27th May 2025

Type 1 Diabetes Mellitus and Hypogylcaemia

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 

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a potentially life threatening complication of T1DM, it can be the first presentation of T1DM in around 6% of cases and the mortality rate is estimated at 1%. Rarely, patients with type 2 diabetes mellitus (T2DM) can develop DKA under conditions of extreme stress. The presentation of DKA is the rapid onset of a triad of hyperglycaemia, ketonaemia and metabolic acidosis.

Aetiology 

DKA is caused by uncontrolled lipolysis which releases excess fatty acids that are converted into ketone bodies.

Precipitating factors and clinical presentation

Causes of DKA include the 7 I’s of DKA:

• Infection 
• Insulin missed 
• Ischaemia – acute coronary syndrome, critical limb ischaemia or ischaemic bowel  
• Initial presentation – new onset of diabetes especially in young children 
• Intoxication – cocaine, cannabis and acute intoxication with alcohol 
• Impregnation – pregnancy increases metabolic demands 
• Iatrogenic – drugs (corticosteroids, thiazides, sodium-glucose co-transporter 2 (SGLT2) inhibitors, symphathomimetics, second generation antipsychotics, immune checkpoint inhibitors)

Clinical Presentation

• Nausea and vomiting 
• Abdominal pain 
• Polydipsia, polyuria and dehydration 
• Kussmaul respiration (deep hyperventilation)
• Ketotic breath (acetone or ‘pear drops’ smell)
• Reduced consciousness 
• Hypothermia

Investigations

All patients with suspected DKA should have the following investigations:

• Venous Blood Gas: pH <7.0 indicates severe DKA, hyperkalaemia is common
• Blood ketones or urinary ketones: ketonaemia is blood ketones >3.0 mmol/L
• Blood glucose: hyperglycaemia is >11mmol/L
• Bloods including:
  • Full Blood Count: leukocytosis is common, consider infection if markedly raised white cell count  
  • Urea and Electrolytes: hypernatraemia is common indicating dehydration, hyperkalaemia is common but hypokalaemia on arrival is an indicator of severe DKA as total body potassium is low

Other investigations to be considered include: 

• Urinalysis: ketonuria 2+ on standard urine sticks, may be positive for glucose, leukocytes and nitrites in the presence of urinary tract infection 
• ECG: looking for myocardial ischaemia 
• Amylase and Lipase 
• Cardiac enzymes: raised troponin I if myocardial infarction is suspected  
• Creatinine kinase: if rhabdomyolysis is suspected  
• Chest x-ray: look for consolidation in pneumonia and signs of pulmonary oedema if the patient is desaturating after fluid resuscitation
• Liver function tests: screen for an underlying hepatic cause of DKA 
• Blood, urine and sputum cultures: order if there are signs of infection 
• Pregnancy test: in women of child bearing age, pregnancy increases metabolic demands and can cause DKA in diabetic patients

Diagnostic criteria

The diagnosis of DKA should be made considering the clinical presentation, investigations and diagnostic criteria.

Three criteria must be met to diagnose DKA:

• Hyperglycaemia: blood glucose >11mmol/L OR known diabetes AND
• Ketonaemia: blood ketones >3mmol/L OR ketonuria (2+ or more on standard urine sticks) AND
• Acidosis: bicarbonate <15mmol/L AND/OR venous pH <7.3

Patients with DKA can become critically unwell, consider cardiac monitoring and escalate to a senior and consider critical care support if the patient has any of the following parameters:

• Persistent hypotension (systolic blood pressure <90mmHg) or oliguria (<0.5ml/kg/hr)  despite treatment with intravenous fluids 
• Tachycardia (heart rate >100bpm) or bradycardia (heart rate 60bpm)
• Oxygen saturations <92% on room air 
• Glasgow Coma Scale (GCS) <12 
• Potassium <3.5mmol/L on admission 
• Blood ketones >6mmol/L
• Venous pH <7 
• Venous bicarbonate <5mmol/L
• Anion gap >16
• The patient has kidney failure, is pregnant or other co-morbidities 

Each trust has their own guidelines outlining when to escalate to critical care and these should be followed locally. 

