Type 2 Diabetes

Simplified Pathophysiology

Repeated exposure to glucose and insulin makes the cells in the body become resistant to the effects of insulin. It therefore requires more and more insulin to produce a response from the cells and get them to take up and use glucose. Over time, the pancreas (specifically the beta cells) becomes fatigued and damaged by producing so much insulin and they start to produce less. A continued onslaught of glucose on the body in light of insulin resistance and pancreatic fatigue leads to chronic hyperglycaemia. Chronic hyperglycaemia leads to microvascular, macrovascular and infectious complications as described in the type 1 diabetes section.

 

Risk Factors

Non-Modifiable

  • Older age
  • Ethnicity (Black, Chinese, South Asian)
  • Family history

Modifiable

  • Obesity
  • Sedentary lifestyles
  • High carbohydrate (particularly refined carbohydrate) diet

 

Presentation

Consider type 2 diabetes in any patient fitting the risk factors above. It is easy to screen for diabetes with a HbA1C and early treatment goes a long way to prevent the long term complications. It is possible to reverse diabetes with the proper diet and lifestyle, therefore knowing about it early is worthwhile. Some additional symptoms give extra clues:

  • Fatigue
  • Polydipsia and polyuria (thirsty and urinating a lot)
  • Unintentional weight loss
  • Opportunistic infections
  • Slow healing
  • Glucose in urine (on dipstick)

 

Oral Glucose Tolerance Test (OGTT)

An oral glucose tolerance test (OGTT) is performed in the morning prior to having breakfast. It involves taking a baseline fasting plasma glucose result, giving a 75g glucose drink and then measuring plasma glucose 2 hours later. It tests the ability of the body to cope with a carbohydrate meal.

 

Pre-diabetes

Pre-diabetes is an indication that the patient is heading towards diabetes. They do not fit the full diabetic diagnostic criteria but should be educated regarding diabetes and implement lifestyle changes to reduce their risk of progressing to diabetes. They are not currently recommended to start medical treatment at this point.

 

Pre-diabetes Diagnosis

Pre-diabetes can be diagnosed with a HbA1c or by “impaired fasting glucose” or “impaired glucose tolerance”. Impaired fasting glucose means that their body struggles to get their blood glucose levels in to normal range, even after a prolonged period without eating carbohydrates. Impaired glucose tolerance means their body struggles to cope with processing a carbohydrate meal.

  • HbA1c – 42-47 mmol/mol
  • Impaired fasting glucose – fasting glucose 6.1 – 6.9 mmol/l
  • Impaired glucose tolerance – plasma glucose at 2 hours 7.8 – 11.1 mmol/l on an OGTT

 

Diabetes Diagnosis

Diabetes can be diagnosed if the patient fits the criteria on plasma glucose, an oral glucose tolerance test or HbA1c.

  • HbA1c > 48 mmol/mol
  • Random Glucose > 11 mmol/l
  • Fasting Glucose > 7 mmol/l
  • OGTT 2 hour result > 11 mmol/l

 

Management

Patient education about their condition and the lifestyle changes they need to make is essential. It is important to advise the patient that it is possible to cure type 2 diabetes. This has been proven in clinical studies such as the DiRECT study where they put patients on an 800 calorie per day diet and achieved a good rate of remission.

 

Dietary Modification

  • Vegetables and oily fish
  • Typical advice is low glycaemic, high fibre diet
  • A low carbohydrate may in fact be more effective in treating and preventing diabetes but is not yet mainstream advice

 

Optimise Other Risk Factors

  • Exercise and weight loss
  • Stop smoking
  • Optimise treatment for other illnesses, for example hypertension, hyperlipidaemia and cardiovascular disease

 

Monitoring for Complications

  • Diabetic retinopathy
  • Kidney disease
  • Diabetic foot

 

Treatment Targets

See the section on type 1 diabetes for information on the methods for monitoring blood glucose and HbA1C.

SIGN Guidelines 2017 and NICE Guideline 2015 recommend the following HbA1c treatment targets:

  • 48 mmol/mol for new type 2 diabetics
  • 53 mmol/mol for diabetics that have moved beyond metformin alone

 

Medical Management

NICE Guidelines 2015 (updated 2017):

First line: metformin titrated from initially 500mg once daily as tolerated.

Second line add: sulfonylurea, pioglitazone, DPP-4 inhibitor or SGLT-2 inhibitor. The decision should be based on individual factors and drug tolerance.

Third line:

  • Triple therapy with metformin and two of the second line drugs combined, or;
  • Metformin plus insulin

SIGN Guidelines 2017 suggest the use of SGLT-2 inhibitors and GLP-1 mimetics (e.g. liraglutide) preferentially in patients with cardiovascular disease.

