Type 1 diabetes mellitus
Patients may commonly present in childhood or adolescence with polyuria, polydipsia, weight loss, lethargy, or critically unwell with potentially life-threatening diabetic ketoacidosis (DKA).
Long-term hyperglycaemia in T1DM can lead to many complications including macrovascular damage (e.g. cardiovascular, cerebrovascular or peripheral vascular disease) and microvascular damage (e.g. nephropathy, retinopathy and neuropathy).
The long-term management of T1DM requires a multidisciplinary team approach within primary and secondary care. Treatment is with exogenous insulin administration, diet and exercise education, with an aim to achieve tight glycaemic control to minimise acute risk of DKA and chronic complications.
T1DM is relatively common and accounts for 10% of all patients with diabetes and 85% of patients with diabetes under the age of 20.
The incidence of T1DM has wide geographical variation, but in the UK, 24.5 in every 100,000 children under the age of 14 are diagnosed.
- The risk of T1DM can be influenced by many different gene polymorphisms, particularly those relating to human leukocyte antigen (HLA) alleles, specifically HLA-DR and HLA-DQ alleles.
- The HLA-DQ2 genotype sometimes seen in T1DM is also associated with coeliac disease, and therefore coeliac disease is more common in those with T1DM. People with T1DM are also more likely to have other co-existing autoimmune disorders such as Hashimoto's thyroiditis, Addison's disease, vitiligo, and systemic lupus erythematosus (SLE).
- The risk of developing T1DM is 3-5% if a parent has it, and 40-50% if an identical twin has it.
- The presence of autoantibodies to islet cells, insulin, islet antigens (IA2 and IA2-beta), glutamic acid decarboxylase (GAD), or the zinc transporter ZnT8 indicate autoimmune beta-cell destruction and are suggestive of T1DM. However, it is unclear which of these are involved in initiating the insult or which develop secondary to the insult.
- The wide geographic variation in prevalence of T1DM suggests an environmental contribution to its development, however specific causative factors have not been identified.
- In genetically susceptible patients, environmental associations which have been postulated include:
- Viral infections
- Cow's milk ingestion
- Vitamin D deficiency
- Early introduction of cereals
- Nitrate concentration in drinking water
Normal action of insulin:
- Insulin activates insulin-receptors on the membranes of insulin-responsive tissues (e.g. peripheral muscle and adipose tissue), stimulating the migration of glucose transporters to the cell membrane to facilitate uptake of circulating glucose into these tissues.
- In addition, insulin stimulates glycogen synthesis, and inhibits gluconeogenesis, glycogenolysis and lipolysis.
- In the absence of insulin (as in T1DM), glucose cannot be taken up by insulin-responsive tissues, causing hyperglycaemia.
Pathophysiological process in T1DM:
- T1DM is most commonly a type IV hypersensitivity autoimmune reaction, in which CD4+ T helper cells and CD8+ cytotoxic T cells attack pancreatic beta cells, eventually eliminating any insulin production.
- Destruction of the beta cells occurs over months to years and usually only results in hyperglycaemia once ~90% of the beta cells have been destroyed.
- Progressive beta cell destruction also leads to dysfunction of neighbouring alpha cells which produce the counter-regulatory hormone, glucagon. This dysfunction can cause overstimulation of glucagon, especially after meals, leading to gluconeogenesis, glycogenolysis and ketogenesis, thereby worsening hyperglycaemia and causing a metabolic acidosis (diabetic ketoacidosis).
- The mechanism by which hyperglycaemia causes chronic macrovascular and microvascular damage is thought to be related to oxidative stress, free radical damage, sorbitol production and glycosylation of tissues.
- The most common presentation of T1DM is in the primary care setting with classic symptoms, including the common triad of:
- Polydipsia - due to hyperglycaemia increasing plasma osmolarity, causing the blood to become more concentrated. Increased thirst is also an effect of fluid loss due to polyuria.
- Polyuria/nocturia - due to the body's attempts to excrete glucose renally, as well as secondary to increased fluid intake.
- Weight loss - due to loss of calories (in the form of glucose) in the urine.
- Additional common symptoms include:
- Dry mouth - due to plasma hyperosmolarity and dehydration from polyuria.
- Lethargy - lack of glucose uptake by cells results in reduced ability to meet the body's energy needs.
- Blurred vision - hyperglycaemia can cause an acute, reversible swelling of the lens. This is a different mechanism to that seen in the chronic complication of diabetic retinopathy.
- Classic symptoms may be difficult to identify in very young children (especially under 2 years) who may be in nappies, or may not be able to communicate their thirst. Symptoms of Candida infection (often within the groin) should raise suspicion of T1DM, particularly in this age-group.
- Diabetic ketoacidosis (DKA) represents the second most common form of initial presentation of T1DM (30%, increasing to 50% of those under 3 years of age).
- DKA can be severe and life-threatening, requiring hospitalisation for rehydration and insulin therapy.
- Signs and symptoms concerning for DKA include:
- Nausea and vomiting
- Abdominal pain
- Fruit-smelling ('pear drop') ketotic breath
Diagnosing diabetes mellitus:
- Initial investigations may include a point-of-care capillary blood glucose, capillary ketones and a urine dipstick.