Management 

The three main principles of management are fluid replacement, insulin infusion and correction of electrolyte disturbances.

Fluid replacement 

• Isotonic saline is used initially, even if the patient is severely acidotic. 
• Most patients with DKA are extremely dehydrated and depleted of fluid up to 5-8 litres.
• A slower infusion rate should be considered in young adults aged 18-25 due to the risk of cerebral oedema and patients aged 16-18 should be managed by a paediatric team.

Table 1: Example regime of typical fluid replacement in DKA (adapted from JBDS guidelines) for patients with a systolic BP on admission of 90mmHg and over.

Insulin infusion

• A fixed rate intravenous insulin infusion (FRIII) should be started at a rate of 0.1 unit/kg/hr.
• When the blood glucose reaches <14mmol/L, an infusion of 10% dextrose at 125ml/hr should be started alongside the 0.9% sodium chloride FRIII. The rate of FRIII can be reduced to 0.05units/kg/hr to reduce the risk of hypoglycaemia and hypokalaemia.

Correction of electrolyte disturbance 

• Serum potassium is high in DKA but total body potassium is low. 
• Serum potassium will fall quickly with treatment with insulin and causes hypokalaemia. 
• Potassium should be replaced with the intravenous fluid replacement. 
• Cardiac monitoring should be considered if the potassium correction is more than 20mmol/hour.

Table 2: Guidance for potassium management outlined by the JBDS (adapted from JBDS guidelines)

Other principles of management:

• Identify and treat the underlying cause e.g. infection, myocardial infarction, intoxication. 
• Long-acting insulin should always be continued and short acting insulin should be stopped. 
• Involve the specialist diabetes team.
• Thromboprophylaxis. 

Monitoring 

• Monitor the airway and consider a nasogastric tube to prevent aspiration secondary to gastric paresis and low GCS.
• Measure pH, venous bicarbonate, potassium, blood glucose and ketones at 0, 1, 2, 4, 6 and 12 hours whilst measuring blood glucose and ketones hourly for the first 6 hours and then at 12 hours.
• Monitor for improvement with the following:
  • Reduction of ketones by at least 0.5mmol/L/hr OR 
  • Increase of venous bicarbonate by at least 3mmol/L/hr AND 
  • Reduction in blood glucose of 3mmol/L/hr
• Monitor for cerebral oedema by assessing GCS hourly.
• Monitor for pulmonary oedema by monitoring for desaturation, obtain a chest x-ray if suspected and consider an arterial blood gas.
• Monitor fluid input and output, insert a urinary catheter if anuric after one hour of starting DKA treatment. 

Resolution 

Three criteria need to be met to confirm resolution of DKA:

• pH >7.3 AND 
• Blood ketones 0.6 mmol/L AND 
• Bicarbonate >15mmol/L

Both the acidosis and ketonaemia should have resolved within 24 hours, if this has not occurred then a review from a senior endocrinologist is required. When the above criteria are met and the patient has started eating and drinking then the patient should be switched to subcutaneous insulin; this should be started with a meal and the FRIII should be continued for 30-60 minutes after this is started to permit a successful switch. If DKA has resolved but the patient is not eating and drinking then the patient can be switched to a variable rate intravenous insulin infusion (VRIII) and intravenous fluids should be continued. The patient should be reviewed by a diabetes specialist nurse before they are discharged.

Complications 

Complications can occur from DKA itself or from the treatment. These include:

• Gastric stasis which can increase the risk of aspiration
• Thromboembolism 
• Arrhythmias secondary to hyperkalaemia or iatrogenic hypokalaemia 
• Acute respiratory distress syndrome 
• Acute kidney injury 
• Iatrogenic complications due to incorrect fluid therapy: hypokalaemia, hypoglycaemia and cerebral oedema (children and young adults are most commonly at risk of this following fluid resuscitation, patients should be monitored for signs of cerebral oedema using neuro-observations and monitor for headache, irritability, visual disturbance, focal neurology)

Hypoglycaemia 

Hypoglycaemia is a common complication in diabetes, it is the most common side-effect of insulin or sulfonylurea use in diabetes. Hypoglycaemia is a common concern in individuals with type 1 diabetes mellitus (T1DM) as they depend on exogenous insulin for glucose control. The risk of hypoglycaemia can be a major barrier in the optimal treatment of diabetes and can be life threatening; it should always be ruled out in an acutely unwell patient especially diabetic patients and forms part of the “ABCDE” assessment in the Disability stage.

