thought to be increasing.

Question 5

Insulin is produced and secreted by beta cells within the pancreatic islets of ….

Answer 5

Insulin is produced and secreted by beta cells within the pancreatic islets of Langerhan.

Question 6

Up to 85% of patients with T1DM are found to have circulating autoantibodies. The … antibody, an enzyme found within beta cells of the pancreas, is most commonly identified.

Answer 6

Up to 85% of patients with T1DM are found to have circulating autoantibodies. The anti-glutamic acid decarboxylase (anti-GAD) antibody, an enzyme found within beta cells of the pancreas, is most commonly identified.

Question 7

In T1DM, it is estimated that approximately 15% of patients will have a first-degree relative who has the condition, and there is 30-50% concordance in … twins. There is also a significant link with other autoimmune conditions. The prevalence of T1DM is higher in patients with autoimmune conditions such as Graves’ disease, autoimmune thyroiditis and Addison’s disease.

Answer 7

In T1DM, it is estimated that approximately 15% of patients will have a first-degree relative who has the condition, and there is 30-50% concordance in monozygotic twins. There is also a significant link with other autoimmune conditions. The prevalence of T1DM is higher in patients with autoimmune conditions such as Graves’ disease, autoimmune thyroiditis and Addison’s disease.

Question 8

T1DM has also been linked to certain human … …

Answer 8

T1DM has also been linked to certain human leucocyte antigens (HLA). HLAs are the human form of the major histocompatibility complex (MHC) proteins key to cell-signalling. In particular, they are important for the immune system to be able to distinguish its own cells from pathogens (e.g. from bacteria).

Question 9

It is estimated that up to 95% of patients with … have human leucocyte antigens HLA-DR3 or HLA-DR4.

Answer 9

It is estimated that up to 95% of patients with T1DM have human leucocyte antigens HLA-DR3 or HLA-DR4.

Question 10

Under normal physiological conditions, glucose metabolism is a tightly controlled process maintaining blood glucose levels between … and …

Answer 10

Under normal physiological conditions, glucose metabolism is a tightly controlled process maintaining blood glucose levels between 3.5-8.0 mmol/L.

Question 11

Glucose & insulin during fasting

Answer 11

In normal fasting conditions, insulin concentrations are low as it acts locally on the liver to modulate glucose production. It does this by modulation of glycogenolysis (breakdown of the stored version of glucose termed glycogen) and gluconeogenesis. The latter describes the formation of glucose from non-carbohydrate carbon substrates including amino acids (alanine and glutamate), lactate and glycerol (derived from fatty acids).

Question 12

Glucose & insulin post-prandial

Answer 12

Following a meal (post-prandial), insulin is released from the pancreas in large amounts. The release of insulin is enhanced by the release of other gut hormones including glucagon-like peptide (GLP). Insulin acts on the liver to reduce its glucose output, inhibiting glycogenolysis and gluconeogenesis. Insulin is also essential for the promotion of glucose uptake in peripheral tissues (e.g. muscle and adipose tissue).

In addition to this insulin:

Decreases lipolysis, increases fatty acid and triacylglycerol synthesis.
Increases glucose uptake in adipose tissue and muscle.
Increases protein synthesis in a variety of tissues and prevents protein degradation.

Question 13

In addition to this insulin:

Answer 13

Decreases lipolysis, increases fatty acid and triacylglycerol synthesis.
Increases glucose uptake in adipose tissue and muscle.
Increases protein synthesis in a variety of tissues and prevents protein degradation.

Question 14

Counter-regulatory hormones

Answer 14

Counter-regulatory hormones include glucagon, adrenaline, growth hormone and cortisol. These hormones promote glucose production within the liver (e.g. glycogenolysis, glyconeogenesis) and inhibit peripheral uptake of glucose.

Question 15

In patients with T1DM, the destruction of …-cells leads to the progressive reduction in insulin secretion.

Answer 15

In patients with T1DM, the destruction of beta-cells leads to the progressive reduction in insulin secretion.

Question 16

The absence of insulin leads to an increase in the rate of glucose production from the liver and reduced peripheral uptake of glucose. This is exacerbated by the high levels of glucagon and other counter-regulatory hormones. This results in an osmotic diuresis leading to …(4)

Answer 16

The absence of insulin leads to an increase in the rate of glucose production from the liver and reduced peripheral uptake of glucose. This is exacerbated by the high levels of glucagon and other counter-regulatory hormones. This results in an osmotic diuresis leading to polyuria, polydipsia, dehydration and electrolyte derangement.

Question 17

Why do T1DM patients lose weight?

Answer 17

The peripheral tissue is unable uptake glucose to utilise it as energy. Weight loss occurs secondary to fluid loss and increased muscle and fat breakdown.

Question 18

The development of ketosis leads to… … (diabetic ketoacidosis). High circulating ketones can induce vomiting, further exacerbating dehydration and electrolyte derangement.

Answer 18

The development of ketosis leads to metabolic acidosis (diabetic ketoacidosis). High circulating ketones can induce vomiting, further exacerbating dehydration and electrolyte derangement.

