AD 6th Oct issue | Seite 28

Figure 1 . The risk of DKA .

• Omission of insulin therapy , reduction in insulin dose or inadequate dosing .

• Insulin pump failure , occlusion or infusion site failure .

• Prolonged nausea and vomiting .

• Infections ( eg , pneumonia , COVID-19 , urinary tract infections , sepsis ).

• Eating disorders , diabulimia .

• Binge drinking .

• Pregnancy .

• Very low-carbohydrate / food intake or prolonged fasting .

• Extreme physiological stress ( eg , dehydration , blood loss , major surgery , trauma , myocardial infarction , pancreatitis ).

• Initiation of certain medications ( corticosteroids , pentamidine , check-point inhibitors , antipsychotic drugs , illicit drugs ).

( EKA ), and is a rare complication

such as severe illness , extended fast-

the characteristic ‘ rotting apple ’ or

Treatment with SGLT2 inhibitors

type 1 diabetes ( that is , before insu-

of various different severe metabolic

ing ( for example , gastrointestinal

‘ nail polish ’ breath odour of a patient

in individuals with type 2 diabetes

lin is started ). Indeed , DKA can be

stressors in susceptible individuals

illness , acute abdomen ), may rarely

with ketoacidosis .

causes glycosuria ( glucose wasting )

a presenting feature in up to half

( see box 1 ).

precipitate ketoacidosis , especially in

Most DKA events are sudden .

that induces comparable metabolic

of Australian children with type 1

People with diabetes can also

women with gestational or pre-exist-

Although a profound deficiency of

changes to a low-carbohydrate diet ,

diabetes . 12

experience EKA . In fact , when put

ing diabetes .

insulin is the predisposing state , DKA

including reduced insulin and ele-

DKA can also occur in patients

under the same metabolic stress ( for

EKA has also been described fol-

is invariably associated with a sig-

vated glucagon concentrations .

with type 1 diabetes because of

example , pregnancy , starvation , sep-

lowing excessive chronic alcohol

nificant intercurrent illness or trig-

On average , blood ketone levels

non-adherence or omission of insu-

sis ), EKA is more common in diabetic

intake , often during withdrawal or

ger event ( see box 2 ), that results in

are approximately double in diabetic

lin therapy ( for example , missed

individuals .

because of symptoms preventing

increased release of counter-regu-

patients treated with SGLT2 inhibi-

insulin doses , insulin pump failure ,

EKA is also observed following the use of SGLT2 inhibitors in people with type 2 diabetes . 15 Indeed , SGLT2 inhibitors are contraindicated

food intake such as nausea , vomiting or abdominal pain . 5

EKA may rarely occur in non-diabetic patients with prolonged and

latory ( or stress ) hormones such as glucagon , corticosteroids , catecholamines , leptin and growth hormones . These hormones further oppose the

tors compared with other therapies . 18 These levels are similar to the magnitude of increase observed during pregnancy , where the metabolic

or diabulimia [ an eating disorder where those with type 1 diabetes intentionally give themselves less insulin than they need or stop

in patients with type 1 diabetes , spe-

severely reduced carbohydrate / food

actions of ( inadequate ) insulin and

activity of the placenta and develop-

using their insulin in order to lose

cifically because of the increased risk of EKA in this setting . 16 Recent clinical trials in patients with type 2 diabetes suggest that treatment with SGLT2 inhibitors may double the risk of EKA . 15 Nonetheless , because so many patients with type 2 diabetes are now receiving SGLT2 inhibitors as part of their ongoing care , SGLT2

intake ( for example , prolonged fasting , starvation , illness , gastrointestinal disorders ) because of increased ketogenesis combined with dehydration . 5 For example , EKA has also been reported after bariatric surgery . 17

PATHOGENESIS

KETONES are naturally generated

markedly augment ketogenesis . Intercurrent illnesses are an unavoidable part of normal life . Even in adults with long-standing established type 1 diabetes , such events can sometimes sporadically trigger DKA , even if there is no history of DKA events , poor glucose control or risk-taking behaviour .

ing baby , rather than the urine , provides the metabolic sink for glucose losses . 4 Again , pregnancy-related ketosis is distinct from pathophysiological ketoacidosis . However , both pregnancy and SGLT2 inhibition are ‘ ketosis-prone ’ states ( see box 1 ) and risk factors for EKA , given the right ( or more correctly , the wrong )

weight ]).

Most patients with established type 1 diabetes develop DKA during intercurrent infections that suddenly increase their insulin resistance , while at the same time hypermetabolism , volume depletion and vasodilation associated with infections can amplify ketogene-

inhibitors have become a leading

from fatty acids by the liver as an

Blood ketone levels are naturally

trigger .

sis in some patients . Concurrently ,

cause of EKA . There has been only one recorded event of ketoacidosis in participants without diabetes receiving an SGLT2 . 15

alternative mitochondrial fuel source for metabolically demanding tissues , such as the brain , the heart and skeletal muscle . Ketone production

elevated when following a diet low in carbohydrate ( for example , a “ keto ” diet that is high in fat and very low in carbohydrate , see figure 3 ). This

RISK FACTORS AND TRIGGERS

KETOACIDOSIS is almost always

patients often reduce their insulin dose because of the perceived risk of hypoglycaemia when they feel unwell and are not eating and

EKA is a very rare complication of

increases as insulin levels fall and

is known as physiological ketosis

the result of a trigger event ( see

drinking . Finally , in some adults

pregnancy . 4 Pregnancy naturally acts to amplify ketone production , and

glucagon levels rise in the fasting / starved state as glycogenolysis by the

or nutritional ketosis , which actually has the goal of increasing serum

box 2 ) in susceptible individuals . The most common trigger event

with type 1 diabetes , binge drinking can supress gluconeogenesis and

ketone levels are usually higher in

liver is exhausted ( see figure 2 ).

ketone concentrations of above

in patients with type 1 diabetes is

increase the demand for an addi-

pregnancy because of systemic insu-

The major ketones , acetoacetate

0.5mmol / L . This state is very distinct

severe volume depletion / dehydra-

tional ( ketone ) fuel substrate .

lin resistance and the large metabolic

and β-hydroxybutyrate , are organic

from pathophysiological ketoacidosis

tion due to severe hyperglycaemia ,

Importantly , these same trig-

demands of the developing fetus and

acids that in high enough levels cre-

( see figure 4 ), where levels of ketone

which drives a strong counterreg-

ger events are also implicated in

placenta , particularly in the third trimester . However , intercurrent dia-

ate the ‘ high anion gap ’ metabolic acidosis characteristic of ketoacidosis .

concentrations are much higher and fail to be offset by renal compensa-

ulatory response and unimpeded ketogenesis . This is most likely at

most cases of EKA in ketosis-prone settings ( see box 1 ). For example ,

betes and / or during trigger events

Acetone is also generated , creating

tion of acidosis .

the first presentation of new-onset

severe COVID-19 infection

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