Type 2 diabetes is a condition where a combination of insulin resistance and reduced insulin production cause persistently high blood sugar levels.
Simplified Pathophysiology
Repeated exposure to glucose and insulin makes the cells in the body resistant to the effects of insulin. More and more insulin is required to stimulate the cells to take up and use glucose. Over time, the pancreas becomes fatigued and damaged by producing so much insulin, and the insulin output is reduced.
A high carbohydrate diet combined with insulin resistance and reduced pancreatic function leads to chronic high blood glucose levels (hyperglycaemia). Chronic hyperglycaemia leads to microvascular, macrovascular and infectious complications, as described in the type 1 diabetes section.
Risk Factors
Non-modifiable risk factors:
- Older age
- Ethnicity (Black African or Caribbean and South Asian)
- Family history
Modifiable risk factors:
- Obesity
- Sedentary lifestyle
- High carbohydrate (particularly sugar) diet
Presentation
Presenting features of diabetes include:
- Tiredness
- Polyuria and polydipsia (frequent urination and excessive thirst)
- Unintentional weight loss
- Opportunistic infections (e.g., oral thrush)
- Slow wound healing
- Glucose in urine (on a dipstick)
Acanthosis nigricans is characterised by the thickening and darkening of the skin (giving a “velvety” appearance), often at the neck, axilla and groin. It is often associated with insulin resistance.
TOM TIP: Consider type 2 diabetes in any patient fitting the risk factors above. It is easy to screen for diabetes with an HbA1c, and early treatment helps to prevent long-term complications. It is possible to reverse diabetes with the proper diet and lifestyle, especially at the pre-diabetes stage, so early detection is helpful.
Pre-Diabetes
Pre-diabetes is an indication that the patient is heading towards diabetes. They do not fit the full diagnostic criteria but should be educated about the risk of diabetes and lifestyle changes.
An HbA1c of 42 – 47 mmol/mol indicates pre-diabetes.
The HbA1c is a blood test that reflects the average glucose level over the previous 2-3 months.
Diagnosis
An HbA1c of 48 mmol/mol or above indicates type 2 diabetes.
The sample is typically repeated after 1 month to confirm the diagnosis (unless there are symptoms or signs of complications).
Management
The NICE guidelines (updated 2022) recommendations on managing type 2 diabetes include:
- A structured education program
- Low-glycaemic-index, high-fibre diet
- Exercise
- Weight loss (if overweight)
- Antidiabetic drugs
- Monitoring and managing complications
Treatment Targets
The NICE guidelines (updated 2022) recommend the following HbA1c treatment targets:
- 48 mmol/mol for new type 2 diabetics
- 53 mmol/mol for patients requiring more than one antidiabetic medication
The HbA1c is measured every 3 to 6 months until under control and stable.
Medical Management
First-line is metformin.
Once settled on metformin, add an SGLT-2 inhibitor (e.g., dapagliflozin) if the patient has existing cardiovascular disease or heart failure. NICE suggest considering an SGLT-2 inhibitor in patients with a QRISK score above 10%.
Second-line is to add a sulfonylurea, pioglitazone, DPP-4 inhibitor or SGLT-2 inhibitor.
Third-line options are:
- Triple therapy with metformin and two of the second-line drugs
- Insulin therapy (initiated by the specialist diabetic nurses)
Where triple therapy fails, and the patient’s BMI is above 35 kg/m2, there is the option of switching one of the drugs to a GLP-1 mimetic (e.g., liraglutide).
TOM TIP: SGLT-2 inhibitors are increasingly being recommended. Older patients often have a QRISK score above 10%, making them fall into the “high risk” category for cardiovascular disease. NICE suggests considering SGLT-2 inhibitors alongside metformin as part of the first-line treatment in type 2 diabetics at high risk of cardiovascular disease. SGLT-2 inhibitors are recommended second-line as part of dual therapy in these patients. The significant potential side effect to remember is diabetic ketoacidosis.
Metformin
Metformin increases insulin sensitivity and decreases glucose production by the liver. It is a biguanide (the class of medication). It does not cause weight gain (and may cause some weight loss). It does not cause hypoglycaemia.
Notable side effects of metformin:
- Gastrointestinal symptoms, including pain, nausea and diarrhoea (depending on the dose)
- Lactic acidosis (e.g., secondary to acute kidney injury)
Patients with gastrointestinal side effects with standard-release metformin can try modified-release metformin.
SGLT-2 Inhibitors
SGLT-2 inhibitors end with the suffix -gliflozin. Examples are empagliflozin, canagliflozin, dapagliflozin and ertugliflozin.
The sodium-glucose co-transporter 2 protein is found in the proximal tubules of the kidneys. It acts to reabsorb glucose from the urine back into the blood. SGLT-2 inhibitors block the action of this protein, causing more glucose to be excreted in the urine. Loss of glucose in the urine lowers the HbA1c, reduces the blood pressure, leads to weight loss and improves heart failure. They can cause hypoglycaemia when used with insulin or sulfonylureas.
SGLT-2 inhibitors reduce the risk of cardiovascular disease. Empagliflozin and dapagliflozin are also licensed for heart failure. Dapagliflozin is also licensed for chronic kidney disease.