- Significant hyperglycaemia, ketonaemia or ketonuria is a medical emergency and the patient should be transferred to hospital for further assessment of possible diabetic ketoacidosis.
- However, note that capillary blood glucose and urinalysis should not be used to formally make a diagnosis of diabetes.
- Venous blood glucose
- Fasting blood glucose ≥7.0 mmol/L (≥126 mg/dL).
- Non-fasting blood glucose ≥11.1 mmol/L (≥200 mg/dL).
- Oral glucose tolerance test
- Venous blood glucose concentration ≥11.1 mmol/L, 2 hours after 75 g oral glucose.
- This is rarely required in the diagnosis of T1DM, particularly if a patient already meets the diagnostic thresholds for diabetes based on other tests.
- Glycated haemoglobin (HbA1c)
- HbA1c ≥48 mmol/mol (≥6.5%).
- Reflects the glycaemic control over the preceding 3 months.
- HbA1c can underestimate the degree of hyperglycaemia if there is any concurrent condition affecting red blood cell survival.
Diagnosing T1DM as cause of diabetes mellitus:
This is largely a clinical diagnosis based on the history and clinical presentation, therefore further investigations may not be required.
Investigations which may be useful if the diagnosis is unclear include:
- Autoantibodies to islet cells, islet antigens (IA2, IA2-beta), insulin, glutamic acid decarboxylase (GAD), or zinc transporter ZnT8 indicate autoimmune beta cell destruction and suggest T1DM.
- Fasting C-peptide
- C-peptide is a byproduct of insulin production, and therefore represents the presence of endogenous insulin.
- C-peptide will be low or undetectable in patients with T1DM.
Criteria for a diagnosis of diabetes mellitus (as per the World Health Organisation):
- Random plasma glucose level ≥11.1 mmol/L (≥200 mg/dL) in the presence of symptoms of hyperglycaemia; OR
- Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL); OR
- Plasma glucose level ≥11 mmol/L (≥200 mg/dL) 2 hours after a 75 g oral glucose load; OR
- HbA1c ≥48 mmol/mol (≥6.5%) - note that HbA1c can be unreliable if a patient has any concurrent condition affecting red blood cell survival.
Identifying T1DM as cause of diabetes mellitus:
- Diabetes mellitus can broadly be classified into T1DM, T2DM, and gestational diabetes. It is important to differentiate the type of diabetes due to the difference in long-term management.
- Differentiating the cause of diabetes mellitus is mainly through clinical presentation and history, but may sometimes be supported by laboratory studies.
- Factors supporting a diagnosis of T1DM over other subtypes include:
- Age: most commonly diagnosed in childhood or adolescence but can occur later in life.
- Clinical presentation: polyuria, polydipsia, weight loss, lethargy, or diabetic ketoacidosis (DKA).
- Ketosis: often present, and may develop DKA which can be life-threatening.
- Family history: up to 10% have a close relative with T1DM; may also have personal or family history of other autoimmune disorders such as coeliac disease.
- Autoantibodies: presence of autoantibodies to islet cells, insulin, islet antigens (IA2 and IA2-beta), glutamic acid decarboxylase (GAD), or the zinc transporter ZnT8 indicate autoimmune beta-cell destruction and are suggestive of T1DM. However, their absence does not rule out a diagnosis of T1DM.
- C-peptide: low or undetectable. C-peptide is a byproduct of the conversion of pro-insulin to insulin and therefore reflects endogenous insulin production.
Other causes of diabetes
The similarities between T1DM and the differentials listed include: criteria met for a diagnosis of diabetes mellitus; symptoms of hyperglycaemia; long-term complications including macrovascular and microvascular disease.
1) Type 2 diabetes mellitus (T2DM)
- Results from insulin resistance and a relative insulin deficiency, but the pancreas usually continues to produce some insulin.
- Slower onset and older age at diagnosis.
- Ketosis uncommon.
- Strong association with obesity, cardiovascular risk factors and family history of T2DM (75-90% have an affected close relative).
- Negative for autoantibodies.
- May have initial response to oral anti-hyperglycaemic drugs.
- Onset during pregnancy.
- Caused by insulin resistance relating to pregnancy hormones and an increased demand for insulin during pregnancy.
- Generally resolves after birth but increased risk of T2DM in future.
- Monogenic diabetes caused by mutations in an autosomal dominant gene.
- Strong family history (50% of first-degree relatives will inherit mutation).
- Often absence of autoantibodies.
- Form of T1DM.
- Positive for autoantibodies.
- Low detection of C-peptide.
- Presents in adults.
- Slower onset.
- Often history of prolonged courses of drugs such as corticosteroids, tacrolimus, L-asparaginase or antipsychotics.
7) Endocrinopathies e.g. Cushing's syndrome, acromegaly, phaeochromocytoma, glucagonoma.
Causes of temporary hyperglycaemia
- Critical illness e.g. sepsis
- Neonatal hyperglycaemia