11/14/24, 10\:39 AM Type 2 Diabetes

Type 2 Diabetes

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A comprehensive topic overview

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 a
neuropathy and retinopathy.
, 1,2
Over 5 million people in the UK have diabetes and 90% of these cases are due to T2DM. 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

Aetiology

The pathophysiology of T2DM centres around insulin resistance, which is a complex process that has been simpli
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 e
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 de
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/in
4
Figure 1. Schematic diagram showing e
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Risk factors

Risk factors for developing T2DM include non-modi
6
Non-modi
Non-modi
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
Modi
Modi
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
Speci
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

Clinical features

History

The classic symptom triad of diabetes occurs due to insulin de
diabetes than type 2 diabetes\:
Polyuria (excess urinary volume)\: kidneys
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 speci
Clinical examination
Diabetic retinopathy on fundoscopy
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Evidence of diabetic neuropathy and peripheral vascular disease on foot examination
Evidence of renal replacement therapy (e.g. arteriovenous
Figure 2. Acanthosis nigricans.
9

Di

The symptoms of T2DM overlap with many conditions.
Polyuria and/or polydipsia can also be caused by
Diabetes insipidus (DI)\: anti-diuretic hormone (ADH) de
Diuretics
Psychogenic polydipsia
Tired all the time (TATT) has a wide di
Anaemia
Hypothyroidism
Chronic kidney disease (CKD)
Heart failure
Malignancy
Obstructive sleep apnoea (OSA)
Depression/anxiety

Investigations

Bedside investigations

Bedside tests are not diagnostic but can be suggestive of the condition or complications.
Capillary blood glucose ("BM")
Measured by a
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 de
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).
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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
to diabetes.
12

Diagnosis

T2DM is diagnosed with a HbA1C ≥48mmol/mol
11
If symptomatic then just 1 result is su
If asymptomatic then repeat HbA1C in 2 weeks, and if also ≥48mmol/mol, then the diagnosis is con
Prediabetes (non-diabetic hyperglycaemia)
A condition where there is hyperglycaemia that does not reach the above threshold but has a signi
risk of progression to T2DM along with risks of complications – this is de
13
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 speci
GDM)
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Management

Lifestyle

Modi
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 signiNHS 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 o
Metformin is the
pro
18
Table 2. A summary of anti-diabetic drugs
Drug Mechanism Side-e
Metformin
SGLT-2
inhibitors
st
1 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)
e.g. Dapagli
nd
2 line due to cardio/reno-protective e
works to
Reduce renal glucose reabsorption (inhibits
sodium-glucose cotransporter 2) so more glucose
is excreted in the urine to reduce hyperglycaemia
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
GI upset - changing to modi
(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)
Euglycaemic
diabetic ketoacidosis (DKA)
is a rare but serious side-e
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)
Hypoglycaemia (due to increasing insulin
secretion)
Weight gain
Abnormal LFTs
(cholestasis)
Hyponatraemia
(syndrome of inappropriate ADH secretion
– SIADH)
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DPP4
inhibitors
GLP-1
analogues
Other less-
used options
e.g. Sitagliptin/Linagliptin which increase the
“incretin” e
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 e
e.g. Liraglutide, Semaglutide which are newer
subcutaneous (SC) injections which
Also work on the “incretin e
action
Major weight loss e
patients) with speci
Does not cause hypoglycaemia
Weight-neutral
Can cause
pancreatitis
While having fewer side e
have less e
compared with other options.
Signi
Does not cause hypoglycaemia
Can cause p
ancreatitis
International shortage makes them harder
to access currently, especially with
increasing media coverage over the
bene
Thiazolidinediones (e.g. Pioglitazone) increase insulin sensitivity but are less used due to side
e
and
Acarbose (alpha-glucosidase inhibitor) slows down GI absorption of starchy carbohydrates,
reducing the intensity of glucose (and insulin) spikes post-meal, but can cause signi
(abdominal cramps,

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 2 nd rd
drug (if on metformin) or a 3 already on 2 drugs
drug (triple therapy) if
≥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 de
T2DM, insulin de
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

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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 CKD
19
Target BP in T2DM is \<140/90mmHg in clinic (\<135/85mmHg for home/ambulatory monitoring)
The
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)
If on the maximum dose of ACE/ARB add in dapagli
>30
(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 statins
19
Any patient with T2DM with QRISK >10% should be o
If an MI/stroke occurs, then a high-intensity statin (80mg atorvastatin) should be started as secondary prevention.

