Type 2 Diabetes

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Introduction

Type 2 diabetes mellitus (T2DM) is a common and complex metabolic disease characterised by insulin resistance and subsequent high blood glucose levels (hyperglycaemia).

Its complications are severe and affect multiple organ systems, causing cardiovascular disease (CVD), kidney disease, neuropathy and retinopathy.

Over 5 million people in the UK have diabetes^, and 90% of these cases are due to T2DM.^1,2 The NHS spends 10% of its annual budget on diabetes (over £10 billion), making it a major priority in terms of treatment and prevention.³

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Aetiology

The pathophysiology of T2DM centres around insulin resistance, which is a complex process that has been simplified here.

Normally, plasma glucose levels are tightly regulated by the hormone insulin. Upon eating carbohydrate foods (containing sugar), plasma glucose levels rise. In response, the pancreas secretes insulin to bring glucose levels down by promoting uptake into organs such as the liver and skeletal muscle. 

In T2DM, chronic high insulin levels (chronic hyperinsulinaemia) from excess dietary sugar intake (and other factors such as obesity) cause these organs to develop resistance to the effects of insulin, meaning that more insulin is needed to lower glucose to the same degree. This leads to chronic hyperglycaemia.⁴

Initially, insulin levels remain very high to try to “override” the resistance. However, as the condition progresses, the pancreas begins to “tire” and stops producing insulin. Insulin deficiency is the end-stage of T2DM – unlike in type 1 diabetes, where it is the main pathology (autoimmune destruction of insulin-producing of pancreatic beta-islet cells).⁴

Complications of diabetes result from glucose-related damage to blood vessels supplying vital organs. Hyperinsulinaemia also promotes weight gain (insulin is a “storage” hormone which prevents breakdown of adipose tissue) and hyperglycaemia increases the risk of infection/inflammation.⁴

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Risk factors

Risk factors for developing T2DM include non-modifiable factors, modifiable factors and specific conditions.⁶

Non-modifiable risk factors

Non-modifiable risk factors include:

• Age: >40 years old, although now being seen more in younger people
• Sex: slightly more common in men than women
• Ethnicity: South Asian, Black African and Black-Caribbean groups have a higher risk
• Family history: especially having first-degree relatives with T2DM

Modifiable risk factors

Modifiable risk factors include:

• Obesity: encompasses increased body mass index (BMI)/waist circumference, sedentary lifestyle and consumption of processed carbohydrate/sugary foods. 
• Alcohol excess: beer and cocktails are high in calories and sugar, and alcoholism causes liver damage, which reduces the hepatic uptake of glucose. 
• Smoking: a potent CVD risk factor itself and also associated with insulin resistance.
• Poor sleep/stress: both promote insulin resistance and increase hyperglycaemia through chronically raised cortisol levels and poor dietary/exercise habits.

Medical conditions

Specific medical conditions which increase the risk of T2DM include:^6,7,8

• Polycystic ovarian syndrome (PCOS): causes insulin resistance related to high androgen levels
• Gestational diabetes mellitus (GDM): diabetes in pregnancy usually resolves post-partum but has a high lifetime of developing T2DM
• Mental health conditions and related medications (antipsychotics)
• Steroid-induced diabetes: increases liver gluconeogenesis (production of glucose) and insulin resistance

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Clinical features

History

The classic symptom triad of diabetes occurs due to insulin deficiency (“osmotic” symptoms), which occurs more in type 1 diabetes than type 2 diabetes:

• Polyuria (excess urinary volume): kidneys filter out more glucose into the urine, which, due to an osmotic effect, causes water to follow (osmotic diuresis)
• Polydipsia (excess thirst) 
• Unintentional weight loss 

Other common symptoms include:

• Tired all the time (TATT)
• Frequent/resistant infections, especially genitourinary infections such as urinary tract infection (UTI) & thrush due to glycosuria (glucose in urine) 
• Poor-healing wounds 
• Blurred vision (from diabetic eye complications such as retinopathy) 

Many with T2DM are asymptomatic and are diagnosed incidentally on routine blood tests or during hospital admission after a complication (such as stroke or myocardial infarction (MI)).

Clinical examination

T2DM without complications may not have any physical signs. Raised BMI and waist circumference are common, while more specific signs of insulin resistance, such as acanthosis nigricans (darkened, thickened skin in folds/creases), are rare.

