What is diabetic ketoacidosis (DKA) and how does it affect patients with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus (DM)?

Diabetic Ketoacidosis: Metabolic Pathophysiology and Clinical Overview

Diabetic ketoacidosis (DKA) is a life-threatening hyperglycemic emergency characterized by the triad of hyperglycemia (typically >250 mg/dL), metabolic acidosis with increased anion gap, and elevated ketone bodies, resulting from absolute or relative insulin deficiency combined with elevated counterregulatory hormones. 1

Core Metabolic Mechanism

The fundamental pathophysiology of DKA involves two critical hormonal derangements that work synergistically 1:

• Insulin deficiency (absolute or relative) prevents glucose utilization in peripheral tissues and removes the brake on lipolysis 1
• Elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone) drive hepatic and renal glucose production while simultaneously triggering uncontrolled release of free fatty acids from adipose tissue 1, 2

This hormonal imbalance creates a cascade of metabolic derangements 3:

• Hyperglycemia develops from impaired peripheral glucose uptake combined with accelerated hepatic gluconeogenesis and glycogenolysis 2
• Unrestrained lipolysis releases massive amounts of free fatty acids into circulation 4
• Hepatic beta-oxidation of these fatty acids produces excessive ketone bodies (beta-hydroxybutyrate [bOHB], acetoacetate, and acetone) 1, 4
• Metabolic acidosis results from accumulation of these organic acids, manifesting as decreased serum bicarbonate and arterial pH 1

Diagnostic Criteria

All of the following criteria must be met to establish DKA diagnosis 1:

• Hyperglycemia: Plasma glucose typically >250 mg/dL (>13.9 mmol/L), though approximately 10% present with euglycemic DKA (glucose <200 mg/dL) 1
• Metabolic acidosis: Arterial pH <7.30 (mild: 7.25-7.30; moderate: 7.00-7.24; severe: <7.00) 5
• Serum bicarbonate: <18 mEq/L in mild DKA, <10 mEq/L in severe DKA 5
• Positive ketones: Elevated blood ketones or bOHB, with positive urine ketones 5
• Elevated anion gap: Typically >10-12 mEq/L 5

Critical Diagnostic Nuance: Euglycemic DKA

Euglycemic DKA (glucose <200 mg/dL) occurs in approximately 10% of cases and requires either hyperglycemia OR prior diabetes history for diagnosis. 1 This variant is associated with 1:

• Reduced food intake or prolonged fasting
• Pregnancy
• Alcohol use
• Liver failure
• SGLT2 inhibitor therapy (increasingly common cause) 1, 2

Ketone Measurement: Technical Considerations

Beta-hydroxybutyrate (bOHB) is the predominant ketone in DKA and should be specifically measured in blood for both diagnosis and monitoring. 1 This is critical because:

• Nitroprusside-based tests (dipsticks, tablets) only detect acetoacetate and acetone, NOT bOHB 1
• During successful DKA treatment, bOHB falls while acetoacetate may paradoxically increase, making nitroprusside tests unreliable for monitoring therapy 1
• Blood bOHB measurement provides accurate assessment of ketosis severity and treatment response 1

Epidemiology and Mortality

The incidence of DKA has risen concerningly over the past decade 1:

• Type 1 diabetes: 44.5-82.6 per 1,000 person-years 1
• Type 2 diabetes: Up to 3.2 per 1,000 person-years 1
• Overall mortality: Approximately 5% in experienced centers, though this has plateaued in recent years 5, 3
• DKA accounts for approximately 1% of all diabetes-related hospitalizations 1

Precipitating Factors

Infection is the single most common precipitating cause of DKA, occurring in 30-50% of cases, with urinary tract infections and pneumonia being most frequent. 2, 6 Other major triggers include:

Medication-Related

• Insulin omission or non-compliance (most common in recurrent DKA, especially in patients with psychiatric illness, eating disorders, or financial barriers) 2
• SGLT2 inhibitors (now a leading cause, including in non-diabetic patients using these drugs for heart failure or chronic kidney disease) 2