Question 19

LADA - what is this?

Answer 19

Latent-onset autoimmune diabetes in adults (LADA) refers to a variant of T1DM that occur later in life.

It refers to a group of patients who have autoimmune destruction of beta cells (as evidenced by positive autoantibodies). It tends to have a gradual onset.

Question 20

LADA diagnosis

Answer 20

It can be suspected in patients who develop diabetes in adult life with associated ketosis, weight loss, low BMI and family history of autoimmune disease. Patients are frequently diagnosed with T2DM whose initial treatments will be ineffectual. Like other cases of T1DM, insulin therapy is required.

Question 21

The majority of patients will develop T1DM in childhood or adolescence with features of … (4)

Answer 21

The majority of patients will develop T1DM in childhood or adolescence with features of lethargy, polyuria, polydipsia and weight loss.

Question 22

Symptoms of T1DM (4)

Answer 22

Polyuria & polydipsia
Weight loss
Vomiting
Lethargy

Question 23

Signs of T1DM(2)

Answer 23

Mild-moderate dehydration (dry skin, dry mucous membranes, reduced skin turgor)
BMI < 25

Question 24

Signs and symptoms of …

Answer 24

T1DM

Question 25

Diabetic ketoacidosis - signs and sy,proms

Answer 25

Confusion
Moderate-severe dehydration (sunken eyes, prolonged capillary refill time)
Vomiting +/- diarrhoea
Abdominal pain
Decreased urine output
Reduced GCS
Coma
Shock (tachycardia, hypotension)
Kussmaul breathing (Deep sighing respiration)

Question 26

Confusion
Moderate-severe dehydration (sunken eyes, prolonged capillary refill time)
Vomiting +/- diarrhoea
Abdominal pain
Decreased urine output
Reduced GCS
Coma
Shock (tachycardia, hypotension)
Kussmaul breathing (Deep sighing respiration)

Signs of?

Answer 26

DKA

Question 27

Signs and symptoms of …

Answer 27

DKA

Question 28

The majority of patients with T1DM will be children or adolescents but the diagnosis should not be discounted in adults (…).

Answer 28

The majority of patients with T1DM will be children or adolescents but the diagnosis should not be discounted in adults (LADA).

Question 29

Patients with suspected T1DM should be…

Answer 29

Patients with suspected T1DM should be referred the same day to a specialist diabetic team for further assessment to confirm the diagnosis and start immediate management.

Question 30

Further investigations should be reserved for patients presenting diabetic … (FBC, UE, CRP, LFT, ABG etc) or where … or MODY are suspected (e.g. c-peptide, genetic testing).

Answer 30

Further investigations should be reserved for patients presenting diabetic ketoacidosis (FBC, UE, CRP, LFT, ABG etc) or where LADA or MODY are suspected (e.g. c-peptide, genetic testing).

Question 31

Management of T1DM requires …

Answer 31

Management of T1DM requires life-long exogenous insulin to prevent acute complications (e.g. DKA) and long-term sequelae (e.g CKD, IHD, Retinopathy).

Question 32

In clinical practice, there are three main insulin regimes that are used in patients with T1DM:

Answer 32

Basal-bolus regime: typically involves the use of rapid- or short-acting insulin before meals and a long-acting preparation for basal requirements. This regime is thought to best mimic the physiological function of the pancreas in response to meals and provides better flexibility in control of blood glucose. It is the standard approach for patients newly diagnosed with T1DM.
One, two, or three injections per day regime: traditionally a biphasic regime with the use of both short-acting and intermediate-acting insulin as separate injections or a mixed product.
Continuous insulin infusion via a pump: supplies rapid- or short-acting insulin. It may be used in patients who are experiencing troubling hypoglycaemic episodes with multiple daily injections regimes.

Question 33

Basal-bolus regime:

Answer 33

Basal-bolus regime: typically involves the use of rapid- or short-acting insulin before meals and a long-acting preparation for basal requirements. This regime is thought to best mimic the physiological function of the pancreas in response to meals and provides better flexibility in control of blood glucose. It is the standard approach for patients newly diagnosed with T1DM.

Question 34

One, two, or three injections per day regime:

Answer 34

One, two, or three injections per day regime: traditionally a biphasic regime with the use of both short-acting and intermediate-acting insulin as separate injections or a mixed product.

Question 35

Continuous insulin infusion via a pump:

Answer 35

Continuous insulin infusion via a pump: supplies rapid- or short-acting insulin. It may be used in patients who are experiencing troubling hypoglycaemic episodes with multiple daily injections regimes.

Question 36

Insulin regimes T1DM options (3)

Answer 36

Question 37

All patients with T1DM are advised to monitor their own blood sugars at least …

Answer 37

All patients with T1DM are advised to monitor their own blood sugars at least four times a day (e.g. three times before meals and once before bed). There may be times when blood glucose monitoring is recommended more frequently including sporting activities, pregnancy and in those with hypoglycaemic episodes.