Clinical examination findings may be caused by complications of diabetes, including:

• Diabetic retinopathy on fundoscopy
• Evidence of diabetic neuropathy and peripheral vascular disease on foot examination
• Evidence of renal replacement therapy (e.g. arteriovenous fistula or renal transplant scar) 

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Differential diagnoses

The symptoms of T2DM overlap with many conditions.

Polyuria and/or polydipsia can also be caused by  

• Diabetes insipidus (DI): anti-diuretic hormone (ADH) deficiency causing increased water loss from the kidneys
• Diuretics
• Psychogenic polydipsia 

Tired all the time (TATT) has a wide differential, which includes conditions such as 

• Anaemia
• Hypothyroidism
• Chronic kidney disease (CKD)
• Heart failure
• Malignancy
• Obstructive sleep apnoea (OSA)
• Depression/anxiety

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Investigations

Bedside investigations

Bedside tests are not diagnostic but can be suggestive of the condition or complications.

Capillary blood glucose (“BM”)

Measured by a fingerprick test. BM stands for Boehringer Mannheim (the original pharmaceutical company involved).

Normal BM ranges (mmol/L):¹⁰

• Pre-meal = 4-5.9
• 2 hours post-meal = ≤7.8

Urine dipstick (urinalysis)

Urinary glucose (glycosuria) is common.

Urinary ketones (ketonuria) in an unwell patient can indicate diabetic ketoacidosis (DKA), an acute life-threatening complication of insulin deficiency (usually in type 1 diabetes).

Urinary protein (proteinuria) can indicate diabetic nephropathy.

Laboratory investigations

HbA1C

The primary blood test to diagnose and monitor T2DM is HbA1C (glycosylated haemoglobin).¹¹

HbA1c is a measure of average blood glucose concentration (using glucose bound to haemoglobin/Hb) as a surrogate marker) in the preceding 3 months (average lifespan of a red blood cell/RBC). It cannot be used in circumstances where Hb is abnormal (e.g. haemoglobinopathies) or where RBCs are broken down early (e.g. haemolytic anaemia).

Alternative tests include the original fasting or random plasma venous glucose (PVG) test or serum fructosamine.¹¹

Other blood tests

Other important blood tests include:¹¹

• Urea & electrolytes (U&E): to assess renal function, which can be impaired by diabetic nephropathy and certain diabetic medications (e.g. metformin).
• Liver function tests (LFT): can indicate fatty liver disease, which is associated with T2DM and metabolic syndrome (also a useful baseline as some anti-diabetic medications can interfere with liver function)
• Cholesterol/lipids: dyslipidaemia commonly co-exists with T2DM and is another important CVD risk factor

Urine albumin-creatinine ratio (UACR)

Urine albumin-creatinine ratio (UACR) is an early morning urine sample which detects microalbuminuria (albumin in urine) and compares it with creatinine (a normal urinary waste product).

In diabetic nephropathy, glomerular basement membrane damage allows small proteins like albumin to leak abnormally through the filtration system into the urine – leading to a raised UACR. This can be an early indicator kidney damage related to diabetes.¹²

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Diagnosis

T2DM is diagnosed with a HbA1C ≥48mmol/mol¹¹

• If symptomatic then just 1 result is sufficient
• If asymptomatic then repeat HbA1C in 2 weeks, and if also ≥48mmol/mol, then the diagnosis is confirmed

Plasma venous glucose (PVG) was previously used for diagnosis, and the below criteria are useful to remember (repeat a second test if asymptomatic).

Table 1. Interpretation of plasma venous glucose.

Test	Interpretation
Fasting PVG (mmol/L)	≥7 = T2DM · 6.1-6.9 = Impaired fasting glucose (a form of pre-diabetes)
Random PVG (mmol/L)	≥11.1 = T2DM 7.9-11.0 = Impaired glucose tolerance (a form of pre-diabetes) if done as part of an oral glucose tolerance test (OGTT)
Oral glucose tolerance test (OGTT)	A fasting sample is taken (diagnosis as above) and then the patient is given a sugary drink (containing 75g glucose). Further sample after 2 hours and the thresholds above are used to determine T2DM or impaired glucose tolerance. Now only done in specific situations (e.g. diagnosis of GDM)14

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Management

Lifestyle

Modification of lifestyle plays a central role. Weight loss of >5% body weight (or more if obese) can put T2DM into remission or prevent the development of T2DM in >50% of those with pre-diabetes.¹⁵

Structured education on the following factors are important:

• Diet: improved glycaemic control can be achieved with diets low in sugar, especially with low carbohydrate and low ultra-processed food diets. These diets improve insulin resistance and promote weight loss. Low-calorie diets (800-1500kcal/day) can lead to significant weight loss and rapid reversal of T2DM, forming the basis for the NHS Type 2 Diabetes Path to Remission Programme.^15,16
• Exercise: increased physical activity such as walking, high-intensity cardio and resistance training can improve insulin resistance. Aiming for ≥2.5 hours of physical activity a week is recommended. Muscle mass is particularly important for the uptake of plasma glucose (stored as glycogen).¹⁷
• Reducing alcohol consumption (<14 units/week), stopping smoking, and improving sleep and stress are also important changes.

