Therapy of Type 1 Diabetes

Addressees and Objectives

This guideline is directed at all people with type 1 diabetes and all occupational groups that care for people with type 1 diabetes, especially:

• Registered diabetologists,

• General practitioners and internists,

• Doctors working in hospitals (diabetes specialists, anaesthesiologists, surgeons, radiologists),

• Nurses/professional caregivers (in the operating theatre and/or wards or in the field of diagnostics) and

• Outpatient or inpatient diabetes consultants and other professional groups in diabetology.

In addition, the guideline is directed at higher-level institutions such as health insurance companies or medical services.

In preparing and updating these guidelines, the authors pursue the following objectives:

1. Reduce the rate of diabetes-associated complications and diabetes-associated secondary damage. The diagnosis and treatment of lipodystrophy is also described for the first time;

2. Improve the quality of life of people with type 1 diabetes;

3. Contribute to the adequate care of people with type 1 diabetes in hospitals, both in regular and intensive care units. In particular, the implementation of safe protocols to protect against hypoglycaemia in intravenous insulin therapy should be supported;

4. Ensure correct treatment of acute complications and thus reduce the risk of complications due to treatment;

5. Reinforce the correct training of people with type 1 diabetes, especially in the outpatient sector.

Definition and Classification of Type 1 Diabetes

Currently, the disease diabetes mellitus is classified into 4 main types (as per etiological classification) according to the American Diabetes Association ADA [1]:

1. Type 1 diabetes (as a result of autoimmune beta-cell destruction, which usually leads to absolute insulin deficiency), Subform: idiopathic;

2. Type 2 diabetes (due to progressive loss of insulin secretion from the beta cell, often against the background of insulin resistance);

3. Other specific diabetes types (subtypes A: genetic defects of beta cell function; B: genetic defects of insulin efficacy; C: exocrine pancreatic disease, D: diabetes due to endocrinopathies; E: drug or chemical-induced; F: diabetes resulting from infections; G: rare forms of immune-mediated diabetes; H: other genetic syndromes occasionally associated with diabetes);

4. Gestational diabetes (glucose tolerance disorder diagnosed for the first time in pregnancy with a 75 g oral glucose tolerance test).

Type 1 diabetes occurs primarily in younger years but can also manifest itself in later life. Even today, when type 1 diabetes is diagnosed, a severe metabolic derailment in the form of ketoacidosis can be seen in about 15–30% of cases, reaching as far as loss of consciousness [2].

Within the category type 1 diabetes, 2 subtypes are currently distinguished: the immune-mediated form and the idiopathic form.

Type 1 diabetes (immune-mediated, autoimmune disease)

Type 1 diabetes is caused by a cell-mediated, chronic autoimmune destruction of beta cells. The following serological markers are suitable for diagnosing type 1 diabetes [3] [4] [5] [6] [7] [8]:

• Islet cell antibodies (ICA)

• Insulin autoantibodies (IAA) (for children and adolescents but not for adults)

• Autoantibodies against glutamate decarboxylase of the B cell (GAD65A)

• Autoantibodies to tyrosine phosphatase (IA-2ª) and IA-2ß

• Autoantibodies against the zinc transporter 8 of the B-cell (ZnT8)

Type 1 diabetes is diagnosed when one or more of these autoantibodies are detected. At least one of these autoantibodies is detectable in 85–90% of patients with stage 3 diagnosis, i. e. simultaneous hyperglycaemia.

Idiopathic type 1 diabetes

Patients with idiopathic type 1 diabetes have a permanent insulin deficiency, tend to repeated episodes of ketoacidosis and are autoantibody negative, without etiopathogenetic classification of autoimmune type 1 diabetes. There is no association with HLA risk alleles. This form of type 1 diabetes is inherited with high penetrance, occurs very rarely and is predominantly in patients with an Asian or African background [9]. ¹

Therapy Goals

The therapy for type 1 diabetes aims to avoid diabetes-related reductions to the quality of life. It is also important to achieve for those affected to accept the disease and be satisfied with the therapy regime.

