Diabetes mellitus

What is diabetes mellitus?^{1 2}

Diabetes mellitus is a metabolic disorder characterised by persistent hyperglycaemia (random plasma glucose more than 11 mmol/L) with disturbances of carbohydrate, protein, and fat metabolism resulting from defects in insulin secretion (leading to insulin deficiency), insulin action (leading to insulin resistance), or both.

The main types of diabetes mellitus are:

• Type 1 diabetes mellitus: results from the body's failure to produce sufficient insulin.

• Type 2 diabetes mellitus: results from a dual defect in insulin resistance and insulin secretion. In many people, insulin resistance develops first, with insulin secretion later becoming insufficient to maintain normoglycaemia.³

• Gestational diabetes: pregnant women who have never had diabetes before but who have high blood glucose levels during pregnancy are said to have gestational diabetes. Gestational diabetes affects about 4% of all pregnant women. It may precede development of type 2 (or rarely type 1) diabetes.

Note that older terms such as 'insulin-dependent diabetes' and 'juvenile-onset diabetes' are no longer used; previously, they referred to type 1 diabetes, but type 2 may also require insulin treatment, and can also develop in childhood. In addition, type 1 diabetes can develop at any age.

The diagnosis of type 1 diabetes is based on clinical grounds in adults presenting with hyperglycaemia (random plasma glucose more than 11 mmol/L), bearing in mind that adults with type 1 diabetes typically (but not always) present with one or more of the following:

• Ketosis.

• Rapid weight loss.

• Age of onset younger than 50 years.

• Body mass index (BMI) below 25 kg/m².

• Personal and/or family history of autoimmune disease.

Suspect type 1 diabetes in a child or young person presenting with hyperglycaemia (random plasma glucose more than 11 mmol/L) and the characteristic features of:

• Polyuria.

• Polydipsia.

• Weight loss.

• Excessive tiredness.

HbA1c measurements may be elevated if type 1 diabetes has developed slowly, but may be normal or only slightly elevated if hyperglycaemia and symptoms have evolved quickly, as is often the case in young people.

Suspected type 1 diabetes needs urgent (same-day) referral and treatment. Untreated type 1 diabetes can lead rapidly to serious illness and death.

Diagnosis of type 2 diabetes:

• Suspect a diagnosis of type 2 diabetes if persistent hyperglycaemia that may be accompanied by clinical features:

  • Symptoms such as polydipsia, polyuria, blurred vision, unexplained weight loss, recurrent infections, and tiredness. NB: these may be mild or absent.

  • Signs such as acanthosis nigricans (a skin condition causing dark pigmentation of skin folds, typically the axillae, groin, and neck), which suggests insulin resistance.

  • The presence of risk factors (see below).

• Persistent hyperglycaemia is defined as:

  • HbA1c of 48 mmol/mol (6.5%) or more.

  • Fasting plasma glucose level of 7.0 mmol/L or more.

  • Random plasma glucose of 11.1 mmol/L or more in the presence of symptoms or signs of diabetes.

• If the person is symptomatic, a single abnormal HbA1c or fasting plasma glucose level can be used, although repeat testing is sensible to confirm the diagnosis.

• If the person is asymptomatic, do not diagnose diabetes on the basis of a single abnormal HbA1c or plasma glucose result. Arrange repeat testing, preferably with the same test, to confirm the diagnosis. If the repeat test result is normal, arrange to monitor the person for the development of diabetes, the frequency depending on clinical judgement.

Severe hyperglycaemia in people with acute infection, trauma, circulatory or other stress may be transitory and is not diagnostic of diabetes.