Question 38

The main targets are detailed below: (T1DM)

Answer 38

On waking: fasting blood glucose 5–7 mmol/L
Before meals: blood glucose 4–7 mmol/L
Post meals: test after 90 minutes, blood glucose 5–9 mmol/L

Question 39

Long term T1DM control

Answer 39

Long-term control is monitored with HbA1c. This blood test is a measure of glycated haemoglobin, indicative of the average blood glucose over 3 months. It should be repeated every 3-6 months to assess glycemic control.

Patients and clinicians should target a HbA1c < 48 mmol/L (6.5%). Factors that may demand a higher threshold include hypoglycaemic episodes, occupation and co-morbidities.

Question 40

Patients and clinicians should target a HbA1c < …. mmol/L (6.5%). Factors that may demand a higher threshold include hypoglycaemic episodes, occupation and co-morbidities.

Answer 40

Patients and clinicians should target a HbA1c < 48 mmol/L (6.5%). Factors that may demand a higher threshold include hypoglycaemic episodes, occupation and co-morbidities.

Question 41

Monitoring for complications - T1DM

Answer 41

A regular diabetic assessment looking at all aspects of care, including surveillance for complications, is essential for all patients to improve morbidity and mortality.

On an annual basis (more frequently if required), patients should receive a diabetic review. This includes assessment of injection site problems, retinopathy, nephropathy, diabetic foot problems (e.g. neuropathic problems), cardiovascular risk factors and thyroid disease.

Question 42

Screening in T1DM

Answer 42

Retinopathy: annual screening
Nephropathy: renal function (eGFR) and albumin:creatinine ratio (ACR)
Diabetic foot problems: full examination including footwear, monofilament assessment of neuropathy, vascular assessment +/- dopplers.
Cardiovascular risk factors: primary/secondary prevention strategy with optimisation of blood pressure, lipids, weight, smoking and others
Thyroid disease: screening blood test

Question 43

Education - T1DM

Answer 43

Education

The Dose Adjustment For Normal Eating (DAFNE) programme is aimed at providing type 1 diabetic patients with a way of calculating the amount of carbohydrate in each meal to adjust their insulin accordingly.

Question 44

Honeymoon period - T1DM

Answer 44

The honeymoon period can occur in newly diagnosed patients in whom there is residual beta cell function.

This may negate the need for exogenous insulin for a period. The honeymoon period can last for weeks to months before a deterioration in glycemic control and the need for exogenous insulin.

Question 45

‘Sick-day rules’ refer to a number of recommendations in T1DM with an intercurrent illness. Advice includes: (5)

Answer 45

Continue insulin therapy, alterations may be required, advice from a specialist may be sought
Increase frequency of blood glucose monitoring
Consider ketone monitoring
Maintain good hydration and when possible a normal meal pattern, meals may be replaced by carbohydrate based drinks
Seek urgent medical attention if unable to tolerate oral intake, drowsy or sustained vomiting

Question 46

The two main acute diabetic complications seen in patients with T1DM are …

Answer 46

The two main acute diabetic complications seen in patients with T1DM are hypoglycaemia and diabetic ketoacidosis.

Question 47

Microvascular complications - T1DM

Answer 47

Uncontrolled diabetes results in small vessel disease affecting the kidneys, nerves and retinas (amongst other systems).

Question 48

Uncontrolled diabetes results in small vessel disease affecting the kidneys, nerves and …(amongst other systems).

Answer 48

Uncontrolled diabetes results in small vessel disease affecting the kidneys, nerves and retinas (amongst other systems).

Question 49

… … is one of the major eye-related disorders that can occur in patients with diabetes. More than 95% of patients will have detectable changes after 20 years. Other disorders include cataracts and ocular palsies.

Answer 49

Diabetic retinopathy is one of the major eye-related disorders that can occur in patients with diabetes. More than 95% of patients will have detectable changes after 20 years. Other disorders include cataracts and ocular palsies.

Question 50

Retinopathy - T1DM

Answer 50

Persistent damage to the retina leads to areas of ischaemia and release of angiogenic factors such as vascular endothelial growth factor (VEGF). This promotes new formation of vessels that are weak and friable. This leads to complications including haemorrhage, fibrosis and retinal detachment.

Question 51

Non-proliferative: Retinopathy

Answer 51

Non-proliferative:
Background (R1): dot and blot haemorrhages, hard exudates, cotton wool spots
Pre-proliferative (R2): intraretinal microvascular abnormalities (IRMA), venous beading

Question 52

Proliferative retinopathy

Answer 52

Proliferative:

Proliferative (R3): new vessels at the disc and elsewhere (NVD, NVE), fibrosis, traction retinal detachmen

Question 53

Maculopathy - retinopathy

Answer 53

Maculopathy: exudates, oedema, NVE

Question 54

Good glycemic control and regular screening to assess early changes are key to preventing and managing disease. … is used to manage proliferative disease. The aim of this is to burn holes within the ischaemic retina to prevent the release angiogenesis factors (e.g. VEGF), which stimulate new vessel formation.