In order to avoid diabetes-related reductions to the quality of life, the therapy should be designed in such a way that the risk of severe metabolic disorders (severe hypoglycaemia and/or severe hyperglycaemia with ketoacidosis or diabetic coma) is as low as possible. Furthermore, the therapy should be conducted in such a way as to reduce the risk of developing microangiopathies (retinopathy, nephropathy) and other diabetes-associated secondary damage (neuropathy, accelerated macroangiopathy).

A further therapeutic goal in the treatment of type 1 diabetes is to avoid additional risk factors for consequential damage. This is done by monitoring and, if present, undergoing proper therapy for blood pressure, lipid profile and obesity-induced insulin resistance. The documentation in the Diabetes Health Pass (Gesundheitspass) can be helpful.

Recommendations	Degree of recommendation
In adults with type 1 diabetes, an HbA1c value of 7.5% (≤ 58 mmol/mol) should be targeted at ≤ as long as no problematic hypoglycaemia occurs. [10] [11]	B
In adults with type 1 diabetes, HbA1c ≤ 6.5% (≤ 48 mmol/mol) may also be targeted if there is a low intrinsic risk of hypoglycaemia (e. g. new onset of type 1 diabetes, stable low glycaemic viability). [10] [11] (strong consensus)	0
In adults with type 1 diabetes, a less tight HbA1c value < 8.5% (69 mmol/ mol) should be sought if therapy safety cannot be guaranteed, if severe hypoglycaemia has frequently occurred, extensive comorbidities or advanced macrovascular complications are present. [10] [11] (strong consensus)	B
Adults with type 1 diabetes with an HbA1c value > 9% (75 mmol/mol) or higher can be assumed to have polyuria symptoms and a significantly increased risk of secondary diseases. Expert consensus (strong consensus)	Statement
In people with type 1 diabetes and severe hypoglycaemia in recent months, the HbA1c target should be raised. [12] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] (strong consensus)	B
In people with type 1 diabetes and low life expectancy or significant comorbidities, an increase in blood glucose can be considered with the sole therapeutic goal of symptom-free treatment. [15] (strong consensus)	0

Therapy for Type 1 Diabetes

The type 1 diabetes therapy concept consists of insulin therapy, nutritional knowledge, training, glucose self-monitoring and psychosocial care.

Insulin therapy

The indication for insulin therapy in type 1 diabetes is permanent and lifelong. A prerequisite for the substitution of lacking insulin in people with type 1 diabetes is knowledge of the physiological insulin requirement as well as the pharmacokinetic and pharmacodynamic properties of the insulins used for therapy ([Table 1]). For the planning of insulin therapy, the following are also important: (a) consideration of how the additive insulin requirement depends on the dietary intake (prandial insulin always in addition to basal insulin requirement) and (b) the ratio between basal and prandial insulin requirement.

Table 1 Types of insulin - efficacy, adverse effects, interactions and contraindications (with data from [16]).

	Effect
	Onset	Maximum	Duration	Usually used	References
Human insulins
NPH insulin	1–2 h	6–7 h	14 h	2×daily	[17] [18]
Normal insulin	30–60 min	3 h	8 h	0–30 min before meals	[19]
Mixed insulin NPH (70)/Normal (30)	30–60 min	3–3.5 h	14 h	Before breakfast and dinner	[20] [21]
Insulin analogues
Degludec	1–2 h1	8–14 h low	> 42 h	1× daily	[22] [23] [24]
		maximum
Detemir	1 h	7–9h	19–26 h	1 or 2 × daily	[18] [25] [26]
Glargin U100	1 h	8–12 h	20–27 h	1 or 2 × daily	[25] [26] [27]
Glargin U300	1–6 h1	12–16 h low	30–32 h	1 × daily	[27] [28]
		maximum
Aspart	20–25 min	120–150 min	4–5 h	0–15 min before meals	[29] [30]
Alulisin	20–25 min	120–150 min	4–5 h	0–15 min before meals	[19]
Lispro	20–25 min	120–150 min	4–5 h	0–15 min before meals	[31]
Faster Aspart	15 min	120 min	4 h	Immediately before meals	[29]
Mixed insulin protamine. Aspart	20–25 min	2–3 h	10–14 h	0–15 min before breakfast and dinner	[30] [31] [32] [33]
(70)/Aspart (30);
protamine. Lispro (70), Lispro (30)
Combination insulin	20–25 min	2–3 h	> 30 h	0–15 min before one or before two main meals	[34] [35]
Degludec (70)/Aspart (30)

