Type 1 diabetes mellitus (T1DM) is one of the most common long-term conditions affecting children and young adults worldwide; however, its global prevalence is variable and an exact figure of those affected is difficult to determine,
. The incidence of childhood T1DM appears to be increasing in many parts of the world, including Europe,,,,
. Of the estimated 4.5 million people living with diabetes in the UK, 10% have T1DM
. There are around 31,500 children and young adults up to the age of 18 years with diabetes in the UK — 95% of these have T1DM,
T1DM was traditionally thought to be more common in children and adolescents. The age of diagnosis in these patient groups has a bimodal distribution, with a first peak at 4–6 years and a second at 10–14 years,
. Around 45% of children with diabetes are diagnosed before ten years of age
. However, a recent study by Thomas et al. has shown that T1DM can present throughout the first six decades of life
. It found that 42% of T1DM diagnoses occur after 30 years of age, which represents around 4% of diagnoses for all patients with diabetes
. Late-onset T1DM may be commonly misdiagnosed as type 2 diabetes mellitus (T2DM), thereby making it difficult to determine accurate incidence and prevalence figures
Although around 85% of newly diagnosed cases of T1DM are sporadic
, T1DM is strongly influenced by genetic factors. Individuals with a first-degree relative with T1DM have a 1-in-20 lifetime risk of developing the condition
. Monozygotic (identical) twins have a concordance rate of >60%, whereas dizygotic (non-identical) twins have a concordance rate of 6–10%
T1DM is also more common in non-Hispanic whites than Asians
. Geography appears to have an inconsistent bearing on incidence of T1DM: for example, in Europe and China, the risk of T1DM seems to increase with increase in geographical latitude, but this is not true in the United States,,
. Environmental factors also seem to play a role; when people migrate from a region of low to high incidence, their risk of developing T1DM increases.
It appears that, in those with genetic predisposition, exposure to environmental factors results in T1DM. Suspected factors include viral infections, immunisations, diet and vitamin D deficiency, but none are proven.
This article outlines the pathogenesis and diagnosis of T1DM, the types of insulin, insulin regimens and strengths available for its day-to-day management, and how to adjust doses. Reference is also made to the role and importance of both carbohydrate (CHO) counting and blood glucose monitoring. Discussion of diabetic emergencies lies outside the scope of this piece and has therefore been omitted.
Pathogenesis and diagnosis of T1DM
T1DM is a heterogeneous condition resulting from pancreatic beta-cell destruction, leading to a severe impairment of insulin secretion and eventual absolute insulin deficiency
. In the majority of patient cases (type 1A), an autoimmune-mediated attack on beta-cells occurs, while in a small minority (type 1B), an idiopathic destruction or failure of beta-cells occurs
The model for the natural history of T1DM suggests that in genetically susceptible individuals, exposure to an environmental trigger induces beta-cell autoimmunity, resulting in the development of islet-reactive auto-antibodies
. This process heralds the development of insulitis — inflammation in and around the beta-cells — mediated by cytotoxic CD8+ T cells, resulting in a progressive and predictable loss in insulin secretory function
. With this model, clinical T1DM does not present until >80–90% of the beta-cells have been destroyed,
The clinical course of T1DM is characterised by the rapid onset of osmotic symptoms, including polyuria, polydipsia, weight loss and fatigue, in the presence of hyperglycaemia, up to 67% of patients can present with the potentially life-threatening acute complication of diabetic ketoacidosis (DKA) at diagnosis
. Detectable autoantibodies include glutamate decarboxylase-65, islet antigen-2, zinc transporter-8, islet cell antibody and tetraspanin, with detectability diminishing with duration of T1DM,,,,
Since the underlying pathogenesis of T1DM is absolute insulin deficiency, the treatment of the condition relies on supplementation of the deficient hormone. On a day-to-day basis, insulin is supplemented by way of multiple, subcutaneous injections (in times of acute illness, insulin may also need to be delivered intravenously).
Patients with T1DM potentially face several decades of exposure to sub-optimal glycaemic control owing to the early age of diagnosis. Therefore, the aim of insulin therapy in T1DM is to mimic the physiological insulin secretion from a functional pancreas of a person without diabetes to maximise the chances of attaining normal blood glucose levels. This is best achieved by using a basal bolus insulin regimen or an insulin pump. Evidence has shown that the more time a patient has blood glucose levels within the normal range, the lower the risk of complications
. However, achieving tight control of blood glucose levels, both fasting and postprandial, without resultant hypoglycaemia can be extremely challenging for people with T1DM.
Other treatment options are available, but these are used only in very specific instances. Whole-pancreas transplantation is a treatment option for those patients with T1DM who have severe hypoglycaemia (requiring third-party assistance) with hypoglycaemia unawareness, but the procedure is not without significant risk. If the patient has associated end-stage chronic kidney disease, then a kidney transplant may be carried out contemporaneously. Pancreatic islet cell transplantation, which involves extracting pancreatic islet cells from a cadaveric donor and injecting it into the portal vein in the liver of the patient under local anaesthesia, may be another option in such patients. Both procedures require subsequent life-long immunosuppression.
Some therapies, including bone marrow stem cell transplantation, immunotherapy and use of an artificial pancreas, are currently in the experimental phase.
The following sections provide more information on the types of insulin, insulin regimens and strengths available for management of T1DM, as well as how to adjust doses.
Types of insulin
All available insulins can be classified based on their source. Animal insulins are extracted and purified from animal sources (e.g. porcine insulin from pigs). Although they were widely used in the past, they are no longer initiated in people with diabetes. Human insulins are produced by recombinant DNA technology, and insulin analogues are human insulins that are modified to produce either an extended duration of action or faster absorption. Analogue insulins are preferred in T1DM owing to their proximity of action to endogenous insulin.