Answer 54

Good glycemic control and regular screening to assess early changes are key to preventing and managing disease. Photocoagulation is used to manage proliferative disease. The aim of photocoagulation is to burn holes within the ischaemic retina to prevent the release angiogenesis factors (e.g. VEGF), which stimulate new vessel formation.

Question 55

Diabetic nephropathy usually develops 15-25 years following the onset of diabetes and can progress to …

Answer 55

Diabetic nephropathy usually develops 15-25 years following the onset of diabetes and can progress to end-stage renal disease (ESRD).

Question 56

The earliest sign of diabetic nephropathy is the presence of …., which can be assessed with an albumin:creatinine ratio (ACR).

Answer 56

The earliest sign of diabetic nephropathy is the presence of microalbuminuria, which can be assessed with an albumin:creatinine ratio (ACR). An ACR 3 - 30 mg/mmol is suggestive of microalbuminuria, now categorised as moderately increased albuminuria.

Question 57

The earliest sign of diabetic nephropathy is the presence of microalbuminuria, which can be assessed with an albumin:creatinine ratio (ACR). An ACR 3 - 30 mg/mmol is suggestive of microalbuminuria, now categorised as moderately increased albuminuria.

Answer 57

A1: < 3 mg/mmol, normal or mild increase
A2: 3 - 30 mg/mmol, moderately increased
A3: > 30 mg/mmol, severely increased

Question 58

Microalbuminuria is a marker of systemic microvascular damage and patients should be treated with an…

Answer 58

Microalbuminuria is a marker of systemic microvascular damage and patients should be treated with an ACE inhibitor even in the presence of normotension. Chronic kidney disease (CKD) in diabetes is evidenced by a persistently low eGFR < 60 mmol/L and/or an ACR persistently > 3 mg/mmol/L.

Question 59

n. Chronic kidney disease (CKD) in diabetes is evidenced by a persistently low eGFR < 60 mmol/L and/or an ACR persistently > … mg/mmol/L.

Answer 59

n. Chronic kidney disease (CKD) in diabetes is evidenced by a persistently low eGFR < 60 mmol/L and/or an ACR persistently > 3 mg/mmol/L.

Question 60

The main types of diabetic neuropathy are listed below. (4)

Answer 60

Symmetrical polyneuropathy: typically a peripheral neuropathy that occurs in the leg secondary to loss of vibration, pain and temperature sensation.
Mononeuropathy: damage to a single cranial or peripheral nerve (e.g. third nerve palsy).
Diabetic amyotrophy: a spectrum of disease affecting the lumbosacral plexus leading to symmetrical pain, weakness and wasting in the proximal muscles of the leg.
Autonomic neuropathy: a spectrum of conditions related to damage of the autonomic nervous system, which can effect multiple systems.

Question 61

Diabetic foot

Answer 61

Diabetic foot problems refer to a wide range of pathologies that are thought to occur secondary to the combination of peripheral neuropathy and poor vascular supply.

Question 62

Diabetic foot

Answer 62

Due to loss of sensation and poor blood supply, patients are at risk of a number of complications including diabetic ulcers, secondary infection (e.g. cellulitis, osteomyelitis), skin necrosis and eventually amputation.

Question 63

Diabetic foot - Charcot’s joint

Answer 63

Another well-known problem is Charcot’s joint. This is a complex neuropathic arthropathy that results from loss of sensation and subsequent repeated micro-trauma to the foot (traditionally the mid-foot). Microtrauma in the presence of poor peripheral blood flow leads to remodelling, swelling and distortion of the whole joint.

Question 64

Foot ulcer - diabetic patients

Answer 64

It is estimated that 10-15% of diabetic patients will develop a foot ulcer during their illness and approximately 50% of diabetic hospital admissions are related to diabetic ulcers and foot problems. The management of diabetic foot disease is essential to help recognise and treat complications early. There are now recognised diabetic foot services that are available to help manage patients with these conditions.

Question 65

Diabetes is a significant risk factor for … and related macrovascular complications.

Answer 65

Diabetes is a significant risk factor for atherosclerosis and related macrovascular complications.

Question 66

Optimisation of cardiovascular risk factors on an annual basis is essential to prevent premature cardiovascular disease. This involves: (4)

Answer 66

Smoking cessation
Nutritional support & exercise
Consideration of anti-lipid therapy (e.g. atorvastatin)
Blood pressure control (e.g. ACE inhibitor)

Question 67

… refers to a group of metabolic disorders that result from an inability to produce and/or reduced sensitivity to insulin.

Answer 67

Diabetes mellitus refers to a group of metabolic disorders that result from an inability to produce and/or reduced sensitivity to insulin.

Question 68

T2DM is a complex, polygenic disease that is strongly associated with …

Answer 68

T2DM is a complex, polygenic disease that is strongly associated with obesity.

Question 69

T2DM has been shown to have a genetic basis. The risk of developing the condition is as high as 75% if both parents have suffered from the condition. Moreover, in … twins, there is a 50-90% concordance for developing the condition.