Other types of diabetes include:

• Monogenic diabetes - diabetes caused by single-gene mutations. For example:

  • Maturity-onset diabetes of the young (MODY): including several forms of diabetes with monogenetic defects of beta-cell function (impaired insulin secretion), usually manifesting as mild hyperglycaemia at a young age and usually inherited in an autosomal-dominant manner.⁴

  • Neonatal diabetes: incorporating several different monogeneic causes, this is diabetes that presents prior to 6 months of age in most cases, although it can present up to one year of age.⁵

• Latent autoimmune diabetes of adults (LADA). LADA is a slowly-progressive form of adult-onset, autoimmune diabetes, with an initial period (usually defined as at least six months) in which insulin therapy is not required.⁶ It is often misdiagnosed initially as type 2 diabetes, but progresses to requiring insulin more rapidly than in people with typical type 2 diabetes.

• Ketosis-prone type 2 diabetes. Primarily reported in African-American and Latino populations (although it can occur in anyone), this is a non-autoimmune form of diabetes which typically presents with diabetic ketoacidosis and evidence of severe insulin deficiency, but later enters into remission without the need for ongoing insulin treatment, although further ketotic episodes occur in most people.⁷

• Secondary diabetes: accounts for a small minority of patients with diabetes mellitus. Causes include:
  

  • Pancreatic disease: cystic fibrosis, chronic pancreatitis, pancreatectomy, carcinoma of the pancreas.

  • Endocrine: Cushing's syndrome, acromegaly, thyrotoxicosis, phaeochromocytoma, glucagonoma.

  • Drug-induced: thiazide diuretics, corticosteroids, atypical antipsychotics, antiretroviral protease inhibitors.

  • Congenital lipodystrophy.

  • Acanthosis nigricans.

  • Genetic:

    • Wolfram's syndrome (which is also referred to as DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy and deafness).⁸

    • Friedreich's ataxia.

    • Dystrophia myotonica.

    • Haemochromatosis.

    • Glycogen storage diseases.

Diagnostic classifications for diabetes are evolving over time, as more is understood about differing pathophysiologies, and different phenotypes are described. A 2018 Lancet paper proposed a new classification model for adult-onset diabetes.⁹ Researchers from Sweden and Finland say the model can identify individuals with increased risk of complications at diagnosis:

• Cluster 1: SAID (severe autoimmune diabetes) - type 1 diabetes and latent autoimmune diabetes in adults (LADA).

• Cluster 2: SIDD (severe insulin-deficient diabetes) - high HbA₁C, impaired insulin secretion and moderate insulin resistance.

• Cluster 3: SIRD (severe insulin-resistant diabetes) - obesity and severe insulin resistance.

• Cluster 4: MOD (mild obesity-related diabetes) - obesity without insulin resistance.

• Cluster 5: MARD (mild age-related diabetes) - similar to cluster 4 but comprising older adults and only modest metabolic disarrangement.

Individuals in cluster 3 (most resistant to insulin) have a significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5 who had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) have the highest risk of retinopathy.

Type 1 diabetes mellitus¹

The development of type 1 diabetes mellitus is based on a combination of a genetic predisposition and an autoimmune process that results in gradual destruction of the beta cells of the pancreas, leading to absolute insulin deficiency. There is usually a pre-diabetic phase where autoimmunity has already developed but with no clinically apparent insulin dependency. Insulin autoantibodies can be detected in genetically predisposed individuals as early as 6-12 months of age.¹⁰

Possible triggers for the process may include viruses, dietary factors, environmental toxins, and emotional or physical stress. Early cessation of breast-feeding has also been linked to increased risk of developing type 1 diabetes, but the association is unproven and controversial.¹¹

• Approximately 8% of those with diabetes have type 1 diabetes - usually juvenile-onset, but it may occur at any age. It may be associated with other autoimmune diseases. It is characterised by insulin deficiency.

• A sibling of a person with type 1 diabetes has 6-7% risk of developing it themselves. This risk increases to 30-70% in identical twins. The risk for a child is 1-9% if a parent has type 1 diabetes.

• It is associated with HLA DR3 and DR4 and islet cell antibodies around the time of diagnosis.

• Type 1 diabetes typically presents with a sudden onset of symptoms in children and young people (over hours to days); in adults, the onset of symptoms can be slower (days to weeks, or longer).

