27th May 2025

Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by autoimmune destruction of pancreatic beta cells resulting in insulin deficiency and subsequently hyperglycaemia. Patients often initially present in childhood with a history of polyuria, polydipsia, weight loss and lethargy; or acutely unwell with diabetes ketoacidosis (DKA). The management of T1DM is with lifestyle modifications including diet and exercise and insulin therapy in a multidisciplinary team. The aims of treatment are to reduce risk of chronic complications of long-term hyperglycaemia including micro- and macrovascular damage and DKA.

Epidemiology

T1DM is a common condition causing up to 10%  of diabetes and causes over 85% of diabetes in young people. T1DM   has the highest incidence of presentation individuals less than 20 years of age, although it can present at any age. In the UK, the incidence is 1 in 25, 000 per year, the worldwide prevalence is 1, 110, 100 in 0-19 year-olds and there is a wide geographical variation and it is increasing annually.

Aetiology

T1DM is caused by autoimmune destruction of pancreatic beta cells which results in absolute insulin deficiency. Although the cause of the immune mediated destruction is not fully understood, a number of genetic and environmental factors are attributed.

Genetic Factors 

Genetic factors that increase the risk of T1DM include different gene polymorphisms, specifically human leukocyte antigen (HLA) alleles HLA-D2 and HLA-DQ. The HLA-DQ2 genotype is often seen in T1DM and also associated with coeliac disease. Individuals with a close relative with T1DM are at an increased risk of developing the disease. 

People with T1DM have an increased chance of having other autoimmune disorders, for example: Addison’s disease, Hashimoto’s thyroiditis, vitiligo and systemic lupus erythematous (SLE).

Environmental Factors 

Environmental factors are thought to be involved in contributing to developing T1DM but no cause has been found. Suggested environmental factors include viral infections, cow’s milk intake, vitamin D deficiency, early introduction of cereals and nitrate concentration in drinking water. 

Pathophysiology

T1DM develops from the autoimmune destruction of insulin-producing beta cells in the islets of Langerhans in the pancreas, which results in absolute insulin deficiency. T1DM is considered a type IV hypersensitivity autoimmune reaction; CD4+ T helper cells and CD8+ cytotoxic T cells attack pancreatic beta cells and over time stop insulin production. 

Destruction of pancreatic beta cells occurs sub-clinically for months to years as inflammation of beta cells (insulitis). Hyperglycaemia develops when around 90% of the beta cells have been destroyed. 

Patients that lack insulin are unable to use glucose in adipose tissue and peripheral muscle. This leads to secretion of counter-regulatory hormones including glucagon from overstimulation of pancreatic alpha cells, adrenaline, cortisol and growth hormone. These hormones, particularly glucagon, lead to gluconeogenesis, glycogenolysis and ketogenesis especially after meals; which lead to hyperglycaemia and metabolic acidosis (which presents as diabetic ketoacidosis).

Long term complications of T1DM is explained by chronic hyperglycaemia which leads to chronic microvascular  and macrovascular damage. Vascular damage is caused by hyperglycaemia induced oxidative stress, glycosylation of proteins in tissues, free radical damage and sorbitol production. Oxidative stress causes damage to the vascular endothelium by neutralising nitric oxide, which leads to low-density lipoproteins entering the vessels and deposit into the vessel wall driving inflammation and atheroma formation.

Microvascular complications include retinopathy, nephropathy and neuropathy and macrovascular complications include cardiovascular, cerebrovascular and peripheral vascular disease.

Diagnosis

Clinical Presentation 

T1DM mostly presents in childhood and most commonly diagnosed aged 10-14 years. There are three possible initial presentations including classical presentation, diabetic ketoacidosis and silent (asymptomatic) discovery.

The classical presentation in children and young people is hyperglycaemia without acidosis. Patients typically present with the triad of symptoms of polydipsia, polyuria or nocturia and weight loss. These symptoms are usually present in about 90% of patients but may not be the initial complaint. Other symptoms include dry mouth, lethargy and blurred vision. Presentations can include perineal candidiasis in young children and girls, acute visual disturbances and cataracts.

• Polydipsia occurs due to increased thirst as a result of increased plasma osmolality from hyperglycaemia. 
• Polyuria occurs when the glucose concentration rises above the renal threshold which leads to increased urinary glucose excretion, glycosuria causes osmotic diuresis which presents as polyuria and hypovolaemia and dehydration. In children, polyuria can present as excess wet nappies, bedwetting and daytime incontinence in a previously continent child.
• Weight loss occurs as a result of hypovolaemia and catabolism resulting in loss of calories (glucose) through urine, it is present in about 50% of patients. As a result of insulin deficiency, there is dysregulation of glucose utilisation in peripheral muscle and adipose tissue resulting in breakdown of muscle and fat. As polydipsia develops, patients are more thirsty than hungry and they develop nausea and anorexia from ketosis which contributes to weight loss further.

Diabetes ketoacidosis (DKA)  is the second most common presentation of T1DM (30% to 50% of children under 3 years). DKA can be severe and life threatening, it requires hospitalisation for rehydration and insulin therapy. Signs and symptoms of DKA include 

• Nausea and vomiting 
• Abdominal pain
• Dehydration 
• Tachypnoea
• Drowsiness 
• Fruit-smelling (‘pear drop’) ketotic breath 
• Coma 

Silent or asymptomatic discovery is the least common presentation where children are diagnosed before the onset of clinical symptoms. It is usually seen in children that are being closely monitored by a family member or clinician with high suspicion. 