¹ Under steady state conditions, the time of onset of action is of low clinical relevance due to the long effect and the flat action profile.

Individual insulin needs

In principle, the individual insulin requirement of people with type 1 diabetes resulting from an absolute insulin deficiency depends on the physiological insulin secretion. This occurs both without food intake (=basal insulin requirement) and after food intake (=prandial insulin requirement), i. e. discontinuous and pulsatile. When dosing insulin, it must be taken into account that the absolute insulin requirement also depends on the individual insulin sensitivity of the respective patient. The therapeutic insulin requirement can therefore only be deduced preliminarily based on the insulin secretion of a healthy person.

Strategies of insulin therapy

Simple and more complex (intensified) strategies are available for insulin therapy.

Conventional therapy

Conventional therapy is characterized by a binding specification of both the insulin dose and the sequence and size of the meals (fixed carbohydrate portions). A blood glucose self-measurement is recommended 3–4 times daily. As a rule, fixed insulin mixtures are used, which are administered twice a day for breakfast and dinner and, as far as possible, adapted to the eating behaviour of the patients. A simple conventional insulin therapy can only be successful with a fixed diet plan.

In contrast to intensified therapy, this form of insulin therapy is a subordinate therapy option for people with type 1 diabetes in the following cases:

• For people who cannot meet the requirements of an intensified therapy (due to cognitive impairment, illness or age),

• For people who decide against intensified therapy after receiving extensive information on the risks and benefits,

• For people with a significant problem adhering to long-term therapies.

Since medium and long-term glycaemic control is crucial for reducing the risk of diabetes-associated complications, conventional insulin therapy can be sufficient if the individual HbA1c target values are reached, hypoglycaemia is avoided, and the quality of life is not restricted by the therapy.

Recommendations	Degree of recommendation
Self-management using rtCGM or iscCGM (FGM) should be offered if individual therapy goals are not achieved. Expert consensus (strong consensus)	B
In order to use the advantages of a rtCGM/iscCGM system effectively, adequate training and regular diabetic care by diabetic teams experienced in the use of these systems are required. Expert consensus (strong consensus)	statement

Recommendations	Degree of recommendation
For people with type 1 diabetes, neither a specific form of nutrition or diet is required, nor are specific diet foods required. They are subject to the general recommendations on healthy eating. Expert consensus (strong consensus)	Statement

Recommendations	Degree of recommendation
The disease type 1 diabetes should be clearly indicated in the medical record during a hospital stay. Expert consensus per [65] (strong consensus)	A
In all people with type 1 diabetes, an order to monitor blood glucose must be issued during an inpatient stay. Trained patients should be able to continue self-management as far as possible. The blood glucose levels should be accessible to all treating members of the healthcare team. If no HbA1c value from the last 3 months is available, this should be determined. Expert consensus (strong consensus)	A
Hospitalized patients with type 1 diabetes should receive intensified insulin therapy with basal insulin and bolus insulin/pump therapy. Expert consensus per [11] (strong consensus)	A

Recommendations	Degree of recommendation
The administration of fast-acting insulin only for correction by means of a post injection plan is inferior to such insulin therapy; for this reason, the administration of insulin should not exclusively take place in the form of a post injection plan. Expert consensus per [11] (strong consensus)	B

