What are the causes of Diabetic Ketoacidosis (DKA)?

Causes of Diabetic Ketoacidosis (DKA)

DKA results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, 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 occur together 1:

• Reduced effective insulin action leads to impaired glucose utilization in peripheral tissues and increased hepatic/renal glucose production, causing 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

Most Common Precipitating Factors

Infection (Leading Cause)

• Infection is the single most common precipitating cause of DKA in patients with established diabetes 1, 2
• Acute febrile illness increases insulin requirements through stress hormone elevation 1

Insulin Omission or Inadequate Dosing

• Discontinuation or inadequate insulin dosing is a common precipitating factor, particularly in recurrent DKA 3, 2
• Recurrent DKA is almost always due to insulin omission, with higher incidence in patients with psychiatric illness (especially depression), those from single-parent homes, and underinsured patients 4
• Psychological problems and lack of financial resources are the most common causes of DKA in patients with established diabetes 4

New-Onset Diabetes

• First presentation of type 1 diabetes, particularly in children and adolescents who may present with ketoacidosis as the initial manifestation 4
• Some patients retain residual β-cell function initially but eventually become insulin-dependent and at risk for ketoacidosis 4

Medication-Induced DKA

SGLT2 Inhibitors (Emerging Major Cause)

• SGLT2 inhibitors are now a leading cause of DKA, including euglycemic DKA, particularly as their use expands to heart failure and chronic kidney disease in non-diabetic patients 1
• The mechanism involves reduction in insulin doses due to improved glycemic control, increased glucagon levels leading to enhanced lipolysis and ketone production, and decreased renal clearance of ketones 1
• Risk is present in both diabetic and non-diabetic patients taking SGLT2 inhibitors 1
• Traditional DKA presents with glucose >250 mg/dL, but SGLT2 inhibitor-induced DKA presents with severe metabolic acidosis and blood glucose as low as 177-180 mg/dL or even lower 1

Other Medications

• Drugs affecting carbohydrate metabolism can precipitate DKA, including corticosteroids, thiazides, and sympathomimetic agents 3

High-Risk Clinical Scenarios

Acute Illness and Stress

• Any significant stressful situation, fever, or infection increases insulin requirements and can precipitate DKA 5, 2
• Prolonged hyperglycemia from omitting insulin, eating significantly more than planned, or developing fever/infection can result in DKA 5

Reduced Caloric Intake

• Reduced caloric intake is particularly dangerous in patients on SGLT2 inhibitors 1
• Fasting contributes to stress hormone excess, which combined with insulin deficiency leads to DKA 6

Pregnancy

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

Menstruation

• Psychological stress during menstruation can precipitate DKA 3
• Patients must not discontinue basal insulin during menstruation, even if food intake is reduced 3

Special Populations at Risk

• 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
• Children and adolescents with eating disorders have higher frequency of recurrent DKA 4

Additional Contributing Factors

• Alcohol consumption can alter insulin requirements and precipitate hyperglycemia 5
• Progression of kidney or liver disease affects insulin metabolism 5
• Diseases of the adrenal, pituitary, or thyroid gland alter glucose metabolism 5
• Dehydration contributes to stress hormone excess 6

Clinical Pitfall to Avoid

Do not assume normal or near-normal glucose levels exclude DKA—with SGLT2 inhibitor use, euglycemic DKA (glucose <250 mg/dL) is increasingly common and can be missed if clinicians rely solely on traditional glucose thresholds for diagnosis 1, 7.