More recently a number of biosimilar insulins have been made available (e.g. AbasaglarÂ® [Eli Lilly], a biosimilar of insulin glargine [LantusÂ®, Sanofi]). Biosimilar insulins may provide a cheaper alternative to standard insulin; however, it is important to note these insulins are not interchangeable, and for this reason, insulin should always be prescribed by brand rather than by generic name.
The main types of insulin are classified on the basis of onset or duration of action (see Table 1) and can be used in different insulin regimens.
Basal-bolus insulin is the regimen of choice in patients with T1DM. It uses a basal or background long-acting insulin to attempt to mimic physiological insulin secretion and a bolus rapid-acting insulin with each main meal to attempt to achieve normal post-meal blood glucose levels.
Rapid-acting insulin analogues, such as insulin aspart (NovoRapidÂ®, Novo Nordisk), insulin lispro (HumalogÂ®, Eli Lilly) or insulin glulisine (ApidraÂ®, Sanofi) are preferred to short-acting insulins such as HumulinÂ® S (Eli Lilly) or ActrapidÂ® (Eli Lilly), as they have a quicker onset of action, can be given just before or with a meal, and are associated with 30% less hypoglycaemia
. A recently launched formulation of insulin aspart (FiaspÂ®, Novo Nordisk) has an even quicker onset of action than NovoRapid (see Table 1).
Long-acting insulin analogues, such as insulin detemir (LevemirÂ®, Novo Nordisk) and insulin glargine injection (Lantus) have a longer duration of action than intermediate-acting insulins and produce a more constant background level. As a result, they are injected once daily, but can be used twice a day. If injected once daily, it should be given at roughly the same time each day because the duration of action may not extend to 24 hours
. Insulin degludec (TresibaÂ®, Novo Nordisk), and insulin glargine (ToujeoÂ®, Sanofi) have a >24-hour duration of action, so with these insulins there is some flexibility with the timing of injection (see Table 1).
The National Institute for Health and Care Excellence (NICE) now recommends using insulin detemir (Levemir) twice a day as the basal insulin of choice for patients with T1DM, as it was found to be the most effective, both clinically and financially, with better quality-adjusted life years over a patient’s lifetime
Other long-acting insulins can be considered if the patient is on an existing insulin regimen that is achieving their agreed targets, or if twice-daily basal insulin injection is not acceptable to the patient. NICE recommends that if a patient with T1DM is not achieving the required results, then a T1DM specialist should be asked for advice on management.
Twice-daily regimens are not usually recommended for adults with newly diagnosed T1DM, unless specifically chosen by the patient. Twice-daily insulin regimens involve injecting insulin with breakfast and the main evening meal. The insulin preparation used combines a ready-made biphasic mixture of rapid- or short-acting insulin with intermediate-acting insulin.
In patients with T1DM who opt to use a twice-daily regimen, a mixture of rapid and intermediate insulin (NovoMixÂ® 30, Novo Nordisk, or Humalog Mix 25, Eli Lilly) is preferred as it can be given just before or with meals.
At time of publication, there are no biphasic mixtures of long-acting with rapid-acting insulin available.
Traditionally, most insulins are manufactured at a concentration of 100units/mL; however, higher strength insulins are now available, including insulin lispro 200units/mL (Humalog), insulin degludec 200units/mL (Tresiba) and insulin glargine 300units/mL (Toujeo).
These higher strength insulins are generally used by patients with T2DM, who sometimes require high doses of insulin owing to resistance, enabling them to inject the same dose of insulin in a smaller volume. As such, they can also be beneficial in those experiencing lipohypertrophy. In the case of insulin glargine (Toujeo), there is also reduction in nocturnal hypoglycaemia
. These higher strength insulins are only available as prefilled pens, so by dialling up the dose, rather than the volume, there should not be any confusion about the number of units of insulin delivered. To avoid insulin errors arising from different insulin strengths being available, insulin should never be withdrawn using an insulin syringe from a prefilled pen or cartridge
It is important to note that the generic insulins are not routinely interchangeable. Insulin glargine is available as Lantus 100units/mL and Toujeo 300units/mL, but they do not simply differ in potency by a factor of three — as such, caution needs to be exercised when changing from one to another. Product literature (summary of product characteristics) should be consulted to guide decisions on substituting insulins.