Answer 69

T2DM has been shown to have a genetic basis. The risk of developing the condition is as high as 75% if both parents have suffered from the condition. Moreover, in monozygotic twins, there is a 50-90% concordance for developing the condition.

Question 70

Importantly, T2DM is considered a … disease with numerous genetic variants contributing to overall disease risk. Certain ethnicities (e.g. Asian/African) have a 2-4x increased risk of developing the condition.

Answer 70

Importantly, T2DM is considered a polygenic disease with numerous genetic variants contributing to overall disease risk. Certain ethnicities (e.g. Asian/African) have a 2-4x increased risk of developing the condition.

Question 71

Environmental risk factors have a significant impact on the development of T2DM. Obesity and inactivity account for the majority of this risk (80-85%). Obesity is associated with insulin resistance and the metabolic syndrome.

Other major environmental risk factors include: (5)

Answer 71

Poor dietary habit (low fibre, high glycemic index diet)
Low birth weight
Medications
Polycystic ovarian syndrome
History of GDM

Question 72

The two principle mechanisms involved in the development of T2DM are peripheral insulin resistance and inadequate insulin secretion.

Answer 72

It has long stood that peripheral insulin resistance was at the centre of T2DM. The importance of reduced insulin secretion and beta-cell dysfunction in the pathophysiology is now acknowledged.

Question 73

During normal control of glucose homeostasis, the release of insulin following ingestion of a meal leads to the uptake of glucose into cells (peripheral muscle).

Insulin is able to bind to insulin receptors on the cell surface. Binding leads to a number of downstream responses including effects on lipid metabolism, protein metabolism and cellular growth. In general, these are anabolic effects that:

Answer 73

Inhibit proteolysis and lipolysis
Inhibit hepatic gluconeogenesis
Promotes hepatic glycogen synthesis

Question 74

Activation of the insulin receptor also initiates translocation of the glucose receptor GLUT-… (found in the cytosol of adipose and striated muscle) to the cell surface. This allows movement of glucose intracellularly.

Answer 74

Activation of the insulin receptor also initiates translocation of the glucose receptor GLUT-4 (found in the cytosol of adipose and striated muscle) to the cell surface. This allows movement of glucose intracellularly.

Question 75

As hyperglycaemia develops, the beta cells within the Islets of Langerhans must secrete more insulin to deal with the increase in glucose leading to hyperinsulinaemia. These high levels of insulin are still inadequate to restore glucose homeostasis. It is thought that high glucose levels (and lipids) are toxic to beta cells leading to a depletion in their cellular mass. This is termed …. During autopsy, patients with T2DM have shown to have deposition of amyloid within islet cells supporting the idea of beta cell depletion.

Answer 75

As hyperglycaemia develops, the beta cells within the Islets of Langerhans must secrete more insulin to deal with the increase in glucose leading to hyperinsulinaemia. These high levels of insulin are still inadequate to restore glucose homeostasis. It is thought that high glucose levels (and lipids) are toxic to beta cells leading to a depletion in their cellular mass. This is termed glucotoxicity. During autopsy, patients with T2DM have shown to have deposition of amyloid within islet cells supporting the idea of beta cell depletion.

Question 76

Clinical features of T2DM

Answer 76

Patients may complain of lethargy, polyuria, polydipsia, weight loss, and recurrent infections (e.g. thrush, balanitis) or be picked up on routine testing.

Question 77

Diagnosis of T2DM

Answer 77

The major diagnostic tool in T2DM is the measurement of glycated haemoglobin (HbA1c).

Question 78

HbA1c (glycated haemoglobin) is measured in the blood and reflects the average blood glucose concentration over a … month period (the average survival time of an erythrocyte). Glycated haemoglobin occurs due to non-enzymatic irreversible modification of the beta globin chain in haemoglobin. As blood glucose levels increase the amount of glycation of haemoglobin also increases.

Answer 78

HbA1c (glycated haemoglobin) is measured in the blood and reflects the average blood glucose concentration over a three month period (the average survival time of an erythrocyte). Glycated haemoglobin occurs due to non-enzymatic irreversible modification of the beta globin chain in haemoglobin. As blood glucose levels increase the amount of glycation of haemoglobin also increases.

Question 79

In general, the diagnosis of diabetes is made if the level of HbA1c is ≥ … mmol/mol (6.5%), which correlates with an average blood glucose level of 7.8 mmol/L. Patients with a level between 42-47 mmol/mol (6-6.4%) are at risk of developing diabetes and said to be ‘pre-diabetic’. Importantly, the use of HbA1c as a diagnostic tool is dependent on whether the patient is symptomatic.

Answer 79

In general, the diagnosis of diabetes is made if the level of HbA1c is ≥ 48 mmol/mol (6.5%), which correlates with an average blood glucose level of 7.8 mmol/L. Patients with a level between 42-47 mmol/mol (6-6.4%) are at risk of developing diabetes and said to be ‘pre-diabetic’. Importantly, the use of HbA1c as a diagnostic tool is dependent on whether the patient is symptomatic.