Recommendations	Degree of recommendation
People with type 1 diabetes and clinical suspicion of moderate or severe diabetic ketoacidosis should be admitted to hospital immediately. They should be treated in the clinic on the basis of a detailed written treatment plan. [75] (strong consensus)	A
The monitoring of people with type 1 diabetes who are being treated for diabetic ketoacidosis should be carried out under intensive medical conditions. During the treatment of severe ketoacidosis, clinical evaluation and monitoring should be performed at least every hour. Expert consensus as per [67] (strong consensus)	A
Diabetic ketoacidosis should be treated according to the following therapy principles:	A
Circulation stabilization with initial volume of 1 l of isotonic solution (0.9% NaCl) in the first hour; Then, additional liquids and electrolytes equal depending on age, height, weight and possible concomitant diseases (total fluid intake can be up to 6 l/24 h and more for a patient weighing 70 kg); Potassium replacement already in the standard range depending on the severity of the ketoacidosis by administering 40 mEq/L potassium chloride per 1000 ml NaCl 0.9%, example see below; Slow normalization of blood glucose using low-dose insulin; intravenous insulin administration via Perfusor (0.05–0.1 U/kg kg/h IV). Compensation of acidosis and ketosis (addition of bicarbonate only at pH < 7.0 and then up to a correction of 7.1); Avoidance of therapy complications (hypokalaemia, cerebral oedema); Diagnosis and therapy of the triggering causes of DKA. Expert consensus as per [76] (strong consensus)

Recommendations	Degree of recommendation
For diagnosing lipohypertrophy, an inspection of the injection sites and palpation of the skin should be carried out at least once a year, and quarterly in the case of abnormalities and in particular in the case of inexplicably fluctuating metabolic conditions. Expert consensus (strong consensus)	B
From the age of 11 or after a diabetic duration of 5 years, people with type 1 diabetes without known diabetes-associated secondary diseases or comorbidities should undergo the following early detection examinations on a regular basis:	B
Determination of the albumin-creatinine ratio and calculation of the glomerular filtration rate for early detection of microalbuminuria and nephropathy. Expert consensus EK IV as per [77] (strong consensus) An ophthalmological retinal screening of fundus in mydriasis If no diabetic retinal changes are detected, the screening interval should be two years for known low risk (=no ophthalmological risk and no general risk). If the ophthalmologist does not know the general risk factors, he should treat the patient as if the patient had an unfavourable general risk profile; for all other risk constellations, the screening interval should be one year. [78] (strong consensus) Anamnesis and examination for early diagnosis of neuropathy, at least annually. Expert consensus as per NVL neuropathy [79] (strong consensus) Anamnesis and examination for early detection of foot complications, at least annually. Expert consensus as per [80] (strong consensus) Examination of the cardiovascular system, risk-adapted [Expert consensus as per [81].] In addition to a physical examination, this includes the determination of biochemical parameters for cardiovascular risk factors, such as blood pressure measurement, determination of blood lipids for the early detection of lipid metabolism disorders. Expert consensus (strong consensus)

Intensified therapy

The intensified insulin therapy is defined as the administration of at least three insulin injections per day. Above all, however, it is characterised by substituting the basal insulin requirement with long-acting basal insulin and by substituting prandial insulin requirement with rapid-acting bolus insulin at mealtimes (basal bolus principle). Synonyms of intensified insulin therapy are functional insulin therapy and flexible insulin therapy. This therapy can be performed with insulin syringes, insulin pens or insulin pump pens (see recommendations).

Insulin types

There are currently two different groups of insulin available in Germany for insulin replacement therapy for people with type 1 diabetes: human insulin and insulin analogues ([Table 1]).

The use of animal insulin can be very necessary for a few people; the possibility of importing animal insulin is hereby referred to.