Table 1 below describes the onset and action of various insulins
|Generic name||Brand name and manufacturer||Strength (Units/mL)||Usual timing of injection||Onset||Duration|
|Ultra rapid-acting insulin||Insulin aspart||FiaspÂ®, Novo Nordisk||100||2 minutes before and up to 20 minutes after meals||5–10 minutes||3–5 hours|
|Rapid-acting insulin||Insulin lispro||HumalogÂ®, Eli Lilly||100 + 200||0–15 minutes before or soon after meals||10–20 minutes||2–5 hours|
|Insulin aspart||NovoRapidÂ®, Novo Nordisk||100||0–15 minutes before or soon after meals||10–20 minutes||2–5 hours|
|Insulin glulisine||ApidraÂ®, Sanofi||100||0–15 minutes before or soon after meals||10–20 minutes||2–5 hours|
|Short-acting insulin||Insulin soluble||HumulinÂ® S, Eli Lilly; ActrapidÂ®, Novo Nordisk; InsumanÂ®Rapid, Sanofi||100||15–30 minutes before meals||15–45 minutes||6–12 hours|
|Insulin porcine||Hypurin Porcine NeutralÂ®, Wockhardt UK||100||15–30 minutes before meals||15–45 minutes||6–12 hours|
|Intermediate-acting insulin||Isophane insulin||HumulinÂ®I, Eli Lilly; InsulatardÂ®, Novo Nordisk; Insuman BasalÂ®, Sanofi; HypurinÂ® Porcine Isophane, Wockhardt UK||100||Usually once or twice daily||1–2 hours||12–20 hours|
|Long-acting insulin||Insulin glargine||LantusÂ®, Sanofi||100||Once daily, any time (at same time each day)||1.5–2 hours||24 hours|
|Insulin glargine||AbasaglarÂ®, Eli Lilly||100||Once daily, any time (at same time each day)||1.5–2 hours||24 hours|
|Insulin glargine||ToujeoÂ®, Sanofi||300||Once daily, any time (at same time each day)||Steady state occurs after 3–4 days||24–36 hours|
|Insulin detemir||LevemirÂ®, Novo Nordisk||100||Once or twice daily (at same time each day)||Steady state occurs after 2–3 doses||24 hours|
|Insulin degludec||TresibaÂ®, Novo Nordisk||100 + 200||Once daily, any time (at same time each day)||Steady state occurs after 2–3 days||Beyond 42 hours|
|Pre-mixed insulin||Insulin soluble + insulin isophane||HumulinÂ® M3, Eli Lilly; InsumanÂ® Comb 15/25/50, Sanofi||100||20–30 minutes before meals||0.5–2 hours||12–24 hours|
|Insulin soluble porcine + insulin isophane porcine||HypurinÂ® Porcine 30/70, Wockhardt UK||100||20–30 minutes before meals||0.5–2 hours||12–24 hours|
|Insulin aspart + insulin aspart protamine||NovoMixÂ® 30, Novo Nordisk||100||0–15 minutes before or soon after meals, usually twice daily||10–20 minutes||15–24 hours|
|Insulin lispro + insulin lispro aspart protamine||HumalogÂ® Mix25, Eli Lilly; Humalog Mix50, Eli Lilly||100||0–15 minutes before or soon after meals, usually twice daily||10–20 minutes||15–24 hours|
Subcutaneous insulin is injected, most often using a pen device that is either disposable or contains a cartridge refill. Most pen devices are very similar, with easy-to-use dial-up systems that always display the number of units of insulin to be administered. Many have an audible click that confirms that the dose has been administered. Patients with diabetes may have visual or dexterity problems; as such, they should be shown a range of devices when initiating insulin, so that they can choose one that is easy for them to use.
All insulin not in use should be stored in a refrigerator at 2–8oC. If this is not possible, insulin should be kept away from direct sunlight and sources of heat, or it may lose potency. When in use, insulin can be stored at room temperature for four weeks (or longer depending on the brand used).
In 2011, the National Patient Safety Agency recommended that all patients commencing insulin should be issued with an information booklet. An ‘insulin passport’ was also recommended to provide accurate identification of the insulin products used by the patient and enable the sharing of this information between different healthcare professionals across healthcare settings. However, the insulin passport does not indicate the dose of insulin, and relies on the patient to carry the passport with them and make sure it is kept up to date
Box 1: Carbohydrate counting
The basal-bolus insulin regimen can be made more physiological by employing CHO counting. CHOs have the most significant effect on post-meal blood glucose
. CHO counting is a meal-planning approach that aims to match the bolus insulin dose with the actual CHO content of the meal
Patients using this approach start by eating consistent amounts of CHO at meals, while recording pre- and post-meal blood glucose levels. Baseline insulin requirements are then matched to this CHO intake, using the blood glucose results. Once pre- and post-meal blood glucose levels are in the target range, insulin-to-CHO ratios are determined. Patients also learn how to estimate or calculate the amount of CHOs in a meal — either in grams or as CHO portions (one CHO portion = 10g of CHO). This may be done using reference guides, visual aids or printed information available on food packaging. A number of apps are also available that help calculate the CHO content of a meal.
Once the patient has learned how to count CHOs and has determined their insulin-to-CHO ratio, they are ready to use this meal-planning approach. They calculate or estimate the CHO content at each meal and then administer the insulin dose required for that amount of CHO, depending on their pre-determined insulin-to-CHO ratio.
In cases of high blood glucose before or between meals, a correction dose of insulin may be used to lower blood glucose, but this could precipitate hypoglycaemia. Correction doses for hyperglycaemia are recommended on ‘sick days’ to prevent DKA.
CHO counting allows flexibility in meal times and food choices, while attempting to minimise adverse metabolic control and health outcomes. In adults with T1DM, there is some evidence that CHO counting improves glycaemic control,
. There also appears to be some positive impact on psychological aspects and hypoglycaemia, without significant adverse changes to weight
Continuous subcutaneous insulin infusion (CSII or ‘insulin pump’)
An insulin pump is a small programmable device that holds rapid-acting insulin in a reservoir and delivers a continuous infusion of insulin through a cannula that has been inserted subcutaneously, usually in the abdominal area. The pump automatically delivers small pulses of insulin to keep blood glucose in the desired range between meals and overnight. The rate of insulin delivery is predetermined and programmed into the pump, and can be different from hour to hour if needed. Patients can administer bolus insulin doses at mealtimes via the pump at the touch of a button using CHO counting (see Box 1).
Insulin pump therapy is indicated in patients who have T1DM in whom attempts at tightening glycaemic control with multiple-dose injection (MDI) therapy have led to disabling hypoglycaemia, or when glycated haemoglobin (HbA1c) levels have remained >69mmol/mol on MDI therapy despite a high level of care. It is initiated and managed by specialist centres only
Insulin pump therapy can also be used in other circumstances where good glycaemic control is essential but is not being achieved owing to hypoglycaemia, such as during pregnancy. It is also used in patients whose blood glucose control can be erratic and unpredictable (e.g. those with gastroparesis).
Currently in the UK, there are numerous pump brands to choose from — the majority of which are with tubing (connected to the cannula via a tube), although there are some that are in patch form (attached to the skin via a patch). Furthermore, some of the pumps (MiniMedâ„¢ Paradigm Veoâ„¢ and MiniMed 640G, Medtronic; AnimasÂ® VibeÂ®, Animas; A6 TouchcareÂ® Medtrum) have features that link up with continuous glucose monitors and, with the exception of Animas Vibe, suspend insulin delivery in the event of hypoglycaemia (known as a ‘closed-loop’ system).
