Diabetes Mellitus

Definition Diabetes is a chronic metabolic disease characterised by elevated blood glucose levels leading to serious damage to heart, blood vessels, eyes, kidneys, feet and nerves.

Epidemiology Around 4.3 million people are living with diabetes in the UK, along with an estimated further 850,000 people with diabetes who have not yet been diagnosed. More than 2.4 million are at high risk of developing Type 2 diabetes.

The large majority – 90% – of people with diabetes have Type 2, 8% have Type 1 and 2% have rarer forms of diabetes.¹

The number of adults living with diabetes worldwide is projected to more than double by 2050: an increase from 529 million in 2021 to more than 3.1 billion in 2050.²

Type 2 diabetes diagnoses are rising at a faster rate among those under 40 years of age than among those over 40, and the number of children with Type 2 diabetes in England and Wales has increased by more than 50% in the past 5 years. This rise is due to the increased risk of diabetes linked to excess weight, with over 64% of adults and nearly 38% of children in England classed as overweight or obese.³

Types of diabetes

• Type 1 diabetes/ Juvenile diabetes/Insulin-dependent diabetes: This is a chronic condition when autoimmune destruction of pancreatic Beta cells leads to lack of insulin production. The cause or means of prevention are unknown.
• Type 2 diabetes: This is secondary to insulin resistance (IR) +/- insulin deficiency. The most common type of diabetes, usually affecting adults but increasingly common in children and young adults. This may be preventable as contributing factors include being overweight and lack of exercise. There is frequently a positive family history.
• Latent autoimmune diabetes in adults (LADA): essentially ‘slow-onset’ Type 1 diabetes. Also called T1.5D
• Monogenic D: Due to underlying genetic mutation, accounts for 1-2% of diabetes. Often referred to as MODY: Maturity Onset Diabetes of the Young. The onset is usually around 25 years of age. Various gene defects can lead to different forms of MODY.
• Gestational diabetes: Impaired glucose tolerance in pregnancy secondary to insulin resistance and pancreatic Beta cell dysfunction causes gestational diabetes. There is a significantly increased risk of developing Type 2 diabetes in later years.⁴
• Type 3c diabetes, or pancreatogenic diabetes: This is diabetes secondary to pancreatic disease, often involving the exocrine functions of pancreas as well. Includes pancreatic surgery, haemachromatosis, cystic fibrosis, pancreatic cancer.
• Ethnically linked diabetes: Some forms of diabetes are found only in people of certain ethnicities, eg, J-Type diabetes, which is separate from Type 1 and Type 2.
• Prediabetes: This is defined as glucose raised above normal levels but not greater than diagnostic levels for Type 2 diabetes: HbA1c between 42 and 47mmol/mol.⁵ Prediabetes increases the risk of developing Type 2 diabetes. It is associated with an increased risk of all-cause mortality and CVD in the general population, and even greater increased risk for people with a history of CVD.⁶
  Note that prediabetes overlaps with two other conditions:
  • Impaired fasting glucose (IFG): defined by fasting plasma glucose >6.0mmol/l and <6.9mmol/l.
  • Impaired glucose tolerance (IGT): diagnosed where a 2-hr oral glucose tolerance test is >7.8mmol and <11.1mmol.

People with prediabetes should be referred to a local, evidence-based education programme promoting lifestyle changes, as these interventions alone can reduce the risk of developing Type 2 diabetes by as much as 25-72%.⁷

Metformin can be offered to certain people at especially high risk of Type 2 diabetes if their HbA1c continues to rise despite lifestyle modification, or they are unable to participate in such programmes, especially if the BMI>35.⁸ This may include people at high risk due to their ethnicity, or from antipsychotic treatment for severe mental illness. (Note lifestyle modification otherwise remains the preferred option as some evidence indicates the elevated CVD risk with prediabetes is due to non-glycaemic risk factors, and that reversion to normoglycaemia is only beneficial if accompanied by significant lifestyle changes.^9,10) Metformin should be prescribed for 6-12 months initially, with HbA1c checked at 3 monthly intervals, and stopped if no benefits are seen.⁸

Diagnosis – Type 1 diabetes

Clinical features

Symptoms are often of rapid onset. They require immediate specialist referral. Include:

• Increased thirst.
• Increased urination.
• Weight loss – often rapid.
• Feeling tired/no energy.
• May be acutely unwell.
• May have personal or family history (FH) of auto-immune disease, especially coeliac and auto-immune thyroid disease or FH of T1 diabetes.