Recommendations	Degree of recommendation
Human insulins (normal insulin or human insulins with delayed onset of action) or insulin analogues (short-acting or long-acting) are to be used for the therapy of people with type 1 diabetes.[36] [37] [38] [39] [40] [41] [42] [43] (strong consensus)	A
If strict therapeutic goals are pursued, the use of short-acting and long-acting insulin analogues is associated with advantages in terms of reducing HbA1c and risk of hypoglycaemia as compared to normal insulin. [43] [44] [45] (strong consensus)	Statement

Insulin application

Adequate handling and correct application of the insulin used are prerequisites for successful insulin therapy. Information and review must be an integral part of the structured training.

Continuous subcutaneous insulin infusion (CSII)

Recommendations	Degree of recommendation
In people with type 1 diabetes, the use of insulin pump therapy should be examined if the individual therapy goals are not achieved using intensified insulin therapy. [46] [47] [48] [49] [50] (strong consensus)	B
In people with type 1 diabetes, the use of insulin pump therapy should be checked in cases of frequent hypoglycaemia or recurrence of severe hypoglycaemia using intensive insulin therapy. [49] [51] (strong consensus)	B
People with type 1 diabetes can be offered insulin pump therapy in the following constellations:	In cases of frequently irregular daily routines, e.g. shift work, activities with varying physical activity, problems with the implementation of classic ICT/syringe therapy (among other things to improve the quality of life) [52, 53],	0

Recommendations	Degree of recommendation
In cases of planned pregnancy (begin before conception) or at the beginning of a pregnancy, For low insulin requirements, expert consensus (EC/EK) IV, In cases of insufficient glycaemic control of the metabolic situation using ICT, e. g. dawn phenomenon. [54] [55] [56] [57] [58] (strong consensus)
Prerequisites for the start of insulin pump therapy in people with type 1 diabetes are:	Mastery of an intensified insulin therapy on the part of the patient, The provision of care by a qualified diabetology staff with appropriate experience in the use of insulin pumps, Insulin pump therapy training by a well-trained training team. Expert consensus (strong consensus)	Statement

Blood glucose self-monitoring, rtCGM and iscCGM (FGM)

The precision of the blood glucose self-monitoring is sufficient for self-management, even if it is lower compared to laboratory measurements [59] [60].

Nutrition

It is of crucial importance for the therapy of type 1 diabetes that patients are able to assess the glucose efficacy of their diet in order to adjust the insulin dosage accordingly. Recommendations on the objectives, content and modalities of training for type 1 diabetes are given in section 4.4 Training/structured training and treatment programmes.

Training/structured training and treatment programmes

In the treatment of type 1 diabetes, patients must – of their own accord – implement the essential therapeutic measures (insulin substitution usually several times a day, hypoglycaemia prophylaxis, etc.) in accordance with their individual therapy goals. The success of therapy and the prognosis of people with type 1 diabetes therefore depend very much on their ability to treat themselves [61] [62] [63]. The knowledge and skills required for this are taught in structured patient training courses. The training measures are intended to enable patients (empowerment or capacity to self-manage) “... to integrate diabetes into their own lives as best as possible on the basis of their own decisions, to avoid acute or long-term negative consequences of diabetes and to maintain their quality of life” [62].

Forms of diabetes training

Basic training

In basic training and treatment programmes, which should be carried out as soon as possible after the manifestation of diabetes or the changeover to a different therapy regime, basic knowledge and skills for the implementation of diabetes therapy, for informed decision-making and for coping with the disease are developed together with the patient. Repeated or supplementary training measures have the primary objective of supporting patients with type 1 diabetes in the event of difficulties in implementing therapy in everyday life and of offering concrete assistance with problems related to diabetes (e. g. lack of skills, problems in everyday life).