Anti-diabetic drugs

It is common for newly diagnosed patients to undergo a period of lifestyle change. However, if HbA1C remains elevated or complications develop, then oral drug treatment is usually offered.

Metformin is the first-line drug, but beyond this, the next choices depend on individual patient circumstances and risk profiles. These are summarised below:¹⁸  

Table 2. A summary of anti-diabetic drugs

Drug	Mechanism	Side-effects/risks
Metformin	1st line drug for T2DM in the biguanide family, which works to Reduce insulin resistance of target cells (better uptake of glucose) Reduce liver gluconeogenesis (stops liver glycogen being converted back to plasma glucose)	GI upset – changing to modified-release (MR) preparation can improve this Do not use in renal failure (eGFR <45ml/min) or post-MI due to the risk of lactic acidosis (pause when acutely dehydrated for the same reason) Does not cause hypoglycaemia (does not increase insulin)
SGLT-2 inhibitors	e.g. Dapagliflozin/empagliflozin, which have become 2nd line due to cardio/reno-protective effects and works to Reduce renal glucose reabsorption (inhibits sodium-glucose cotransporter 2) so more glucose is excreted in the urine to reduce hyperglycaemia	Euglycaemic diabetic ketoacidosis (DKA) is a rare but serious side-effect – glucose levels are normal (rather than elevated) due to excess loss of glucose in urine UTI and genital thrush are common due to glycosuria Does not cause hypoglycaemia by itself and should be paused in acute illness (like metformin)
Sulfonylureas	e.g. Gliclazide which is an older drug which works to Increase endogenous insulin secretion by stimulating pancreatic β-islet cells Causes rapid reduction in HbA1C and is useful if osmotic symptoms	Hypoglycaemia (due to increasing insulin secretion) Weight gain Abnormal LFTs (cholestasis) Hyponatraemia (syndrome of inappropriate ADH secretion – SIADH)
DPP4 inhibitors	e.g. Sitagliptin/Linagliptin which increase the “incretin” effect Gut hormones like glucose-like-peptide-1 (GLP-1) to provoke extra insulin release post-meal These drugs block dipeptidyl peptidase-4 which normally breaks down GLP-1, increasing the insulin release effect	Does not cause hypoglycaemia Weight-neutral Can cause pancreatitis While having fewer side effects, they also have less effect in reducing HbA1C compared with other options.
GLP-1 analogues	e.g. Liraglutide, Semaglutide which are newer subcutaneous (SC) injections which Also work on the “incretin effect” to enhance GLP-1 action Major weight loss effect (only used in obese patients) with specific criteria for continuation	Significant weight loss Does not cause hypoglycaemia Can cause pancreatitis International shortage makes them harder to access currently, especially with increasing media coverage over the benefits for rapid weight loss.
Other less-used options	Thiazolidinediones (e.g. Pioglitazone) increase insulin sensitivity but are less used due to side effects like haemorrhagic cystitis (increased risk of bladder cancer), deranged LFTs, weight gain and fluid retention (worsening of heart failure). Acarbose (alpha-glucosidase inhibitor) slows down GI absorption of starchy carbohydrates, reducing the intensity of glucose (and insulin) spikes post-meal, but can cause significant GI upset (abdominal cramps, flatulence and diarrhoea)

HbA1C targets and thresholds

HbA1C targets should be individualised (e.g. a younger patient with signs of early complications or diagnosis <10 years ago may have stricter targets, whereas an older patient at risk of falls and polypharmacy may have relaxed targets).

Table 3. A general guide to HbA1c targets. 