Adjusting insulin doses
In the initial months after diagnosis of T1DM, a degree of insulin secretion and residual beta-cell function remains, resulting in a period of low requirements of exogenous insulin (known as the ‘honeymoon phase’). As this residual function diminishes with time, insulin requirements increase.
The aim of insulin therapy is to maintain as close to normal blood glucose levels as possible, and as such, an individual patient’s insulin doses are likely to change continually. To safely make insulin dose adjustments, the individual should have capillary blood glucose levels monitored at least before every meal and at bedtime. Suboptimal fasting blood glucose levels can usually be optimised by adjusting the dose of the basal insulin by 10-20% increments or reductions as needed. However, care must be taken to avoid nocturnal hypoglycaemia. Pre-meal blood glucose levels are usually optimised by adjusting the preceding bolus insulin dose. Patients must receive education and support to enable them to make decisions on self-management of insulin on a day-to-day basis.
However, blood glucose levels are influenced by many other factors, such as changes in diet, levels of physical activity and intercurrent illness, all of which need to be considered when adjusting insulin doses. This can often be a complicated process and may require specialist input.
Blood glucose monitoring
Glucose monitoring is an integral part of T1DM management and an essential tool in achieving tight glycaemic control. The practice has evolved from urine dipstick analysis to finger capillary blood glucose measurements for self-monitoring of blood glucose (SMBG) to, more recently, continuous and flash glucose monitoring (CGM and flash GM, respectively).
The most common use of SMBG worldwide is in modern, lightweight and relatively inexpensive glucose meters that utilise a single drop of capillary blood, obtained from finger-pricking with a lancet, on a testing strip. These meters may have a wide range of additional features, such as insulin bolus dose calculators, memory of test results, and alerts for readings outside a preset target,
. Most meters can be connected to a wide variety of online software, such as DiasendÂ® (Glooko)
, and glucose data can be downloaded for analysis
NICE guidance for adults with T1DM recommends patients receive a choice of blood glucose meters by their clinicians. SMBG is advised at least four times a day (before each meal and at bedtime)
. The advice is extended to 10 times a day or more in the following circumstances:
- An increase in the frequency of hypoglycaemia;
- Inability to achieve the desired HbA1c;
- During periods of illness;
- If there is a legal requirement (i.e. before driving [as per the UK’s Driver and Vehicle Licensing Agency requirements]);
- Before, during and after sport;
- During pregnancy and breast feeding;
- Certain lifestyles (such as long-distance travel or high-risk occupations);
- Impaired awareness of hypoglycaemia,
The importance of SMBG on glycaemic control cannot be emphasised enough. Data from the T1DM Exchange Clinic Network, which included 20,555 patients from 67 paediatric and adult endocrinology units in the United States, revealed a very clear and significant inverse relationship of frequency of SMBG and HbA1c
. The impact of a lowered HbA1c on long-term complications in T1DM is elaborated later.
While HbA1c reflects the exposure of haemoglobin to glucose over 120 days, it does not indicate the variation in blood glucose levels in response to activity, diet or insulin therapy, unlike SMBG
. This variation is paramount in pattern identification and reduction in excursions of blood glucose readings to avoid DKA and hypoglycaemia. Furthermore, a persistently low HbA1c may be concealing a pattern of recurrent hypoglycaemia, revealed only by regular SMBG, that may result in a reduction or loss of hypoglycaemia awareness.
A 2016 survey of 1,000 respondents conducted by Diabetes UK found one in four individuals with diabetes were refused prescription for blood glucose test strips or have had the number of strips prescribed restricted
. More worryingly, 52% of these individuals lived with T1DM. Furthermore, 66% of the total respondents were not given a choice of blood glucose meter, with one in four not happy with the meter provided. Such rationing of the essential tools in T1DM management is unsafe and puts the health of people with T1DM at risk, both in the short and long term.
SMBG using test strips and meters comes with its own challenges — the most striking of which is the impact of finger-tip pain
. With a wide variety of meters available to patients, accuracy of readings is highly dependent on whether these meters are compliant with the recommended ISO15197 standards
. In addition, good hand washing, storage and expiry of testing strips, and anaemia can influence readings
. The burden of frequent finger testing has been largely reduced by the advent of CGM and flash GM.
CGM system measures real-time interstitial glucose every few minutes. It consists of a sensor, inserted underneath the skin, and a transmitter which transfers data to a pager-like display device (the receiver). The receiver can also be combined with an insulin pump or a smartphone. CGM systems require calibration with the conventional SMBG method to ensure accuracy of mean glucose readings in the receiver
. These also incorporate alarms and alerts for hypoglycaemia and hyperglycaemia.
