What causes Diabetic Ketoacidosis (DKA)?

What Causes Diabetic Ketoacidosis (DKA)

DKA is caused by 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 cause involves two simultaneous hormonal derangements 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 (lipolysis) and drive unregulated hepatic ketone production 1

This dual mechanism distinguishes DKA from hyperosmolar hyperglycemic state (HHS), where residual insulin is sufficient to prevent significant ketogenesis but inadequate to control hyperglycemia 2, 3

Most Common Precipitating Factors

Infection is the single most common precipitating cause of DKA 1, 4

Primary Triggers (in order of frequency):

• Infection - the leading precipitating factor in established diabetes 1
• Insulin omission or inadequate dosing - particularly common in established type 1 diabetes 1, 5
• New-onset type 1 diabetes - DKA may be the initial presentation, especially in children 1, 6
• Nonadherence to insulin therapy - a major preventable cause 4

Secondary Precipitating Factors:

• Myocardial infarction 1
• Cerebrovascular accident (stroke) 1
• Pancreatitis 1
• Trauma 1
• Alcohol abuse 1

Medication-Induced DKA

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 3

The mechanism involves 3:

• 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

Other Diabetogenic Medications:

Drugs that impair carbohydrate metabolism and may precipitate DKA 1:

• Corticosteroids
• Thiazide diuretics
• Sympathomimetic agents (dobutamine, terbutaline)

High-Risk Clinical Scenarios

Situations That Increase DKA Risk:

• Acute illness or febrile illness - increases insulin requirements through stress hormone elevation 1, 6
• Reduced caloric intake - particularly dangerous in patients on SGLT2 inhibitors 3
• Pregnancy - especially in type 1 diabetes, with up to 2% of pregnancies complicated by DKA 3
• Dehydration - impairs insulin delivery and increases counterregulatory hormones 3
• Surgery or perioperative fasting 3

Special Populations at Risk

• Elderly individuals in chronic care facilities who become hyperglycemic and cannot access fluids 1
• Pediatric patients with new-onset diabetes 6
• Patients with autoimmunity initially thought to have type 2 diabetes 3

Critical Pitfall to Avoid

Always check blood or urine ketones in any ill diabetic patient regardless of blood glucose level, particularly those on SGLT2 inhibitors, pregnant patients, or those with reduced oral intake, as euglycemic DKA (glucose <250 mg/dL) is increasingly common and can be missed if clinicians rely solely on hyperglycemia for diagnosis 3, 6