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.
Diabetes annual review checklist22
HbA1C and individualised target (as well as compliance with medications)
Lifestyle advice and education
Bedside parameters – BMI, BP, urine dip for protein (UACR if positive)
Other lab tests – U&E, lipids & calculation of QRISK
Diabetic foot check
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Inspection for footwear, ulcers, infection, gangrene etc.
Palpation of foot pulses and capillary re
Neuropathy testing of sensation (using a 10g mono
Referral to orthotics, podiatrists and specialists may be needed
Ensure annual diabetic retinopathy screening

Implications for driving

The DVLA has speci
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 speci
criteria will be assessed to decide whether they are

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.

References

Diabetes UK. N u m b e r o f p e o p l e l i v i n g w i t h d i a b e t e s i n t h e U K t o p s 5 m i l l i o n f o r t h e LINK]
Diabetes UK. U s , d i a b e t e s a n d a l o t o f f a c t s a n d s t a t s . 2019. Available from\: [LINK]
NHS England. N H S P r e v e n t i o n P r o g r a m m e c u t s c h a n c e s o f T y p e 2 d i a b e t e s f o r t h o u s a n d s . De Fronzo et al. T y p e 2 d i a b e t e s m e l l i t u s . Nature Reviews (2015). Available from\: [LINK]
Image\: Ozhank. License\: [CC0 1.0]
Diabetes UK. D i a b e t e s r i s k f a c t o r s . Accessed 2024. Available from\: [LINK]
2022. Available from\: [LINK]
Vounzoulaki et al. P r o g r e s s i o n t o t y p e 2 d i a b e t e s i n w o m e n w i t h a k n o w n h i s t o r y o f ge s t a t i o n a l d i a b e t e s \: s y s t e m a t i c r e v i e w
a n d m e t a-a n a l y s i s . BMJ (2020). Available from\: [LINK]
Diabetes UK. S t e r o i d-i n d u c e d d i a b e t e s . Accessed 2024. Available from\: [LINK]
Image\: Mark Brady; Prashanth Rawla, License\: [CC BY-SA 4.0].
Diabetes.co.uk. N I C E r e c o m m e n d e d t a r g e t b l o o d gl u c o s e l e v e l r a n ge s ( F a c t s h e e t ) . Accessed 2024. Available from\: [LINK]
NICE CKS. D i a b e t e s – t y p e 2 . W h e n s h o u l d I s u s p e c t t y p e 2 d i a b e t e s i n a n a d u l t ? Last revised in November 2023. Available
from\: [LINK]
GP Notebook. N I C E g u i d a n c e - d i a b e t i c r e n a l d i s e a s e i n t y p e I I d i a b e t e s . Last reviewed 24 Oct 2023. Available from\: [LINK]
Diabetes UK. P r e d i a b e t e s . Accessed 2024. Available from\: [LINK]
Diabetes.co.uk. O r a l G l u c o s e T o l e r a n c e T e s t . Updated in 2023. Available from\: [LINK]
NHS England. N H S T y p e 2 D i a b e t e s P a t h t o R e m i s s i o n P r o g r a m m e . Accessed 2024. Available from\: [LINK]
Forouhi et al. D i e t a r y a n d n u t r i t i o n a l a p p r o a c h e s f o r p r e v e n t i o n a n d m a n a ge m e n t o f t y p e 2 d i a b e t e s . BMJ from\: [LINK]
(2018). Available
Colberg et al. E x e r c i s e a n d T y p e 2 D i a b e t e s . Diabetes Care (2010). Available from\: [LINK]
NICE (NG28). V i s u a l s u m m a r y o n c h o o s i n g m e d i c i n e s f o r t y p e 2 d i a b e t e s . 2022. Available from\: [LINK]
NICE CKS. D i a b e t e s - t y p e 2 \: S c e n a r i o \: M a n a g e m e n t – a d u l t s . Updated November 2023. Available from\: [LINK]
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NICE CKS. Scenario\: I n s u l i n t h e r a p y - t y p e 2 d i a b e t e s . Updated January 2021. Available from\: [LINK]
NICE CKS. D i a b e t e s - t y p e 2 \: W h a t a r e t h e c o m p l i c a t i o n s ? Updated November 2023. Available from\: [LINK]
Diabetes UK. Diabetes care to expect. Accessed 2024. Available from\: [LINK]
DVLA. D i a b e t e s a n d d r i v i n g . Accessed 2024. Available from\: [LINK]

Reviewer

Professor Parth Narendran
Consultant Diabetologist

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Contents

Introduction
Aetiology
Risk factors
Clinical features
Di
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