Situation	HbA1C (mmol/mol)
On lifestyle or metformin alone	≤48
On >1 drug or any drug causing hypoglycaemia	≤53
Intervention threshold for starting a 2nd drug (if on metformin) or a 3rd drug (triple therapy) if already on 2 drugs	≥58

Insulin

If the above treatment fails (i.e. already on “triple therapy” or established complications) or rapid control is required (e.g. due to very high HbA1C or osmotic symptoms), then subcutaneous insulin injections may be needed.²⁰

Insulin is the mainstay treatment for type 1 diabetes, which is a disease of insulin deficiency from the start, whereas in T2DM, insulin deficiency occurs much later.

Insulin comes in many forms and is often started as a twice-daily intermediate-acting preparation (unlike the traditional “basal-bolus” regimen used in type 1 diabetes), alongside metformin.

The main risks of insulin are hypoglycaemia and weight gain. Lipodystrophy from recurrent subcutaneous injections can also occur.

BM monitoring is important; however, new technologies such as continuous glucose monitoring (CGM) and insulin pumps have become more widely available.

Cardiovascular risk reduction

It is important to optimise other CVD risk factors (such as hypertension, hyperlipidaemia, and CKD) to prevent MI and stroke, and these aspects link closely with one another.

CVD risk calculators (such as QRISK3, which calculates the 10-year risk of having a cardiovascular event) are used to assist with this.

Hypertension, microalbuminuria and CKD¹⁹

Target BP in T2DM is <140/90mmHg in clinic (<135/85mmHg for home/ambulatory monitoring)

The first-line drug treatment is ACE inhibitors (ACE) (e.g. ramipril) or angiotensin receptor blockers (ARB) (e.g. losartan) regardless of age

If there is CKD (with microalbuminuria), then tighter control may be needed.

Table 4. Management of microalbuminuria. 

UACR (mg/g)	Management
>3	Should be on ACE or ARB regardless of BP (even if normotensive)
>30	If on the maximum dose of ACE/ARB add in dapagliflozin (SGLT-2)
>70	Stricter BP target <130/80mmHg in clinic (or <125/75mmHg at home or ambulatory monitoring) and refer to renal specialist

Cholesterol and statins¹⁹

Any patient with T2DM with QRISK >10% should be offered a statin (atorvastatin 20mg) as primary prevention of CVD.

If an MI/stroke occurs, then a high-intensity statin (80mg atorvastatin) should be started as secondary prevention.

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Complications

The complications of T2DM occur primarily due to vascular damage caused by hyperglycaemia and can be split into macrovascular and microvascular.²¹

Macrovascular (large vessel) complications include:

• Myocardial infarction (MI) and associated ischaemic heart disease (IHD)
• Stroke or transient ischaemic attack (TIA) and associated cerebrovascular disease
• Peripheral vascular disease (PVD) causing intermittent claudication and critical limb ischaemia, with an associated risk of infection, ulceration, necrosis and amputation (“Diabetic foot”)

Microvascular (small vessel) complications include:

• Diabetic nephropathy causing CKD, initially starting with microalbuminuria, progressing to end-stage renal disease
• Diabetic retinopathy causing visual loss and blindness – requires annual screening
• Diabetic neuropathy causing peripheral nerve damage and with PVD increases risk of infection, trauma, ulceration and amputation (“Diabetic foot”)

Other complications related to diabetes include Charcot’s foot/arthropathy (red hot swollen foot with osteolysis and deformity), frozen shoulder, carpal tunnel syndrome and De Quervain’s tenosynovitis.

Implications for driving

^{The DVLA has specific driving regulations for diabetes, which depend on whether the patient holds a Group 1 (normal car) or Group 2 (Heavy Goods Vehicle/HGV) license.23}

If T2DM is managed with lifestyle alone or medications that do not cause hypoglycaemia, the DVLA does not need to be informed. However, for those on hypoglycaemic drugs (gliclazide, insulin), the DVLA should be informed, and specific criteria will be assessed to decide whether they are fit to drive.

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Key points

• T2DM is a complex multi-organ disease caused by hyperglycaemia related to insulin resistance, with obesity and family history playing an important role
• HbA1C is the main test for diagnosis, and other important tests include measurement of BP, BMI, UACR, U&E and lipids to assess risk of cardiovascular disease
• Management involves lifestyle change, especially weight loss, and anti-diabetic drugs such as metformin, dapaglifozin and gliclazide. Insulin is a last resort.
• Complications include CVD, nephropathy, retinopathy and neuropathy and should be assessed annually. There may be implications for driving.

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Reviewer

Professor Parth Narendran

Consultant Diabetologist

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Editor

Dr Chris Jefferies

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References

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