Blood tests

• Random blood glucose >11.0mmol/l
• Fasting blood glucose >7.0mmol/l
• Urine and blood ketones are likely to be +ve
• BMI likely <25
• Age likely <50yrs

Other tests (not a priority)

• Urine C-peptide (some specialist services may offer)
• Glutamic acid decarboxylase (GAD) antibodies are +ve in approx. 80% of adults at diagnosis, but less in children and young adults
• Islet tyrosine phosphatase 2 (IA2) antibodies (offered in some centres)

Diagnosis – Type 2 diabetes

Clinical features

Symptoms can be mild and may take several years to be noticed. Complications can be present before diagnosis.

Symptoms include:

• Increased thirst.
• Increased urination.
• Increased hunger.
• Blurred vision (retinopathy may be detected by high street optometrist).
• Weight loss.
• Oral/genital thrush.
• Tingling/loss of sensation in feet or foot ulcer.

Blood tests

• HbA1c, non-fasting
  • If person is symptomatic, a single HbA1c ≥48mmol/mol confirms a diagnosis of diabetes.
  • If asymptomatic, an HbA1c ≥48mmol/mol is suggestive of diabetes, and must be repeated within 4 weeks to confirm dia If a repeat HbA1c is ≥48mmol/mol then the diagnosis is confirmed.
  • If repeat HbA1c is <48mmol/mol then refer for local, evidence-based education program designed to increase understanding and knowledge of Type 2 diabetes and develop self-management skills. Offer patient information resources and repeat HbA1c at least annually.
• If HbA1c is not available or unsuitable, fasting blood glucose >7.0mmol/l is diagnostic of diabetes.
• HbA1c as a diagnostic test is NOT recommended in:
  • Children and young people.
  • Suspected Type 1 diabetes.
  • Person with symptoms for less than 2 months.
  • Person taking medication which may cause rapidly elevating glucose levels, such as corticosteroids, antipsychotics.
  • Anaemia: iron deficiency, haemolytic.

Management of Type 1 diabetes

People living with Type 1 diabetes will need insulin with the type, dosage and dosing regime specific to their lifestyle, needs and wishes. Monitoring is mandatory. Hypoglycaemia and weight gain are unwelcome side effects.

Most patients with Type 1 diabetes are under secondary care.

Management of Type 2 diabetes in adults

Managing the care of people with Type 2 diabetes must include managing the risk of CV and renal complications and not target reducing blood glucose as the primary aim. Research on new diabetes medications has highlighted the extra benefits certain drugs offer and modern guidelines reflect these advances.

A holistic and individual approach is recommended.

Treatment decisions must consider not only individualised HbA1c targets but include CVD risk status:

• QRISK2 ≥10%
• Presence of congestive heart failure
• Established atherosclerotic CVD
• CKD

These factors will then guide treatment decisions from diagnosis continuing throughout the persons’ life. Guidelines are available to provide best care from diagnosis, including from NICE, the European Association for the Study of Diabetes and the American Diabetes Association. Note guidelines vary in regard to certain recommendations.

Management of all people must start with a discussion of lifestyle modifications aimed at weight reduction and maintenance, healthy food choices, promotion of physical activity, sitting, strengthening, good sleep patterns, smoking cessation, possible diabetes remission.

Specific advice is available for safe prescribing in people with frailty.¹¹

Drugs effective in diabetes management include:

• Metformin. First-choice medication for all people if tolerated; some people experience GI upset (modified release is available). Not advised for IBS, IBD, pancreatic insufficiency or if drinking excess alcohol. Can be either as single therapy or in combination with other drugs. Caution eGFR. Some possible CV benefits.
• SGLT-2 inhibitors (Sodium-glucose cotransporter-2 inhibitors). Reduce blood glucose levels via increased excretion of glucose from kidneys by blocking reabsorption, promoting blood glucose reduction and weight loss. Reduce BP by an average 4mmHg systolic, 2mmHg diastolic. Certain SGLT-2 inhibitors demonstrate benefits in atherosclerotic CVD, HFrEF, HFpEF and CKD. Recommended by NICE as the preferred add-on to metformin for people with Type 2 diabetes and established atherosclerotic CVD, HF, or QRISK2 >10%. NICE has also published guidance recommending their use in patients with Type 2 diabetes and certain categories of CKD. (Some SGLT-2 inhibitors are also approved for use in people with CKD and/or HF who do not have diabetes.) Caution re: different eGFR recommendations for each drug and reduced glucose lowering efficacy at reduced eGFR. Genital thrush is common side effect, risk of euglycaemic diabetic ketoacidosis is very rare.
• DPP-4 inhibitors, also known as gliptins. Inhibit the breakdown of incretins: glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Associated with few side effects, no weight loss, modest blood glucose reduction. No CVD/renal protection. Caution re: certain gliptins in HF.
• Associated with useful blood glucose reduction. Caution in people with HF. The CVD outcome data is weaker and less conclusive for pioglitazone than other drugs.
• GLP-1 mimetics (glucagon-like peptide-1 receptor agonists). Delay gastric emptying, promote satiety via effect on brain satiety centre, improve pancreatic Insulin production and inhibit glucagon production. Net effect is a useful weight reduction (used independently for weight reduction in people with and without diabetes) and blood glucose lowering. Certain drugs from this class are recognised to provide CVD protection. Care with eGFR requirements. Majority of these drugs are given as subcutaneous injections.
• Stimulate pancreatic beta cells to produce insulin. Major risk of hypoglycaemia. CVD outcome data weak and inconclusive.
• Insulin is an important drug when combinations of oral/injection drugs no longer effective. Can be used alone or in combination with other drugs.

Other considerations for management:

• Review lipid levels.
• BP control.

Remission of Type 2 diabetes¹²

• Defined by a HbA1c <48mmol/mol maintained for at least 3 months after stopping all glucose-lowering treatment.
• Testing to confirm remission should continue for at least 3 months after stopping glucose lowering treatment, at least 3 months after bariatric surgery or 6 months after sustained lifestyle changes.
• Subsequent measurements of HbA1c to document continuation of remission should be no more than every 3 months and at least annually.
• Diabetes reviews including HbA1c, renal function, BP and weight measurements and foot check should continue and be carried out at least annually. Retinal screening should continue.
• Patients should be coded: ‘DM in remission’ or ‘T2D in remission’.

Monitoring in primary care

People living with diabetes should be reviewed at regular intervals.

• Most people with Type 1 diabetes will be under regular review and their monitoring will be supervised by specialist teams, usually in secondary care.
• People with Type 2 diabetes will be monitored in primary care on an individual basis, the timing and manner dependent on where they are along their treatment pathway. For example, on new diagnosis or the addition of new therapies this will be at shorter time intervals and may be F2F or via telephone or virtually.
• Regular tests will include: HbA1c; weight measurement; glucose monitoring; BP; lipid measurements: to include total cholesterol, LDL-cholesterol, non-HDL-cholesterol, triglycerides; U&Es to include eGFR; LFTs; and uACR.
• Foot checks should be at least annually and include vascular (may include ultrasound) and sensation assessments. Advise on need for urgent review if ulcers, infection are noted. Footwear inspection is recommended.
• Retinal screening is essential for all people with diabetes, the timing at least annually or dependent on the individual’s status.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is an acute, major, life threatening condition involving hyperglycaemia, ketoacidosis and ketones in urine. It is caused by absolute or relative insulin deficiency which prevents glucose entering the cells. The liver responds by rapidly breaking down fat stores providing ketones for energy. Excess production of ketones causes an accumulation in blood and urine and will result in acidosis. DKA is most common in Type 1 diabetes but can occur in Type 2. It is often triggered by infection, insufficient/no insulin treatment, trauma including surgery and can occur at the time of new diagnosis of Type 1 diabetes.

Presentation

Increased thirst and urination, weight loss, nausea and vomiting often with diffuse abdominal pain and altered conscious state. Patients appear ill, laboured breathing smelling of acetone/fruity, tachycardia and general dehydration is often present.

Tests

Blood glucose electrolytes, Bicarbonate, urine dipstix for ketones and possible infection, blood test for ketones (more reliable than urinary ketones), arterial blood gases, FBC and tests for possible underlying trigger, possible infection.