NICE recommends offering real-time CGM in children and young people with T1DM who have any of the following:
- Frequent severe hypoglycaemia;
- Impaired awareness of hypoglycaemia associated with adverse consequences (seizures, anxiety etc.);
- Inability to recognise, or communicate about, symptoms of hypoglycaemia (e.g. because of cognitive or neurological disabilities)
It should also be considered for children who:
- Are neonates, infants or of pre-school age;
- Undertake high levels of physical activity (e.g. sport at a regional, national or international level);
- Have comorbidities (e.g. anorexia nervosa) or who are receiving treatments (e.g. corticosteroids) that can make blood glucose control difficult
For adults with T1DM, NICE recommends CGM for those patients who are willing to use it for at least 70% of the time and have any of the following criteria:
- More than one episode a year of severe hypoglycaemia with no obviously preventable precipitating cause;
- Complete loss of awareness of hypoglycaemia;
- Frequent (more than two episodes a week) asymptomatic hypoglycaemia that is causing problems with daily activities;
- Extreme fear of hypoglycaemia;
- Hyperglycaemia (HbA1c level of 75mmol/mol [9%] or higher) that persists despite testing at least 10 times a day
At time of writing, CGM is not available on NHS prescription in the UK, and individual funding requests for those who meet the eligibility criteria (local/national) via local diabetes teams or self-funding are the only routes open to patients
Flash GM also measures interstitial glucose via a sensor inserted underneath the skin, which can be worn for a fortnight
. Readings are obtained by scanning the sensor, and trends of the preceding eight hours can be visualised on the accompanying software. Unlike CGM, the flash GM system does not require calibration but, crucially, does not incorporate alarms for hypoglycaemia or hyperglycaemia. Results from the IMPACT study, a 6-month randomised controlled trial involving 241 people with T1DM using flash GM versus SMBG, showed a significant reduction in the number of episodes of (–25.8%, P <0.001) and time spent in hypoglycaemia (–38%, P <0.001) in those who used flash GM. There was, however, no significant reduction in HbA1c between the two groups
Currently, this technology (FreeStyle LibreÂ®, Abbott) has only been available on prescription in some regions of the UK from 1 November 2017, subject to local guidelines and clinical commissioning group approval
With a range of glucose monitoring systems available, it is vital to ensure patients are educated with self-monitoring skills and interpretation of data in relation to diet, lifestyle and insulin dosage through validated, structured education programmes. Furthermore, these skills need to be reviewed regularly.
All patients with T1DM must receive education about the condition — including insulin self-management, managing hypoglycaemia, sick day rules, driving and long-term complications — at the time of diagnosis.
In addition, NICE recommends that patients are offered a structured education programme of proven benefit, for example the dose-adjustment for normal eating (DAFNE) or an alternative evidence-based programme delivered by trained educators, 6–12 months after diagnosis.
Hypoglycaemia is a common acute complication of T1DM
. It is defined as a capillary blood glucose of <4mmol/mol and requires immediate treatment with a quick-acting CHO (e.g. Lucozade). Hypoglycaemia is usually associated with varying warning symptoms, such as sweating and tremulousness (trembling, quivering or shaking), but can sometimes be asymptomatic. Hypoglycaemia, hypoglycaemia awareness and safe driving must be discussed at every medical consultation, and the immediate management of hypoglycaemia reiterated. Individuals at risk of hypoglycaemia should be offered intramuscular glucagon to be used by a family member in an emergency.
DKA is a less common, but potentially life-threatening, complication of T1DM that arises from an acute absolute deficiency of insulin, either owing to lack of insulin administration or precipitated by intercurrent illness,,,
. Insulin deficiency results in an uncontrolled rise in blood glucose leading to dehydration and breakdown of alternate sources of energy, causing ketone formation and metabolic acidosis
. The mainstay of treatment is intravenous insulin, plenty of intravenous fluids and management of the underlying precipitant
All patients with T1DM should be provided with a means to test urine or blood ketones, along with written sick day rules detailing how to adjust insulin doses to prevent hyperglycaemia and subsequent ketoacidosis. They should be advised to present themselves to hospital should they experience vomiting or a rise in ketones.
Chronic hyperglycaemia causes damage to blood vessels, leading to long-term diabetes complications. This damage can be macrovascular (causing ischaemic heart disease, peripheral vascular disease and cerebrovascular disease) or microvascular (causing nephropathy, retinopathy and neuropathy)
. Peripheral vascular disease and peripheral neuropathy cause diabetic foot disease resulting in ulceration and infection, which may necessitate amputation. Autonomic neuropathy can lead to diabetic gastroparesis, which results in abdominal bloating, pain, nausea and recurrent vomiting. This in turn can cause very erratic and unpredictable blood glucose control with both extreme hypoglycaemia and hyperglycaemia. Other features of autonomic neuropathy affecting the gastrointestinal system are constipation, diarrhoea, faecal incontinence and gall bladder dysmotility. Cardiovascular autonomic neuropathy can lead to tachycardia, abnormal blood pressure regulation and postural hypotension.
The risk of complications increases with increasing HbA1c, and is highest with values above 12% (equivalent to 107.7mmol/mol). The risk also increases with increasing duration of diabetes. The landmark UK T1DM trial, Diabetes Control and Complications Trial (DCCT), showed that tight glycaemic control significantly reduces the risk of developing microvascular complications, and also slows the progression of these complications if already present, albeit at the cost of significant hypoglycaemia
. The 11-year follow-up study of the DCCT cohort Epidemiology of Diabetes Interventions and Complications showed that a sustained period of good glycaemic control has a long-lasting benefit in reducing cardiovascular morbidity and mortality
Cardiovascular disease (CVD) accounts for 44% of deaths in people with T1DM and occurs 10–15 years earlier than in healthy comparators
. The age-adjusted relative risk for CVD in T1DM is around 10 times that of the general population,,,,
. The risk of CVD is increased by uncontrolled hypertension. Hypertension also increases the risk of developing diabetic kidney disease, which accounts for 21% of deaths in people with T1DM
. Controlling blood pressure, especially with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, reduces the risk of cardiovascular death and delays the progression of kidney disease,,
. Modifying other cardiovascular risk factors, such as dyslipidaemia (with statins), obesity and smoking, is also beneficial.
To monitor for the development of diabetes complications, NICE recommends annual measurement (at least) of HbA1c, blood pressure, lipid profile, serum creatinine, urine albumin creatinine ratio and body mass index, and assessment of smoking status
. In addition, patients must receive a foot check and a retinopathy screen yearly. Every opportunity must be used to provide education about dietary modification and smoking cessation advice.
NICE recommends that patients with T1DM should achieve, if appropriate, HbA1c <6.5% (48mmol/mol) if it can be done without hypoglycaemia. This may not be appropriate for all patients, and indeed, HbA1c targets must always be individualised
. Women planning pregnancy should also aim to achieve HbA1c <6.5% (48mmol/mol) prior to conception, if possible without problematic hypoglycaemia, to reduce risks to the foetus.