Question 80

Patients with a level between … mmol/mol (6-6.4%) are at risk of developing diabetes and said to be ‘pre-diabetic’. Importantly, the use of HbA1c as a diagnostic tool is dependent on whether the patient is symptomatic.

Answer 80

Patients with a level between 42-47 mmol/mol (6-6.4%) are at risk of developing diabetes and said to be ‘pre-diabetic’. Importantly, the use of HbA1c as a diagnostic tool is dependent on whether the patient is symptomatic.

Question 81

If the patient is symptomatic (e.g. thirst, polyuria), then a single HbA1c reading of … mmol/mol or greater is enough to confirm the diagnosis. If the patient is asymptomatic, the diagnosis should be based on two abnormal readings (either two HbA1c readings, or one HbA1c reading and an additional test such as fasting glucose levels).

Answer 81

If the patient is symptomatic (e.g. thirst, polyuria), then a single HbA1c reading of 48 mmol/mol or greater is enough to confirm the diagnosis. If the patient is asymptomatic, the diagnosis should be based on two abnormal readings (either two HbA1c readings, or one HbA1c reading and an additional test such as fasting glucose levels).

Question 82

There are some situations in which HbA1c should be used with caution due to other co-morbidities. In general, conditions interrupting … (e.g. EPO use, iron-deficiency), haemoglobin structure (e.g. haemoglobinopathies), .. (e.g. CKD, alcoholism), or red cell survival (e.g. haemolysis, splenectomy) will effect the level of HbA1c. In these situations, the HbA1c should be used with caution or an alternative test used (e.g. fasting glucose).

Answer 82

There are some situations in which HbA1c should be used with caution due to other co-morbidities. In general, conditions interrupting erythropoiesis (e.g. EPO use, iron-deficiency), haemoglobin structure (e.g. haemoglobinopathies), glycation (e.g. CKD, alcoholism), or red cell survival (e.g. haemolysis, splenectomy) will effect the level of HbA1c. In these situations, the HbA1c should be used with caution or an alternative test used (e.g. fasting glucose).

Question 83

Normal fasting glucose levels should be approximately …

Answer 83

Normal fasting glucose levels should be approximately 4-6 mmol/L.

Question 84

Fasting plasma glucose levels

Answer 84

The diagnosis of diabetes can be made if the fasting glucose levels are ≥ 7 mmol/L on two separate readings in a patient who is asymptomatic or a single reading if the patient is symptomatic. As discussed above, ‘two readings’ may be two fasting glucose measurements or one fasting glucose measurement and one HbA1c.

Patients with a fasting glucose level between 6-6.9 mmol/L are said to have impaired fasting glucose (IFG), which is a marker of pre-diabetes and increases the risk of developing overt diabetes.

Question 85

Patients with a fasting glucose level between …/L are said to have impaired fasting glucose (IFG), which is a marker of pre-diabetes and increases the risk of developing overt diabetes.

Answer 85

Patients with a fasting glucose level between 6-6.9 mmol/L are said to have impaired fasting glucose (IFG), which is a marker of pre-diabetes and increases the risk of developing overt diabetes.

Question 86

A random blood glucose level ≥ … mmol/L is indicative of diabetes. This measurement is not currently used in the diagnosis of the condition.

Patients with a high random plasma glucose should be assessed for potential complications (e.g. HHS, DKA) and concurrent illness. Concurrent illnesses can increase plasma glucose levels as part of the normal physiological stress response. Patients with high levels should undergo further testing (e.g. HbA1c or fasting glucose levels).

Answer 86

A random blood glucose level ≥ 11.1 mmol/L is indicative of diabetes. This measurement is not currently used in the diagnosis of the condition.

Patients with a high random plasma glucose should be assessed for potential complications (e.g. HHS, DKA) and concurrent illness. Concurrent illnesses can increase plasma glucose levels as part of the normal physiological stress response. Patients with high levels should undergo further testing (e.g. HbA1c or fasting glucose levels).

Question 87

Oral glucose tolerance test

Answer 87

The oral glucose tolerance test (OGTT) measures the ability of the body to deal with a glucose load over a two hour period. Its use has largely been replaced by HbA1c in clinical practice.

The OGTT firstly involves the patient fasting (usually overnight). A glucose measurement can then be taken at time 0 hrs. The patient is then given a 75 g glucose load. Traditionally, a blood sample for glucose is then taken at 2 hours. Levels greater than 11 mmol/L at 2 hours are suggestive of diabetes. Levels ≥ 7.8 mmol/L but < 11.1 mmol/L are suggestive of impaired glucose tolerance (IGT).

The OGTT is usually reserved for assessment of gestational diabetes. It should be noted that NICE produced updated guidelines on the diagnosis of gestational diabetes where the values for diagnosis are set much lower than in non-pregnant patients.

Question 88

Management - T2DM

Answer 88

The management of T2DM requires education, lifestyle changes, medications and the monitoring of complications.