Problem-specific training and treatment programmes

These are aimed at patients in special, diabetic-specific problem situations (e. g. occurrence of secondary diseases, problems with hypoglycaemia). The indication for a problem-specific training and treatment programme may be given if the patient has to implement a specific, new form of therapy in everyday life (e. g. insulin pump therapy, continuous glucose monitoring), if significant problems are associated with acute complications (e. g. hypoglycaemia perception disorder) or in connection with subsequent complications (e. g. neuropathy, sexual disorders, diabetic foot, nephropathy, retinopathy, cardiovascular events) or when special situations exist in everyday life which make the implementation of the therapy more difficult (e. g. shift work, fasting, psychological problems) [61] [64].

Therapy in Special Situations

Hospital stays

Therapy during travel

People with type 1 diabetes are not subject to significant restrictions on travel activity and destinations solely because of having diabetes. Restrictions, if any, result from secondary illnesses. It is often the case that metabolic parameters deteriorate during a journey. Consultation before travel and planning of the trip based on diabetes treatment are useful. There are many well-made recommendations available for planning purposes by self-help organisations, professional associations and also from government organisations, mostly in the form of checklists. These checklists, at least in the case of patients with type 2 diabetes requiring insulin, have also been verified within studies [66] and have found their way into most structured patient training courses.

Acute Complications

Diabetes-associated emergencies in people with type 1 diabetes are either the result of insulin deficiency or insulin overdose. Both hypo- and hyperglycaemia can be life-threatening ([Table 2]).

Table 2 Typical symptoms of hypoglycaemia (from [67] [68] [69] [70] [71]).

Autonomic symptoms	Neuroglycopenic Symptoms	General discomfort
Sweating Trembling Cravings Heart palpitations	Mental confusion Rapid, incoherent speech Difficulty in finding words Irritability Seeing double and other visual disorders Headaches Anxiety Sleepiness Difficulty with dexterity/coordination Limitation of awareness and action Unconsciousness Cramps	Nausea Headache

Hypoglycaemia

The prevention of hypoglycaemia is one of the greatest challenges in achieving a blood glucose level as close as possible to the norm [11] [67].

Definition/severities

The current international classification of hypoglycaemia into mild and severe hypoglycaemia is not based on specific blood glucose values, but exclusively on the ability for self-therapy [12] [68]:

• Mild hypoglycaemia: Hypoglycaemia can be independently treated with carbohydrate intake by the patients.

• Severe hypoglycaemia: The patient depends on outside help in treating the hypoglycaemia (e. g. from relatives or medical personnel) ([Table 3]).

Table 3 Therapeutic measures in hypoglycaemic people with type 1 diabetes.

Mild hypoglycaemia	Severe hypoglycaemia
Therapy by patients possible	Patient is conscious, but therapy is no longer possible by the patient.	If unconscious
		Without IV access (e. g. by family/ others)	With IV access
20 g carbohydrates (preferably glucose; 200 ml fruit juice also possible)	30 g carbohydrates (glucose)	1 mg glucagon IM or subq (Warning: Vomiting and danger of aspiration)	50 ml 40% glucose1 in bolus IV
Measure blood glucose after 15 min and repeat therapy if blood glucose concentration remains low (50–60 mg/dl; 2.8–3.3 mmol/l). After successful therapy, take a meal or snack to avoid recurring hypoglycaemia.		If no response is received after 5 min of therapy at the latest, repeat. After successful therapy, take a meal or snack to prevent recurrent hypoglycaemia.

¹ or 25 ml 40% glucose.

Causes and symptoms

In people with type 1 diabetes, hypoglycaemia is always the result of an absolute or relative insulin overdose. Causes for insulin overdose can include [69]:

• Insulin dosage is too high, insulin injection at the wrong time, or the wrong type of insulin is injected

• Decreased exogenous glucose intake (forgotten meals)

• Glucose consumption is increased (e. g. after sports)

• Endogenous glucose production is lowered (for example after alcohol consumption, in case of renal insufficiency)

• Insulin sensitivity is increased (during the night, after improved glycaemic control, after improved physical fitness).

• Insulin clearance is lowered (for example, in renal insufficiency).