• Patients always need insulin treatment and are prone to ketoacidosis.

• The most at-risk population for type 1 diabetes is Caucasian of northern European ancestry. Incidence is high in Scandinavian people.

Type 2 diabetes mellitus²

• Approximately 90% of those with diabetes; they are usually older at presentation (most often >30 years of age) but it is increasingly diagnosed in children and adolescents.

• Type 2 diabetes is associated with excess body weight and physical inactivity.

• All ethnic groups are affected but there is increased prevalence in people of South Asian, African, African-Caribbean, Polynesian, Middle-Eastern and American-Indian ancestry.

• It is caused by both impaired insulin secretion and insulin resistance and has a gradual onset.

• Some with type 2 diabetes may eventually need insulin treatment.

How common is diabetes mellitus? (Epidemiology)²

The global age-standardised incidence rate of type 2 diabetes significantly increased from 228 per 100,000 people in 1990 to 279 per 100,000 people in 2017. Diabetes is one of the most common chronic diseases in the UK, and, similarly, its prevalence is increasing over time.

Risk factors for type 2 diabetes²

• Obesity, especially central (truncal) obesity.

• Lack of physical activity.

• Ethnicity: people of South Asian, African, African-Caribbean, Polynesian, Middle-Eastern and American-Indian descent are at greater risk of type 2 diabetes, compared with the white population.

  • The reasons for this are complex and likely involve an interplay of biological, lifestyle, social, clinical, and health system factors.¹²

• History of gestational diabetes.

• Impaired glucose tolerance.

• Impaired fasting glucose.

• Drug therapy - eg, combined use of a thiazide diuretic with a beta-blocker.

• Low-fibre, high-glycaemic index diet.

• Metabolic syndrome.

• Polycystic ovary syndrome.

• Family history (2.4-fold increased risk for type 2 diabetes).

• Adults who had low birth weight for gestational age.

Diabetes mellitus symptoms

• Patients with all types of diabetes may present with polyuria, polydipsia, lethargy, boils, pruritus vulvae or with frequent, recurrent or prolonged infections.

• Patients with type 1 diabetes may also present with weight loss, dehydration, ketonuria and hyperventilation. Presentation of type 1 diabetes tends to be acute with a short duration of symptoms.

• Presentation in patients with type 2 diabetes tends to be subacute with a longer duration of symptoms. With the advent of increased screening for diabetes, many people with type 2 diabetes are asymptomatic at diagnosis.

• Patients with diabetes may present with acute or chronic complications, as outlined in the sections on 'Complications', below.

Diagnosis for diabetes mellitus

Since 2011, the World Health Organization (WHO) has recommended glycated haemoglobin (HbA1c) as a diagnostic test for diabetes. An HbA1c of 48 mmol/mol (6.5%) is recommended as the cut-off point for diagnosing diabetes. Note that HbA1c reflects average plasma glucose over the preceding 8-12 weeks; therefore, it may be normal if hyperglycaemia has developed rapidly, and so a value less than 48 mmol/mol does not exclude diabetes diagnosed using glucose tests.¹⁴ See also the separate Glycated Haemoglobin (HbA1c) article.

• Diabetes is usually diagnosed by an HbA1c of 48 mmol/mol (6.5%) or more. If the use of HbA1c is inappropriate (eg, people with end-stage chronic kidney disease), type 2 diabetes is diagnosed by a fasting plasma glucose level of 7.0 mmol/L or greater.

• In an asymptomatic person, the diagnosis of diabetes should never be based on a single abnormal HbA1c or fasting plasma glucose level; at least one additional abnormal HbA1c or plasma glucose level is essential. If the second test results are normal, it is prudent to arrange regular review of the person.

• In a symptomatic person (thirst, increased urination, recurrent infections, weight loss, drowsiness and coma), diabetes can be diagnosed with more confidence on the basis of a single abnormal HbA1c or fasting plasma glucose level (although a second test may be prudent).