Notable side effects of SGLT-2 inhibitors include:
- Glycosuria (glucose in the urine)
- Increased urine output and frequency
- Genital and urinary tract infections (e.g., thrush)
- Weight loss
- Diabetic ketoacidosis, notably with only moderately raised glucose
- Lower-limb amputation may be more common in patients on canagliflozin (unclear if this applies to the others)
- Fournier’s gangrene (rare but severe infection of the genitals or perineum)
TOM TIP: Remember two side effects of SGLT-2 inhibitors. Firstly, an increased frequency of urinary tract infections and genital thrush due to lots of sugar passing through the urinary tract. Secondly, diabetic ketoacidosis. Patients starting SGLT-2 inhibitors are counselled about the features of DKA and when to seek emergency medical input.
Pioglitazone
Pioglitazone is a thiazolidinedione. It increases insulin sensitivity and decreases liver production of glucose. It does not typically cause hypoglycaemia.
Notable side effects of pioglitazone include:
- Weight gain
- Heart failure
- Increased risk of bone fractures
- A small increase in the risk of bladder cancer
Sulfonylureas
Gliclazide is the most common sulfonylurea. Sulfonylureas stimulate insulin release from the pancreas.
Notable side effects of sulfonylureas:
- Weight gain
- Hypoglycaemia
DPP-4 Inhibitors and GLP-1 Mimetics
Incretins are hormones produced by the gastrointestinal tract. They are secreted in response to large meals and act to reduce blood sugar by:
- Increasing insulin secretion
- Inhibiting glucagon production
- Slowing absorption by the gastrointestinal tract
The main incretin is glucagon-like peptide-1 (GLP-1). Incretins are inhibited by an enzyme called dipeptidyl peptidase-4 (DPP-4).
DPP-4 inhibitors block the action of DPP-4, allowing increased incretin activity. Examples of DPP-4 inhibitors are sitagliptin and alogliptin. They do not cause hypoglycaemia.
Notable side effects of DPP-4 inhibitors:
- Headaches
- Low risk of acute pancreatitis
GLP-1 mimetics imitate the action of GLP-1. Examples are exenatide and liraglutide. They are given as subcutaneous injections. Liraglutide can also be used for weight loss in non-diabetic obese patients.
Notable side effects of GLP-1 mimetics:
- Reduced appetite
- Weight loss
- Gastrointestinal symptoms, including discomfort, nausea and diarrhoea
Insulin
Insulin is usually initiated and managed by diabetic specialist nurses.
Rapid-acting insulins (e.g., NovoRapid) start working after around 10 minutes and last about 4 hours.
Short-acting insulins (e.g., Actrapid) start working in around 30 minutes and last about 8 hours.
Intermediate-acting insulins (e.g., Humulin I) start working in around 1 hour and last about 16 hours.
Long-acting insulins (e.g., Levemir and Lantus) start working in around 1 hour and last about 24 hours or longer.
Combinations insulins contain a rapid-acting and intermediate-acting insulin. In brackets is the ratio of rapid-acting to intermediate-acting insulin:
- Humalog 25 (25:75)
- Humalog 50 (50:50)
- Novomix 30 (30:70)
TOM TIP: A common exam scenario involves discussing the possibility of starting insulin with an HGV driver. Patients treated with insulin must fulfil very strict criteria to carry on driving, so starting insulin has enormous implications for professional drivers. This can be a motivating factor for improving diet, exercise and taking medications to improve diabetes control and avoid insulin.
Co-morbidities and Complications
Key complications of type 2 diabetes are:
- Infections (e.g., periodontitis, thrush and infected ulcers)
- Diabetic retinopathy
- Peripheral neuropathy
- Autonomic neuropathy
- Chronic kidney disease
- Diabetic foot
- Gastroparesis (slow emptying of the stomach)
- Hyperosmolar hyperglycemic state
ACE inhibitors are used first-line to manage hypertension in patients of any age with type 2 diabetes.
ACE inhibitors are started in type 2 diabetics with chronic kidney disease when the albumin-to-creatinine ratio (ACR) is above 3 mg/mmol (as opposed to 30 mg/mmol in patients without diabetes).
SGLT-2 inhibitors are started in type 2 diabetics with chronic kidney disease when the albumin-to-creatinine ratio (ACR) is above 30 mg/mmol (in addition to the ACE inhibitor).
Phosphodiesterase‑5 inhibitors (e.g., sildenafil or tadalafil) may be used for erectile dysfunction.
Prokinetic drugs (e.g., domperidone or metoclopramide) may be used for gastroparesis (slow emptying of the stomach). These medications are used with caution due to cardiac side effects.
There are four options for neuropathic pain (e.g., diabetic neuropathy):
- Amitriptyline – a tricyclic antidepressant
- Duloxetine – an SNRI antidepressant
- Gabapentin – an anticonvulsant
- Pregabalin – an anticonvulsant
Hyperosmolar Hyperglycemic State
Hyperosmolar hyperglycemic state (HHS) is a rare but potentially fatal complication of type 2 diabetes. It is characterised by hyperosmolality (water loss leads to very concentrated blood), high sugar levels (hyperglycaemia) and the absence of ketones, distinguishing it from ketoacidosis.
It presents with polyuria, polydipsia, weight loss, dehydration, tachycardia, hypotension and confusion.
It is a medical emergency with high mortality. Involve experienced seniors early. Treatment is with IV fluids and careful monitoring.
Last updated March 2023
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