Blood pressure and total cholesterol targets are <140/80mmHg and <4mmol/L, respectively. However, in the UK only 16.2% of patients with T1DM currently achieve these targets, and no improvements have been made in this figure in the recent years,
. Significant improvements need to be made in healthcare delivery if these targets are to be achieved.
T1DM is a very complex metabolic condition that requires intensive, often specialist-guided, management of blood glucose and other cardiometabolic factors to enable patients with this condition to lead a near normal and productive life, free of complications.
 Silink M. Childhood diabetes: a global perspective. Horm Res 2002;57(Suppl 1):1–5. doi: 10.1159/000053304
 Karvonen M, Viik-Kajander M, Moltchanova E et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000;23(10):1516–1526. doi: 10.2337/diacare.23.10.1516
 Harjutsalo V, Sund R, Knip M & Groop PH. Incidence of type 1 diabetes in Finland. JAMA 2013;310(4):427–428. doi:10.1007/s11892-013-0433-5
 Mamoulakis D, Galanakis E, Bicouvarakis S et al. Epidemiology of childhood type I diabetes in Crete, 1990-2001. Acta Paediatr 2003;92(6):737–739. doi:10.1111/j.1651-2227.2003.tb00610.x
 Karvonen M, PitkÃ¤niemi J & Tuomilehto J. The onset age of type 1 diabetes in Finnish children has become younger. The Finnish Childhood Diabetes Registry Group. Diabetes Care 1999;22(7):1066–1070. doi: 10.2337/diacare.22.7.1066
 Patterson CC, Dahlquist GG, GyÃ¼rÃ¼s E et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 2009;373(9680):2027–2033. doi: 10.1016/S0140-6736(09)60568-7
 Tuomilehto J. The emerging global epidemic of type 1 diabetes. Curr Diab Rep 2013;13:(6)795–804. doi: 10.1007/s11892-013-0433-5
 Diabetes UK. Diabetes Prevalence Model 2016 (November 2016). 2016. Available at: https://www.diabetes.org.uk/professionals/position-statements-reports/statistics/diabetes-prevalence-2016 (accessed July 2018)
 Healthcare Quality Improvement Partnership & Royal College of Paediatrics and Child Health. National Paediatric Diabetes Audit 2013–14: Report 1: Care Processes and Outcomes. 2015. Available at: https://www.rcpch.ac.uk/sites/default/files/2018-03/npda_national_report_2013-14.pdf (accessed July 2018)
 Hsia Y, Neubert AC, Rani F et al. An increase in the prevalence of type 1 and 2 diabetes in children and adolescents: Results from prescription data from a UK general practice database. Br J Clin Pharmacol 2009;67(2):242–249. doi: 10.1111/j.1365-2125.2008.03347.x
 Felner EI, Klitz W, Ham M et al. Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus. Pediatr Diabetes 2005;6(4):213–220. doi: 10.1111/j.1399-543X.2005.00132.x
 Elamin A, Omer MI, Zein K & Tuvemo T. Epidemiology of childhood type I diabetes in Sudan, 1987–1990. Diabetes Care 1992;15(11):1556–1559. doi: 10.2337/diacare.15.11.1556
 Writing Group for the SEARCH for Diabetes in Youth Study Group, Dabelea D, Bell RA et al. Incidence of diabetes in youth in the United States. JAMA 2007;297(24):2716–2724. doi:10.1001/jama.297.24.2716
 Thomas NJ, Jones SE, Weedon MN et al. Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. Lancet Diabetes Endocrinol 2018;6(2):122–129. doi: 10.1016/S2213-8587(17)30362-5
 HÃ¤mÃ¤lÃ¤inen AM & Knip M. Autoimmunity and familial risk of type 1 diabetes. Curr Diab Rep 2002;2(4):347–353. doi: 10.1007/s11892-002-0025-2
 Redondo MJ, Fain PR & Eisenbarth GS. Genetics of type 1A diabetes. Recent Prog Horm Res 2001;56:69–89. doi: 10.1210/rp.56.1.69
 Redondo MJ, Jeffrey J, Fain PR et al. Concordance for islet autoimmunity among monozygotic twins. N Engl J Med 2008;359(26):2849–2850. doi: 10.1056/NEJMc0805398
 Bell RA, Mayer-Davis EJ, Beyer JW et al. Diabetes in non-Hispanic white youth: prevalence, incidence and clinical characteristics: the SEARCH for Diabetes in Youth Study. Diabetes Care 2009;32(Suppl 2):S102. doi: 10.2337/dc09-S202
 Rosenbauer J, Herzig P, von Kries R et al. Temporal, seasonal, and geographical incidence patterns of type I diabetes mellitus in children under 5 years of age in Germany. Diabetologia 1999;42(9):1055–1059. doi: 10.1007/s001250051270
 WaldhÃ¶r T, Schober E, Karimian-Teherani D et al. Regional differences and temporal incidence trend of Type I diabetes mellitus in Austria from 1989 to 1999: a nationwide study. Diabetologia 2000;43(11):1449–1450. doi: 10.1007/s001250051553
 Liese AD, Lawson A, Song HR et al. Evaluating geographic variation in type 1 and type 2 diabetes mellitus incidence in youth in four US regions. Health Place 2010;16(3):547–556. doi: 10.1016/j.healthplace.2009.12.015
 American Diabetes Association. Clinical practice recommendations 2005. Diabetes Care 2005;28(Suppl 1):S1–S79. doi: 10.2337/diacare.28.suppl_1.S1
 Maahs DM, West NA, Lawrence JM & Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am 2010;39(3):481–497. doi: 10.1016/j.ecl.2010.05.011
 Atkinson MA. The pathogenesis and natural history of type 1 diabetes. Cold Spring Harb Perspect Med 2012;2(11):a007641. doi:10.1101/cshperspect.a007641
 Pugliese A. Insulitis in the pathogenesis of type 1 diabetes. Paediatr Diabetes 2016;17(Suppl 22):31–36. doi: 10.1111/pedi.12388
 Dunger DB, Sperling MA, Acerini CL et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child 2004;89(11):188–194. doi: 10.1136/adc.2003.044875
 Baekkeskov S, Aanstoot HJ, Reetz A et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA- synthesizing enzyme glutamic acid decarboxylase. Nature 1990;347(6289):151–156. doi: 10.1038/347151a0