Hypoglycaemia is defined as a blood glucose level below normal. In non-diabetic people, normal glucose levels are 3.5-7mmol/L and hypoglycaemia is classed as less than 3.5mmol/L. In a diabetic patient, hypoglycaemia is classed as less than 4mmol/L, it is mild if self treated and severe if unable to self treat and requires medical assistance.

Epidemiology and Aetiology

T1DM patients have approximately two episodes of mild hypoglycaemia per week and up to 30-40% of patients experience severe hypoglycaemia per year. 

There are a number of factors which can cause hypoglycaemia which should be identified and treated quickly. These include excessive insulin administration, delayed or missed meals, increased physical activity and alcohol consumption.

Clinical presentation

Clinical presentation of hypoglycaemia is a combination of autonomic symptoms, neuroglycopaenic symptoms and general malaise.

Table 3: Clinical presentation of hypoglycaemia

Management

The management of hypoglycaemia is guided by whether the severity is mild, moderate or severe. In all cases, patients should be assessed using an ABCDE approach, stop IV insulin and call for help if required. 

Mild hypoglycaemia is when the patient is conscious, orientated and able to swallow. They can be treated orally. Immediately, they should be given 15-20g of a quick-acting carbohydrate. Examples include glucose tablets and fruit juice. This should be followed by giving a long acting carbohydrate such as biscuits, bread, milk or carbohydrate. 

Moderate hypoglycaemia is when the patient is conscious and able to swallow but confused, irritable and disorientated. Initially, these patients can be treated as for mild hypoglycaemia but if the patient is not cooperative, then they should be given two tubes of 40% glucose gel given between the teeth and gums. 

The oral treatment can be repeated up to three times before moving onto parenteral treatment as for severe hypoglycaemia.

Severe hypoglycaemia is when the patient is unconscious, nil by mouth, having seizures or very aggressive. These patients should be given 1mg intramuscular glucagon or intravenous dextrose as 100ml of 20% dextrose or 200ml of 10% dextrose over 15 minutes if intravenous access is available.

Following initial management, it is essential to identify and correct the cause. This includes reviewing the patient’s diabetes treatment regime including oral antihyerglycaemic drugs and insulin. The dose of medications should be adjusted based on the patient’s needs and lifestyle and review the glucose targets as some individuals may benefit from less strict glucose control.

Prevention

The prevention of hypoglycaemia is key in avoiding dangerous side effects. This should be achieved through monitoring blood glucose levels regularly; patient education of self-management including medication adjustments and meal planning and tailoring insulin and oral antihyperglycaemic medication regimes to the individual.

References 

1. https://www.nice.org.uk/guidance/ng17 
2. https://bestpractice.bmj.com/topics/en-gb/25?q=Type%201%20diabetes&c=suggested
3. https://www.uptodate.com/contents/epidemiology-presentation-and-diagnosis-of-type-1-diabetes-mellitus-in-children-and-adolescents?search=type%201%20diabetes&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 
4. https://www.uptodate.com/contents/pathogenesis-of-type-1-diabetes-mellitus?search=type%201%20diabetes&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4
5. https://www.uptodate.com/contents/overview-of-the-management-of-type-1-diabetes-mellitus-in-children-and-adolescents?search=type%201%20diabetes&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2
6. https://bestpractice.bmj.com/topics/en-gb/3000097
7. https://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-clinical-features-evaluation-and-diagnosis?search=diabetic%20ketoacidosis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2
8. https://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-treatment?search=diabetic%20ketoacidosis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
9. https://bestpractice.bmj.com/topics/en-gb/3000305
10. https://www.uptodate.com/contents/hypoglycemia-in-adults-with-diabetes-mellitus?search=hypoglycaemia&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3