Question 89

Lifestyle advice - T2DM

Answer 89

Lifestyle modifications may be the earliest changes instigated in patients with or at risk of developing diabetes (e.g. HbA1c 42-47 mmol/mol). It is essential that these modifications continue once antidiabetic medications are introduced. Lifestyle advice can help patients achieve sustained weight loss, better physical fitness, improved diet and ultimately improved glycaemic control.

Question 90

Lifestyle advice - T2DM

Answer 90

Patients should be encouraged to maintain a healthy balanced diet with plenty of fibre, low-index carbohydrate and controlling the intake of high-fat foods. In those with excess body weight, dietary plans can help with weight loss, targeted plans may be appropriate.

Exercise can lower blood glucose levels as it increases glucose use by muscles. Patients should be informed about the UK physical fitness guidelines and encouraged to exercise daily with at least 150 minutes of moderate intensity activity over a weekly period.

Patients should be encouraged to reduce alcohol consumption and stop smoking. Alcohol increases weight and may exacerbate or prolong hypoglycaemia induced by antidiabetic medications. Smoking cessation advice should be made available and offered to all patients with T2DM.

Question 91

Exercise - T2DM

Answer 91

Exercise can lower blood glucose levels as it increases glucose use by muscles. Patients should be informed about the UK physical fitness guidelines and encouraged to exercise daily with at least 150 minutes of moderate intensity activity over a weekly period.

Question 92

Alcohol and smoking - T2DM

Answer 92

Patients should be encouraged to reduce alcohol consumption and stop smoking. Alcohol increases weight and may exacerbate or prolong hypoglycaemia induced by antidiabetic medications. Smoking cessation advice should be made available and offered to all patients with T2DM.

Question 93

Antidiabetic drugs T2DM

Answer 93

Metformin is one of the most commonly used medications in T2DM. Metformin is a biguanide, which lowers blood glucose levels through inhibition of hepatic gluconeogenesis whilst increasing peripheral insulin sensitivity and enhancing peripheral uptake of glucose. All patients with T2DM should be started on metformin unless contraindicated (e.g. CKD, those at risk of lactic acidosis, poorly tolerated).

Question 94

Metformin is a …, which lowers blood glucose levels through inhibition of hepatic gluconeogenesis whilst increasing peripheral insulin sensitivity and enhancing peripheral uptake of glucose. All patients with T2DM should be started on metformin unless contraindicated (e.g. CKD, those at risk of lactic acidosis, poorly tolerated).

Answer 94

Metformin is a biguanide, which lowers blood glucose levels through inhibition of hepatic gluconeogenesis whilst increasing peripheral insulin sensitivity and enhancing peripheral uptake of glucose. All patients with T2DM should be started on metformin unless contraindicated (e.g. CKD, those at risk of lactic acidosis, poorly tolerated).

Question 95

All patients with T2DM should be started on metformin unless contraindicated - list these

Answer 95

e.g. CKD, those at risk of lactic acidosis, poorly tolerated

Question 96

Step 1 T2DM management

Answer 96

Standard release metformin
Aim for HbA1c < 48 mmol/mol, increasing dose as needed
Monitor renal function, consider modified-release preparations if develop adverse GI effects

Question 97

Step 2 T2DM management

Answer 97

Consider dual antidiabetic therapy if HbA1c rises > 58 mmol/L
Metformin in combination with a second antidiabetic agent:
Sulfonylurea (SU)
Dipeptidyl peptidase-4 inhibitor (DPP-4i)
Pioglitazone
Sodium–glucose cotransporter 2 inhibitor (SGLT-2i)
Aim for HbA1c < 53 mmol/mol

Question 98

Step 3 - T2DM treatment

Answer 98

Step 3 - Consider dual antidiabetic therapy if HbA1c rises > 58 mmol/L
Metformin in combination with a second antidiabetic agent:
Sulfonylurea (SU)
Dipeptidyl peptidase-4 inhibitor (DPP-4i)
Pioglitazone
Sodium–glucose cotransporter 2 inhibitor (SGLT-2i)
Aim for HbA1c < 53 mmol/mol

Question 99

Step 4 T2DM management

Answer 99

In patients on triple antidiabetic therapy and ongoing poor glucose control, consider further intensification
Consider combination treatment with metformin, SU and glucagon-like peptide-1 (GLP-1) mimetic
It should be noted there are strict criteria for the use of a GLP-1 analogue and patients must achieve certain glycemic and weight targets to warrant continuing the medication
If already on an insulin-based regime, seek specialist advice

Question 100

If metformin is contraindicated an alternative treatment ladder is used.

Answer 100

Question 101

Insulin-based regimens - T2DM

Answer 101

The use of insulin should be considered early in the management of patients with T2DM. It is usually considered in patents with poor glycemic control despite dual antidiabetic with metformin and another agent.

Insulin therapy may not be appropriate for those at significant risk of hypoglycaemia, a personal preference against insulin or concerns relating to licensing for driving group 2 vehicles. Obese patients may find insulin may exacerbate weight issues, its use should be avoided where possible.