 Bonifacio E, Lampasona V & Bingley PJ. IA-2 (islet cell antigen 512) is the primary target of humoral autoimmunity against type 1 diabetes-associated tyrosine phosphatase autoantigens. J Immunol 1998;161(5):2648–2654. PMID: 9725268
 Palmer JP, Asplin CM, Clemons P et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983;222(4630):1337–1339. doi: 10.1126/science.6362005
 Wenzlau JM, Juhl K, Yu L et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 2007;104(43):17040–17045. doi:10.1073/pnas.0705894104
 McLaughlin KA, Richardson CC, Ravishankar A et al. Identification of tetraspanin-7 as a target of autoantibodies in type 1 diabetes. Diabetes 2016;65(6):1690–1698. doi: 10.2337/db15-1058
 Dinsmoor RS. Tight control. 2006. Available at: https://www.diabetesselfmanagement.com/diabetes-resources/definitions/tight-control/ (accessed July 2018)
 Dennedy M & Dinneen S. Management of type 1 diabetes mellitus. Medicine 2010;38(11):610–617. doi: 10.1016/j.mpmed.2010.08.002
 National Institute for Health and Care Excellence. Type 1 diabetes in adults: diagnosis and management. NICE guideline [NG17]. 2016. Available at: http://www.nice.org.uk/guidance/ng17/chapter/1-Recommendations#blood-glucose-management-2 (accessed July 2018)
 National Institute for Health and Care Excellence. Type 1 diabetes mellitus in adults: high-strength insulin glargine 300 units/ml (Toujeo). Evidence summary [ESNM62]. 2015. Available at: www.nice.org.uk/advice/esnm62 (accessed July 2018)
 NHS improvement. Patient safety alert: risk of severe harm and death due to withdrawing insulin from pen devices. 2016. Available at: https://improvement.nhs.uk/documents/510/Patient_Safety_Alert_-_Withdrawing_insulin_from_pen_devices.pdf (accessed July 2018)
 The Electronic Medicines Compendium. Home – Electronic Medicines Compendium. Available at: https://www.medicines.org.uk (accessed July 2018)
 National Patient Safety Agency. NPSA Alert – The adult patient’s passport to safer use of insulin – 2011. 2018. Available at: https://www.sps.nhs.uk/articles/npsa-alert-the-adult-patients-passport-to-safer-use-of-insulin-2011/ (accessed July 2018)
 Fu S, Li L, Deng S et al . Effectiveness of advanced carbohydrate counting in type 1 diabetes mellitus: a systematic review and meta-analysis. S ci Rep 2016;6:37067. doi: 10.1038/srep37067
 Bell KJ, Barclay AW, Petocz P et al. Efficacy of carbohydrate counting in type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2014;2(2):133–140. doi: 10.1016/S2213-8587(13)70144-X
 Schmidt S, Schelde B & NÃ¸rgaard K. Effects of advanced carbohydrate counting in patients with type 1 diabetes: a systematic review. Diabet Med 2014;31(8):886–896. doi: 10.1111/dme.12446
 National Institute for Health and Care Excellence. Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. Technology appraisal guidance [TA151]. 2008. Available at: www.nice.org.uk/ta15 (accessed July 2018)
 TREND UK. Blood glucose monitoring guidelines: consensus document [Version 2.0]. 2017. Available at: http://trend-uk.org/wp-content/uploads/2017/02/170106-TREND_BG_FINAL.pdf (accessed July 2018)
 Diasend. Quick guide: how to upload devices. Available at: https://support.diasend.com/hc/en-us/articles/211424209-Quick-guide-Patient-How-to-upload-devices (accessed July 2018)
 Driver and Vehicle Licensing Agency. Assessing fitness to drive: a guide for medical professionals. 2018. Available at: http://www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-medical-professionals (accessed July 2018)
 Miller KM, Beck RW, Bergenstal RM et al. Evidence of a strong association between frequency of self-monitoring of blood glucose and hemoglobin A1c levels in T1D exchange clinic registry participants. Diabetes Care 2013;36(7):2009–2014. doi: 10.2337/dc12-1770
 Frier B, Gadsby R, Hicks D et al. Blood glucose self-monitoring in type 1 and type 2 diabetes: reaching a multidisciplinary consensus. Available at: https://www.diabetesonthenet.com/journals/issue/66/article-details/blood-glucose-self-monitoring-in-type-1-and-type-2-diabetes-reaching-a-multidisciplinary-consensus (accessed July 2018)
 Diabetes UK. Testing times-restrictions accessing test strips and meters for people with diabetes. April 2017. Available at: https://www.diabetes.org.uk/professionals/position-statements-reports/diagnosis-ongoing-management-monitoring/access-to-test-strips-a-postcode-lottery (accessed July 2018)
 Hortensius J, Kars MC, Wierenga WS et al. Perspectives of patients with type 1 or insulin-treated type 2 diabetes on self-monitoring of blood glucose: a qualitative study. BMC Public Health 2012;12:167. doi: 10.1186/1471-2458-12-167
 Boettcher C, Dost A & Wudy SA. Accuracy of blood glucose meters for self-monitoring affects glucose control and hypoglycemia rate in children and adolescents with type 1 diabetes. Diabetes Technol Ther 2015;17(4):275–282. doi: 10.1089/dia.2014.0262
 Ginsberg BH. Factors affecting blood glucose monitoring: sources of errors in measurement. J Diabetes Sci Technol 2009;3(4):903–913. doi: 10.1177/193229680900300438
 Liebl A, Henrichs HR, Heinemann L et al. Continuous glucose monitoring: evidence and consensus statement for clinical use. J Diabetes Sci Technol 2013;7(2):500–519. doi:10.1177/19322968130070022
 National Institute for Health and Care Excellence. Diabetes (type 1 and type 2) in children and young people: diagnosis and management. NICE guideline [NG18]. 2016. Available at: https://www.nice.org.uk/guidance/ng18 (accessed July 2018).
