What are the causes and precipitating factors of diabetic ketoacidosis?

What Causes Diabetic Ketoacidosis

Diabetic ketoacidosis results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone), which together trigger uncontrolled lipolysis and ketogenesis. 1

Core Pathophysiologic Mechanism

The fundamental problem in DKA involves two simultaneous hormonal abnormalities that must both be present 1:

• Reduced effective insulin action leads to impaired glucose utilization in peripheral tissues and increased hepatic/renal glucose production, resulting in hyperglycemia 1
• Elevated counterregulatory hormones combined with insulin deficiency trigger release of free fatty acids from adipose tissue and drive unregulated hepatic ketone production 1
• This dual mechanism explains why either correcting insulin deficiency OR blocking stress hormone excess can prevent DKA development 2

Most Common Precipitating Factors

Infection (Leading Cause)

• Infection is the single most common precipitating cause of DKA, occurring in 30-50% of cases 1, 3
• Urinary tract infection and pneumonia account for the majority of infectious triggers 3
• Acute illness or febrile illness increases insulin requirements through stress hormone elevation 1

Insulin Omission/Non-Compliance

• Recurrent DKA is almost always due to insulin omission, with higher incidence in patients with psychiatric illness, those from single-parent homes, and underinsured patients 1
• Psychological problems and lack of financial resources are the most common causes of DKA in patients with established diabetes 1
• Urban African-Americans are at particular risk of discontinuing insulin due to economic reasons 1

New-Onset Diabetes

• First presentation of type 1 diabetes, particularly in children and adolescents, may present with ketoacidosis as the initial manifestation 1
• Some patients with new-onset diabetes retain residual β-cell function initially but eventually become insulin-dependent and at risk for ketoacidosis 1

SGLT2 Inhibitors: An Emerging Major Cause

SGLT2 inhibitors are now a leading cause of DKA, including euglycemic DKA (glucose <250 mg/dL), particularly as their use expands to heart failure and chronic kidney disease in non-diabetic patients. 1

The mechanism involves 1:

• Reduction in insulin doses due to improved glycemic control
• Increased glucagon levels leading to enhanced lipolysis and ketone production
• Decreased renal clearance of ketones
• Risk present in both diabetic and non-diabetic patients

Critical pitfall: SGLT2 inhibitor-induced DKA presents with severe metabolic acidosis, elevated anion gap, and positive ketones but blood glucose may be only 177-180 mg/dL or even lower, potentially delaying diagnosis if clinicians rely solely on traditional glucose thresholds 1

High-Risk Clinical Scenarios

Insulin Pump Failure

• Insulin pump failure or disconnection creates immediate absolute insulin deficiency and can precipitate DKA within 4-10 hours 1
• Interruption of any insulin delivery (pump malfunction or missed injections) can trigger rapid DKA development 1
• Basal insulin should never be discontinued, even when blood glucose appears normal, because stopping basal insulin markedly increases the risk of rapid ketosis and DKA within 4-10 hours 1

Pregnancy

• Pregnancy, especially in type 1 diabetes, with up to 2% of pregnancies complicated by DKA 1

Reduced Caloric Intake

• Reduced caloric intake is particularly dangerous in patients on SGLT2 inhibitors 1

Other Intercurrent Illnesses

• Surgery, trauma, myocardial ischemia, and pancreatitis can all precipitate DKA 3

Special Populations at Increased Risk

• Children and adolescents experience the fastest progression to DKA because β-cell destruction is most rapid in this age group; DKA can evolve from modest hyperglycemia to severe DKA within hours, especially when infection or other stressors are present 1
• Children and adolescents with eating disorders have a higher frequency of recurrent DKA 1
• Elderly individuals in chronic care facilities who become hyperglycemic and cannot access fluids 1
• Patients with autoimmunity initially thought to have type 2 diabetes 1

Medication-Induced Causes Beyond SGLT2 Inhibitors

• Corticosteroids, sympathomimetic agents (dobutamine, terbutaline), and thiazides can precipitate DKA and independently elevate stress hormone responses 1

Key Clinical Pearls

• Temperature is unreliable in DKA patients—they can be normothermic or even hypothermic despite serious infection, and hypothermia is actually a poor prognostic sign 1
• DKA evolves rapidly, typically within 24 hours, allowing for acute presentation with minimal warning 4
• The mortality rate for DKA is approximately 5% in experienced centers, with worse outcomes at extremes of age (>65 years), in the presence of coma, hypotension, and hypothermia 4