Treatment of hypoglycaemia

People with type 1 diabetes and hypoglycaemia perception disorder can be offered specific structured training (see section “Training/structured training and treatment programmes”).

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is a metabolic derailment due to an absolute or relative insulin deficiency and consecutive metabolization of fatty acids, which can occur with or without hyperosmolar diuresis and thus also without massive hyperglycaemia. Causes of diabetic ketoacidosis:

Diabetic ketoacidosis occurs in clinical routine during:

• Undetected first manifestation of type 1 diabetes mellitus,

• Interruption of an ongoing insulin therapy,

• Interruption of insulin administration during insulin pump therapy,

• Acute, severe diseases associated with an increased, catabolic metabolization and increased insulin requirements.

Biochemical definition and suspected diagnosis

Diabetic ketoacidosis is biochemically defined by:

• Blood glucose > 250 mg/dl (13.9 mmol/l)² and

• Ketonemia and/or

• Ketonuria with arterial pH < 7.35 or

• Venous pH < 7.3; serum bicarbonate < 270 mg/dl (15 mmol/l)

The suspected diagnosis of ketoacidosis must be made if persistent hyperglycaemia > 250 mg/dl (13.9 mmol/l) is detected in combination with ketonuria, in particular if this finding is accompanied by corresponding clinical symptoms ([Table 4]) or a comorbidity is present. Further laboratory tests are required to confirm the diagnosis.

Table 4 Symptoms of diabetic ketoacidosis (from: [67] [72] [73]).

Gastrointestinal Symptoms	Loss of appetite, nausea and vomiting, abdominal pain up to pseudo-peritonitis.
Symptoms of dehydration	Symptoms of dehydration are dry mouth, standing skin folds, muscle cramps (calves, abdomen), soft bulbi, drop in blood pressure, polyuria (primary), oliguria (secondary). The cause is osmotic diuresis due to the increased blood glucose concentration (up to 100–200 g glucose/day!), which leads to a significant loss of fluid. This can lead to microcirculatory disturbances and hyperviscosity with thrombotic events.
Respiratory symptoms	The clinical characteristic of severe derailment is metabolic acidosis, with respiratory compensation. To compensate an acidosis with pH values of 7.1 and less, the carbon dioxide partial pressure in the blood gas analysis drops down to 15 mmHg. The deep, laboured or slightly rapid breathing is called Kussmaul’s respiration. The exhaled air smells of acetone, the typical, fruity smell of ketoacidosis.
Changes in consciousness	While the state of consciousness is not restricted in a mild ketoacidosis, a ketoacidosis of moderate severity is associated with restrictions of consciousness (drowsiness). Patients with severe diabetic ketoacidosis are in a stupor or comatose.

Symptoms

Laboratory chemical diagnostics

The following laboratory parameters are to be determined initially using quality-controlled laboratory standards if diabetic ketoacidosis is suspected: Blood glucose and ketones in urine or blood.

If these values are pathological, an arterial or venous blood gas test should be carried out and potassium levels, serum creatinine, blood count and CRP determined, as they have a decisive effect on the therapeutic regime. For outpatients, an urgent transfer to hospital must be arranged. If infections are suspected, bacterial cultures (e. g. blood, urine, pharynx) should be created.

An extended diagnosis is to be carried out within the framework of causal research and depending on the comorbid diseases.

([Table 6])

Table 6 Example of an infusion plan for the replacement of liquid

Infusion solution	Quantity and period
0.9% NaCl 1000 ml with potassium chloride	1000 ml over the next 2 h
0.9% NaCl 1000 ml with potassium chloride	1000 ml over the next 2 h
0.9% NaCl 1000 ml with potassium chloride	1000 ml over the next 4 h
0.9% NaCl 1000 ml with potassium chloride	1000 ml over the next 4 h
0.9% NaCl 1000 ml with potassium chloride	1000 ml over the next 6 h
Potassium levels in the first 24 h (mmol/l)	Potassium administration per 1000 ml infusion solution (mEq/l)
Higher than 5.5 3.5–5.5  < 3.5	no administration 40 Additional oral administration of potassium, if necessary

After 12 h, the cardiovascular situation is to be assessed and the liquid replacement adjusted accordingly.