• Severe hyperglycaemia in people with an acute infection, trauma, circulatory or other stress may be transitory and should not be regarded as diagnostic of diabetes.

Assessment and monitoring

• Assessment: see the separate Assessment of the Patient with Established Diabetes article.

• Monitoring: see the separate Glycated Haemoglobin (HbA1c) and Self-Monitoring in Diabetes Mellitus articles.

Diabetes mellitus treatment and management

Holistic management for a person with diabetes includes:^{1 2}

• Diabetes education: structured education and self-management (at diagnosis and regularly reviewed and reinforced) to promote awareness.

• Diet and lifestyle: healthy diet, weight loss if the person is overweight, smoking cessation, regular physical exercise.

• Maximising glucose control while minimising adverse effects of treatment, such as hypoglycaemia.

• Reduction of other risk factors for complications of diabetes, including the early detection and management of hypertension, drug treatment to modify lipid levels and consideration of antiplatelet therapy with aspirin.

• Monitoring and early intervention for complications of diabetes, including cardiovascular disease, feet problems, eye problems, kidney problems and neuropathy.

A global assessment of an individual's cardiovascular risk is essential. See the separate Cardiovascular Risk Assessment article.

All individuals with type 1 diabetes should be under the care of a specialist diabetic team.¹ Many people with type 2 diabetes can be managed fully in primary care.²

See the separate articles:

• Management of Type 1 Diabetes.

• Type 2 Diabetes Treatment and Management.

• The Patient with Newly-diagnosed Diabetes.

• Diabetes Diet and Exercise.

• Diabetes Education and Self-management Programmes.

• Antihyperglycaemic Agents used for Type 2 Diabetes.

• Insulin Regimens.

• Precautions with Patients with Diabetes Undergoing Surgery.

• Diabetes and Intercurrent Illness.

• Diabetes in Pregnancy.

• Gestational Diabetes.

Complications of diabetes mellitus

Acute complications

• See Diabetic Ketoacidosis and Hyperosmolar Hyperglycaemic State.

• See Emergency Management of Hypoglycaemia.

Chronic complications

• Cardiovascular disease: see coronary heart disease (Stable Angina, Acute Coronary Syndrome), Cerebrovascular Events and Peripheral Arterial Disease.

• See Diabetic Nephropathy.

• See Diabetic Retinopathy and Diabetic Eye Problems.

• See Diabetic Neuropathy, Autonomic Neuropathy and Neuropathic Pain and its Management.

• See Diabetic Foot, Leg Ulcers and Painful Foot.

• Frequent, recurrent and persistent infections.

Prognosis

Type 1 diabetes¹

• Without insulin replacement, people with type 1 diabetes die within days or weeks.

• With insulin replacement, people with type 1 diabetes can participate normally in the usual activities of daily life but are at risk of complications.

• The risk of complications is greatly reduced by keeping circulating glucose levels to as near normal as possible in order to reduce tissue damage.

• Disability from complications that are not avoided can often be prevented by early detection and active management.

Type 2 diabetes²

• Insulin deficiency in type 2 diabetes progresses with time and usually worsens over a period of years.

• Type 2 diabetes diagnosed in young people is characterised by rapid onset and progression, with more common and progressive comorbidities (such as fatty liver disease and sleep apnoea), and more rapid development of microvascular complications and cardiovascular risk than adult-onset type 2 diabetes, leading to increased morbidity and mortality rates.

• Young-onset type 2 diabetes is associated with greater mortality rates, more complications, and increased cardiovascular disease risk factors than for people with type 1 diabetes of similar duration.

Diabetes mellitus prevention¹⁵

Type 1: despite a great deal of ongoing research, there are currently no interventions before diagnosis that have shown any benefit.

There is interest as to whether vaccination can be applied in autoimmune and inflammatory conditions. Vaccination may play a role further in the prevention of type 1 diabetes .

Type 2: see the separate Prevention of Type 2 Diabetes article.