 

Metformin

Metformin is a “biguanide”. It increases insulin sensitivity and decreases liver production of glucose. It is considered to be “weight neutral” and does not increase or decrease body weight.

Notable Side Effects:

  • Diarrhoea and abdominal pain. This is dose dependent and reducing the dose often resolves the symptoms
  • Lactic acidosis
  • Does NOT typically cause hypoglycaemia

 

Pioglitazone

Pioglitazone is a “thiazolidinedione”. It increases insulin sensitivity and decreases liver production of glucose.

Notable Side Effects:

  • Weight gain
  • Fluid retention
  • Anaemia
  • Heart failure
  • Extended use may increase the risk of bladder cancer
  • Does NOT typically cause hypoglycaemia

 

Sulfonylurea

The most common sulfonyluria is “gliclazide”. Sulfonylureas stimulate insulin release from the pancreas.

Notable Side Effects:

  • Weight gain
  • Hypoglycaemia
  • Increased risk of cardiovascular disease and myocardial infarction when used as monotherapy

 

Incretins (relevant for DPP-4 inhibitors and GLP-1 mimetics)

Incretins are hormones produced by the GI tract. They are secreted in response to large meals and act to reduce blood sugar. They:

  • Increase insulin secretions
  • Inhibit glucagon production
  • Slow absorption by the GI tract

The main incretin is “glucagon-like peptide-1” (GLP-1). Incretins are inhibited by an enzyme called “dipeptidyl peptidase-4” (DPP-4).

A recent meta-analysis (JAMA 2018) showed that GLP-1 mimetics were associated with a reduction in all cause mortality whereas DPP-4 inhibitors were not.

 

DPP-4 inhibitor

The most common DPP-4 inhibitor is “sitagliptin”. It inhibits the DPP-4 enzyme and therefore increases GLP-1 activity.

Notable Side Effects:

  • GI tract upset
  • Symptoms of upper respiratory tract infection
  • Pancreatitis

 

GLP-1 mimetics

These medications mimic the action of GLP-1. A common GLP-1 mimetic is “exenatide”. Exenatide is given as a subcutaneous injection either twice daily by the patient or once weekly in a modifiable-release form. Another GLP-1 mimetic is liraglutide, which is given daily as a subcutaneous injection. They are sometimes used in combination with metformin and a sulfonylurea in overweight patients.

Notable Side Effects:

  • GI tract upset
  • Weight loss
  • Dizziness
  • Low risk of hypoglycaemia

 

SGLT-2 Inhibitors

SGLT-2 inhibitors end with the suffix “-gliflozin”, such as empagliflozin, canagliflozin and dapagliflozin. The SGLT-2 protein is responsible for reabsorbing glucose from the urine in to the blood in the proximal tubules of the kidneys. SGLT-2 inhibitors block the action of this protein and cause glucose to be excreted in the urine.

Empagliflozin has been shown to reduce the risk of cardiovascular disease, hospitalisation with heart failure and all cause mortality in type 2 diabetes (EMPA-REG study). Canagliflozin has been shown to reduce the risk of cardiovascular events such as MI, stroke and death and hospitalisation with heart failure in type 2 diabetes (CANVAS trial). These reduced risks are likely related to the class rather than the individual medications but have not been proven for all SGLT-2 inhibitors.

Notable Side Effect:

  • Glucoseuria (glucose in the urine)
  • Increased rate of urinary tract infections
  • Weight loss
  • Diabetic ketoacidosis, notably with only moderately raised glucose. This is a rare complication
  • Lower limb amputation appears to be more common in patients on canagliflozin. It is not clear if this applies to other SGLT-2 inhibitors

 

Insulin

Here are a few examples of insulins and their duration of action. They will become more relevant when you start seeing them day to day on patient prescriptions. You will get to know them well.

Rapid-acting Insulins

These start working after around 10 minutes and last around 4 hours

  • Novorapid
  • Humalog
  • Apidra

Short-acting Insulins

These start working in around 30 minutes and last around 8 hours

  • Actrapid
  • Humulin S
  • Insuman Rapid

Intermediate-acting Insulins

These start working in around 1 hour and last around 16 hours:

  • Insulatard
  • Humulin I
  • Insuman Basal

Long-acting Insulins

These starts working in around 1 hour and lasts around 24 hours:

  • Lantus
  • Levemir
  • Degludec (lasts over 40 hours)

Combinations Insulins

These containing a rapid acting and an intermediate acting insulin. In brackets is the proportion of rapid to intermediate acting insulin:

  • Humalog 25 (25:75)
  • Humalog 50 (50:50)
  • Novomix 30 (30:70)

 

Last updated December 2018
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