Investigations 

In order to diagnose T1DM, a diagnosis of diabetes mellitus (DM) needs to be established.

Diagnosis of DM

• Capillary blood glucose, capillary ketones and urine dipstick can be indicators of T1DM but should not be used to make a formal diagnosis. 
• Venous blood glucose: fasting blood glucose ≥7.0 mmol/L or non-fasting blood glucose ≥11.1 mmol/L. 
• Oral glucose tolerance test (OGTT): venous blood glucose ≥11.1 mmol/L, 2 hours after ingesting 75 g oral glucose. 
• Glycosylated haemoglobin (HbA1c) ≥48 mmol/mol (≥6.5%).

Diagnosis of T1DM 

The diagnosis of T1DM is usually made by the investigations above in the setting of clinical presentation as mentioned. If the diagnosis is unclear, autoantibodies and fasting C-peptide can be used. 

• Autoantibodies to islet cells, islet antigens (IA2, IA2-beta), insulin, glutamic acid decarboxylase (GAD) or zinc transporter ZnT8.
• Fasting C-peptide level is low or undetectable in T1DM as C-peptide is a product of endogenous insulin production.

Criteria for diagnosis of DM (WHO)

If the patient is symptomatic, only one positive test from the criteria below is required to diagnose DM, if they are asymptomatic, two positive tests on two separate occasions are required to make a diagnosis.

• Random plasma glucose ≥11.1 mmol/L OR
• Fasting plasma glucose ≥7.0 mmol/L OR
• Plasma glucose level ≥11 mmol/L after OGTT 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.

Management 

Short term and long term management is complicated but extremely important as T1DM can reduce life expectancy by up to 13 years and vascular complications can be life changing. Management requires a multi-disciplinary approach and mainly involves strict glycaemic control and insulin therapy. Short term management of T1DM with insulin is potentially life saving by preventing diabetes ketoacidosis. Long term management of T1DM aims to prevent the development of chronic vascular complications by controlling blood glucose levels to as close to normal as possible.

HbA1c

Glycosylated haemoglobin (HbA1c) is an indicator of glucose control over the past three months and is used to guide treatment. The National Institute for Health and Care Excellence (NICE) recommends a target HbA1c level of 48mmol/mol (6.5%) or lower. Target levels are individualised to patients and factors to be considered include the patient age, life expectancy, advanced vascular complications, activities, aspirations, likelihood of complications, co-morbidities, occupation and history of hypoglycaemia

Optimising glucose control involves lifestyle changes including diet and exercise and insulin therapy. HbA1c levels should be measured every 3 months in those under 18 years of age and every three to six months in adults. In addition to this, self glucose monitoring is also an essential part of management.

Self-monitoring of blood glucose 

Patients should be taught self-monitoring skills at the time of diagnosis and initiation of insulin therapy, these should be reviewed at least once a year. They should be taught how to measure their blood glucose, how to interpret the results and what action to take.

Patients with T1DM should test their blood glucose at least four times a day including before meals and before bed. A higher frequency of monitoring is recommended if patient’s agreed HbA1c target is not met, the frequency of hypoglycaemia episodes increases, during illness, before during and after sport, when planning pregnancy, during pregnancy, while breastfeeding, there is a legal requirement to do so (e.g. before driving), if the patient has impaired awareness of hypoglycaemia.

Blood glucose targets

• On waking: fasting plasma glucose 5-7 mmol/L.
• Before meals at other times of day: a plasma glucose of 4-7mmol/L.
• After meals: plasma glucose level 5-9mmol/L.
• Bedtime: plasma glucose should be personalised to the individual considering the timing of their last meal and the insulin dose required and achieve the recommended fasting plasma glucose on waking.

Insulin therapy 

Insulin therapy should be started immediately after diagnosis, it aims to mimic physiological insulin release by using a basal bolus regime or a continuous infusion with an insulin pump.

The total daily dose of insulin can vary from 0.5 to 1 units/kg/day in children, 0.2 to 0.4 units/kg/day in adults and up to 1.5 units/kg/day during puberty. Usually, one half of the total daily dose should be given as basal insulin and one half as bolus dosing which is divided and given before meals. 

Insulin regimens 

• Offer the patient a multiple daily injection basal-bolus insulin regimen from diagnosis over twice-daily mixed, basal only or bolus only insulin regimens.
• A combination of long-acting insulin (insulin detemir, degludec, or glargine) for basal dosing and rapid-acting insulin (insulin lispro, aspart or gluisine) for bolus dosing is recommended for patients.

Basal insulin therapy 

• Twice daily insulin detemir is recommended by NICE or alternatives are recommended as below.
• Once daily insulin glargine if the patient cannot tolerate insulin detemir or has a strong preference for once-daily basal injections.
• Once daily insulin degludec if there are concerns about nocturnal hypoglycaemia .
• Once daily ultra-long acting insulin degludec if the patient needs help from a carer to administer injections.

Bolus dosing 

• Rapid acting insulin analogues injected before meals are the insulin of choice for bolus dosing over rapid-acting soluble human or animal insulins.

Patients should be reminded to rotate injection sites in the same part of the body, most commonly the lower abdomen, to prevent lipodystrophy which can cause poor insulin absorption and poor control of blood glucose.

Other considerations 

• Insulin pumps (continuous subcutaneous insulin infusion, CSII) may be considered for patients in which MDI regimens are not appropriate or unsuccessful. 
• NICE recommend adding metformin if the BMI >- 25kg/m^2