Severity of diabetic ketoacidosis

The classification of diabetic ketoacidosis into 3 degrees of severity follows the classification by the American Diabetes Association (ADA) [74] ([Table 5]).

Table 5 Degrees of severity of diabetic ketoacidosis.

Parameter	Degree of severity
	Mild	Moderate	Severe
pH	< 7.3	≤ 7.2	≤ 7.1
Bicarbonate	< 270 mg/dl (15 mmol/l)	≤ 180 mg/dl (10 mmol/l)	< 90 mg/dl (5 mmol/l)

People with type 1 diabetes significantly underestimate the danger of ketoacidosis, as it is rather rare compared to the acute complication in the form of hypoglycaemia. Often, training on the subject of ketoacidosis took place a while ago and patients do not always remember how they can treat ketoacidosis themselves. Therefore, at regular intervals during check-ups, the topic should be addressed of recognizing ketoacidosis and treating it in a timely manner. It would be recommended to develop an evaluated short training module or other form of easily accessible information on ketoacidosis (e. g. a smartphone app). Patients should always remember that ketoacidosis is a dangerous medical situation and, in case of doubt, immediate medical assistance should be sought through the emergency medical services.

Control of diabetes-associated secondary diseases and associated risk facto

Guideline Information

The evidence-based guideline was prepared on behalf of the German Diabetes Society/Deutsche Diabetes Gesellschaft (DDG). President of the DDG is Prof. Dr. med. Dirk Müller-Wieland (2017–2019).

Expert group appointed by the DDG Board

• Prof. Dr. Thomas Haak, Bad Mergentheim (Coordinator)

• Dr. Stefan Gölz, Esslingen

• Prof. Dr. Andreas Fritsche, Tübingen

• PD Dr. Martin Füchtenbusch, Munich

• Dr. Thorsten Siegmund, Munich

Representatives of other organisations who voted on the recommendations and commented on the content of the guideline:

• Elisabeth Schnellbächer; Association of Diabetes Consultants and

• Training occupations in Germany/ Verband der Diabetesberatungs- und Schulungsberufe Deutschlands, Birkenfeld

• Prof. Dr. Horst H. Klein, German Society for Internal Medicine/ Deutsche Gesellschaft für Innere Medizin, Bochum

• Dr. Til Uebel, German Society for General and Family Medicine/ Deutsche Gesellschaft für Allgemein- und Familienmedizin, Ittlingen

• Diana Droßel, German Diabetes Aid - People with Diabetes/ Deutsche Diabetes Hilfe – Menschen mit Diabetes, Eschweiler

German Diabetes Association: Clinical Practice Guidelines

This is a translation of the DDG clinical practice guideline published in: Diabetologie 2019; 14 (Suppl 2): S142–S152, DOI: https://doi.org/10.1055/a-0898–7429

Conflicts of Interest

An overview of the conflicts of interest can be found in the guideline report at: https://www.awmf.org/uploads/tx_szleitlinien/057–013m_S3-Therapie-Typ-1-Diabetes_2018–04.pdf.

¹ This classification is based on recommendations of the American Diabetic Association (ADA).

² The presence of diabetic ketoacidosis is defined by different international blood glucose limit values. The limit value of 250 mg/dl (13.9 mmol/l) is based on the consensus of the author group. Since the clinical effects of high blood glucose levels can vary strongly, blood glucose levels should be assessed on the basis of the clinical picture. A single blood glucose measurement of more than 250 mg/dl (13.9 mmol/l) without corresponding accompanying parameters is not yet a ketoacidosis.

• References

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• 4 Palmer JP, Asplin CM, Clemons P. et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983; 222: 1337-1339 EK III
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