Question 102

Insulin therapy should be initiated by healthcare professionals experienced with the use of insulin. There are a number of insulin regimes that may be used in patients with T2DM:

Answer 102

Once or twice daily intermediate-acting insulin (NPH)
Intermediate-acting insulin along-side a short-acting insulin as separate injections or a pre-mixed formula
Once daily long-acting insulin therapy (glargine, determir)
Basal-bolus regimes

Question 103

In general, patients are offered an intermediate-acting insulin therapy such as NPH in the initial stages. If glycemic control is particularly bad (e.g. HbA1c > 75 mmol/L) patients may be started on mixed insulin (intermediate and short-acting). Long-acting insulin is usually reserved for patients where hypoglycaemia is a problem with NPH insulin or the patients rely on carers for help with their injections. Finally, patients on a pre-mixed insulin regime that still have inadequate blood glucose control should be assessed for conversion to a basal bolus regime.

Answer 103

In general, patients are offered an intermediate-acting insulin therapy such as NPH in the initial stages. If glycemic control is particularly bad (e.g. HbA1c > 75 mmol/L) patients may be started on mixed insulin (intermediate and short-acting). Long-acting insulin is usually reserved for patients where hypoglycaemia is a problem with NPH insulin or the patients rely on carers for help with their injections. Finally, patients on a pre-mixed insulin regime that still have inadequate blood glucose control should be assessed for conversion to a basal bolus regime.

Question 104

Treatment targets for patients with T2DM are largely based on serial measurements of HbA1c.

Patients with poor glycaemic control require measurement of the HbA1c every 3 months. Patients with stable disease can have their HbA1c measured every 6 months.

The main treatment targets are shown below:

Answer 104

The main treatment targets are shown below:

Management with lifestyle modifications only: aim HbA1c < 48 mmol/mol
Management with lifestyle and a single antidiabetic agent: aim HbA1c < 48 mmol/mol
Management with a drug associated with hypoglycaemia (e.g. SU): aim HbA1c < 53 mmol/mol
Management with higher intensification regimes: aim HbA1c < 53 mmol/mol

Question 105

If HbA1c levels are not adequately controlled by a single drug and rise to ≥ 58 mmol/mol, then intensification of medical therapy should be considered. Additionally, reinforcement about dietary advice, lifestyle changes, adherence to medical treatment should be completed to support patients in achieving a HbA1c < … mmol/mol.

Answer 105

If HbA1c levels are not adequately controlled by a single drug and rise to ≥ 58 mmol/mol, then intensification of medical therapy should be considered. Additionally, reinforcement about dietary advice, lifestyle changes, adherence to medical treatment should be completed to support patients in achieving a HbA1c < 53 mmol/mol.

Question 106

Finally, on annual basis patients should be screened for major complications of diabetes:

Answer 106

Retinopathy: annual retinal screening and eye check
Nephropathy: renal function (eGFR) and albumin:creatinine ratio (ACR)
Neuropathy and diabetic foot: assessment for peripheral neuropathy, autonomic neuropathy, full examination including footwear, monofilament assessment of neuropathy, vascular assessment +/- dopplers.
Cardiovascular risk factors: primary/secondary prevention strategy with optimisation of blood pressure and lipids.

Question 107

Every …-…., patients should have their HbA1c checked and management changed according

Answer 107

Every 3-6 months, patients should have their HbA1c checked and management changed accordingl

Question 108

The two major acute diabetic complications seen in patients with T2DM are …

Answer 108

The two major acute diabetic complications seen in patients with T2DM are hypoglycaemia and hyperosmolar hyperglycaemic state (HHS).

Question 109

T2DM - HHS vs DKA?

Answer 109

It is worth noting that some patients with T2DM are also at risk of developing diabetic ketoacidosis (DKA) due to beta cell dysfunction and a lack of insulin secretion. Patients presenting unwell with type 2 diabetes mellitus should be assessed for DKA (e.g. urinary/plasma ketone levels, pH and bicarbonate) and treated accordingly. Both HHS and DKA are associated with significant mortality if not treated promptly and the reasons for developing these conditions should be explored with the patient during admission (i.e. non-adherence to treatment, intercurrent illness).

Question 110

T2DM - eyes

Answer 110

Diabetic retinopathy is one of the major eye-related disorders that can occur in patients with diabetes. More than 95% of patients will have detectable changes after 20 years. Other disorders include cataracts and ocular palsies. When diagnosed with T2DM, GPs should immediately refer for eye screening.

Question 111

… … is one of the most common causes of chronic and end-stage kidney disease.

Answer 111

Diabetic nephropathy is one of the most common causes of chronic and end-stage kidney disease.

Question 112

Additional considerations are now recommended for the prescription of sodium-glucose transport protein 2 (SGLT2) inhibitors to patients with T2DM and CKD:

Answer 112

Additional considerations are now recommended for the prescription of sodium-glucose transport protein 2 (SGLT2) inhibitors to patients with T2DM and CKD:

Consider an SGLT2 if ACR 3-30 mg/mmol
Offer an SGLT2 if ACR > 30 mg/mmol