 National Institute for Health and Care Excellence. Type 1 diabetes in adults: diagnosis and management. NICE guideline [NG17]. 2016. Available at: https://www.nice.org.uk/guidance/ng17 (accessed July 2018)
 Diabetes UK, INPUT Diabetes & Juvenile Diabetes Research Foundation. Type 1 technology: a guide for adults with type 1 diabetes. 2016. Available at: www.inputdiabetes.org.uk/wp-content/uploads/2016/10/Type1techAdults.pdf (accessed July 2018)
 Diabetes UK. Flash glucose monitoring. 2017. Available at: https://www.diabetes.org.uk/guide-to-diabetes/managing-your-diabetes/testing/flash-glucose-monitoring (accessed July 2018)
 Bolinder J, Antuna R, Geelhoed-Duijvestijn P et al. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. Lancet 2016;388(10057):2254–2263. doi: 10.1016/S0140-6736(16)31535-5
 National Institute for Health and Care Excellence. FreeStyle Libre for glucose monitoring. Medtech Innovation Briefing [MIB110]. 2017. Available at: https://www.nice.org.uk/advice/mib110/chapter/Summary (accessed July 2018)
 Pedersen-Bjergaard U & Thorsteinsson B. Reporting severe hypoglycaemia in type 1 diabetes: facts and pitfalls. Curr Diab Rep 2017;17(12):131. doi: 10.1007/s11892-017-0965-1
 Lin SF, Lin JD & Huang YY. Diabetic ketoacidosis: comparisons of patient characteristics, clinical presentations and outcomes today and 20 years ago. Chang Gung Med J 2005;28(1):24–30. PMID: 15804145
 Wang J, Williams DE, Narayan KM & Geiss LS. Declining death rates from hyperglycemic crisis among adults with diabetes, US, 1985–2002. Diabetes Care 2006;29(9):2018–2022. doi: 10.2337/dc06-0311
 Johnson DD, Palumbo PJ & Chu CP. Diabetic ketoacidosis in a community-based population. Mayo Clin Proc 1980;55(2):83–88. PMID: 6766521
 Faich GA, Fishbein HA & Ellis SE. The epidemiology of diabetic acidosis: a population-based study. Am J Epidemiol 1983;117(5):551–558. doi: 10.1093/oxfordjournals.aje.a113577
 English P & Williams G. Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J 2004;80(943):253–261. doi: 10.1136/pgmj.2002.004291
 Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults. 2nd edn. Available at: http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_DKA_Adults_Revised.pdf (accessed July 2018)
 Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353(25):2643–2653. doi: 10.1056/NEJMoa052187
 Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977–986. doi: 10.1056/NEJM199309303291401
 Reichard P, Nilsson BY & Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329(5):304–309. doi: 10.1056/NEJM199307293290502
 Morrish NJ, Wang SL, Stevens LK et al. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001;44(Suppl 2);14–21. doi: 10.1007/PL00002934
 Soedamah-Muthu SS, Fuller JH, Mulnier HE et al. High risk of cardiovascular disease in patients with type 1 diabetes in the UK: a cohort study using the general practice research database. Diabetes Care 2006;29(4):798–804. doi: 10.2337/diacare.29.04.06.dc05-1433
 de Ferranti SD, de Boer IH, Fonseca V et al. Type 1 Diabetes Mellitus and Cardiovascular Disease: A Scientific Statement From the American Heart Association and American Diabetes Association. Circulation 2014;130(13):1110–1130. doi: 10.1161/CIR.0000000000000034
 de Ferranti SD, de Boer IH, Fonseca V et al. Type 1 Diabetes Mellitus and Cardiovascular Disease: A Scientific Statement From the American Heart Association and American Diabetes Association. Diabetes Care 2014;37(10):2843–2863. doi: 10.2337/dc14-1720
 Krolewski AS, Kosinski EJ, Warram JH et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987;59(8):750–755. doi: 10.1161/01.ATV.16.6.720
 Libby P, Nathan DM, Abraham K et al. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on cardiovascular complications of type 1 diabetes mellitus. Circulation 2005;111(25):3489–3493. doi: 10.1161/CIRCULATIONAHA.104.529651
 Deckert T, Poulsen JE & Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one. 1. Survival, causes of death, and complications. Diabetologia 1978;14:363–370. doi: 10.1007/BF01228130
 The Microalbuminuria Captopril Study Group. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia 1996;39(5):587. doi: 10.1007/BF00403306
 Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 1994;271(4):275–279. doi: 10.1001/jama.1994.03510280037029
 Chaturvedi N & The EUCLID Study Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997;349(9068):1787–1792. doi: 10.1016/S0140-6736(96)10244-0
 NHS Digital. National Diabetes Audit 2012–2013: Report 1, care processes and treatment targets. 2014. Available at: https://digital.nhs.uk/data-and-information/publications/statistical/national-diabetes-audit/national-diabetes-audit-2012-2013-report-1-care-processes-and-treatment-targets (accessed July 2018)
 NHS Digital. National Diabetes Audit 2012–13. Report 2. 2015. Available at: https://digital.nhs.uk/data-and-information/publications/statistical/national-diabetes-audit/national-diabetes-audit-2012-2013-report-2 (accessed July 2018)