Management

Immediate referral to secondary care is required. Treatment will involve fluid resuscitation, reversal of acidosis and ketosis, reduction of blood glucose levels, replenishment of electrolytes, identification and correction of cause.

Medications

Rapid and short acting insulins, electrolyte supplements, eg, potassium chloride, and alkalinising agents, eg, sodium bicarbonate.

Euglycaemic diabetic ketoacidosis

This condition can be found with a normal glucose level in the presence of ketoacidosis. It is possible in both Type 1 and Type 2 diabetes and rarely people with no diabetes. This has been recognised recently in people with Type 2 diabetes since the introduction of SGLT-2 inhibitor drugs in their management.

Sick day rules

If patients with diabetes become ill, it is important they know what to do as it is very likely that blood glucose levels will rise and adjustment of both tablets and insulin will be required.

Advice should include:

• More frequent monitoring if patient has access to monitoring.
• Avoid strenuous exercise.
• Aim to drink >2.5 litres sugar free liquids per day.
• Try to eat normal diet but if no appetite, nausea, or vomiting – replace solid food with liquid calories, eg, soup, milky drinks, yoghurt, custard.
• If unable to manage or keep down any foods or liquids, seek medical advice promptly.

Advice for patients with Type 2 diabetes:

During periods of acute illness, consider temporarily stopping certain oral medication and restarting 24-48 hours later if feeling better.

Think SADMANS rules:

Sulphonylureas: Stop – risk of hypoglycaemia

ACE inhibitor: Stop – risk AKI

Diuretics: Stop – risk dehydration and AKI

Metformin: Stop – risk lactic acidosis

ARBs: Stop – risk AKI

NSAID: Stop – risk AKI

SGLT-2 inhibitor: Stop – risk EKA

Advice for patients with Type 1 diabetes:

Follow SADMANS rules if taking certain medications.

Monitor more frequently, insulin may need adjusting.

Do not stop insulin:

• If blood glucose <10mmol/l continue with normal dosage.
• If blood glucose >10mmol/l, will need extra insulin, seek medical advice.

Prognosis

There is a heavy burden of morbidity and mortality associated with diabetes. Life expectancy is reduced in all types of diabetes and worsened by comorbid CVD, CKD and foot complications. There is a high prevalence of microvascular disease affecting eyes, nerves and kidneys. Clinical studies indicate simple improvements in glycaemic control can reduce the risk of developing microvascular disease.

Macrovascular disease leads to CVD, cerebrovascular disease and lower extremity artery disease. The combination of diabetes, CKD, hypertension and dyslipidaemia contribute to

the development of CVD. Previous clinical studies indicate few beneficial effects on reducing CVD with improvement in glucose control alone, though more recent data suggest SGLT-2 inhibitors/GLP-1 mimetics likely reduce CV risk through mechanisms other than glucose lowering.¹³

Complications of diabetes

Acute complications

• Hypoglycaemia
• Hyperglycaemia
• DKA

Chronic complications

• Brain:  Global atrophy – rate up to three times faster than in normal ageing; Stroke – two-fold increased risk of stroke within first 5 years of diagnosis.
• Eyes: Previously major cause of preventable sight loss among working age people. Rare to develop retinopathy in Type 1 diabetes in first 3-5 years of diagnosis, but up to 20% of people with Type 2 diabetes have retinopathy at diagnosis. Visual loss now rare due to retinal screening and steps taken promptly to prevent deterioration.
• Gum disease: Three times more prevalent than in people with no diabetes.
• Kidney disease: Approximately 40% people with diabetes have kidney disease and CKD is a strong indicator of CVD.
• Erectile dysfunction (ED): More than 50% of men with diabetes experience some degree of ED.
• Non-alcoholic fatty liver disease (NAFLD): Up to 70% people with Type 2 diabetes develop NAFLD.
• Foot ulcers: Most common cause for limb amputation.
• Neuropathy: Approximately 50% people with Type 2 diabetes will develop neuropathy: peripheral, autonomic, focal and proximal.
• CVD (CHD, stroke, PVD)^14: Major cause of death and disability. People with diabetes have approximately twice the risk of CVD compared with those with no diabetes; Accounts for 44% fatalities in people with Type 1 and 52% in people with Type 2 diabetes.

Dr Elizabeth Martin is a GPwSI in Diabetes at Leeds Community Diabetes Service