Clinical Scenarios

• Acute intercurrent illness or febrile states 2
• First presentation of type 1 diabetes (particularly in children and adolescents) 2
• Pregnancy (up to 2% of pregnancies with pregestational diabetes) 1, 2
• Trauma, surgery, or myocardial ischemia 6
• Very-low-carbohydrate/ketogenic diets (especially with SGLT2 inhibitors) 1, 7
• Excessive alcohol intake 1

SGLT2 Inhibitor-Associated DKA: Special Considerations

SGLT2 inhibitors increase DKA risk with a relative risk of 2.46 in type 2 diabetes compared to placebo, though absolute rates remain low at 0.6-4.9 events per 1,000 patient-years. 1 The mechanism involves 2:

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

Critical pitfall: SGLT2 inhibitor-induced DKA often presents with blood glucose 177-180 mg/dL or lower, causing significant diagnostic delay since traditional teaching emphasizes glucose >250 mg/dL. 2

Distinguishing DKA from Other Ketoacidotic States

Alcoholic Ketoacidosis (AKA)

AKA typically presents with normal to mildly elevated glucose (rarely >250 mg/dL) or even hypoglycemia, distinguishing it from DKA which characteristically has glucose >250 mg/dL. 4 Key differences:

• Glucose levels: AKA normal to mildly elevated vs. DKA >250 mg/dL 4
• Clinical context: Recent alcohol binge with poor oral intake vs. known diabetes or new-onset diabetes 4
• Both have positive ketones and metabolic acidosis 4

Hyperosmolar Hyperglycemic State (HHS)

HHS presents with markedly elevated glucose (usually >600 mg/dL), minimal ketosis, and higher mortality (approximately 15%) compared to DKA. 5 Distinguishing features:

• Glucose: HHS >600 mg/dL vs. DKA >250 mg/dL 5
• Ketones: HHS small/absent vs. DKA positive 5
• pH: HHS >7.30 vs. DKA <7.30 5
• Bicarbonate: HHS >15 mEq/L vs. DKA <18 mEq/L 5
• Osmolality: HHS >320 mOsm/kg vs. DKA variable 5
• Presentation: HHS evolves over days to weeks vs. DKA within 24 hours 5
• Mental status: HHS more frequently presents with stupor/coma 5

Importantly, DKA and HHS often present concurrently in mixed presentations. 1

High-Risk Populations

Certain groups face elevated DKA risk and warrant heightened vigilance 1, 2:

• Pregnant individuals with type 1 diabetes (may present with euglycemic DKA and mixed acid-base disturbances) 1
• Elderly patients in chronic care facilities unable to access fluids 2
• Patients with psychiatric illness or eating disorders (higher recurrent DKA rates) 2
• Underinsured patients (insulin omission due to cost) 2
• Patients from single-parent homes 2

Prevention Strategies

Individuals on intensive insulin therapy should never stop or hold basal insulin even when not eating, and must receive detailed sick-day management instructions. 1 Key preventive measures include:

• Home monitoring: Check urine or blood ketones when glucose exceeds 200 mg/dL, especially during illness or with symptoms 1
• Early intervention: Contact diabetes care team immediately with glucose >300 mg/dL, use supplemental short-acting insulin, maintain liquid diet with carbohydrates and salt 2
• SGLT2 inhibitor precautions: Avoid very-low-carbohydrate diets, prolonged fasting, and excessive alcohol; monitor ketones during any illness 1
• Patient education: Structured education programs have reduced DKA hospitalization frequency 6

Common Clinical Pitfalls

• Missing euglycemic DKA in patients on SGLT2 inhibitors or pregnant individuals (always check ketones regardless of glucose level) 1, 2
• Using nitroprusside-based ketone tests for monitoring DKA treatment (use bOHB-specific measurements) 1
• Assuming normal temperature excludes infection (DKA patients can be normothermic or hypothermic despite serious infection; hypothermia is a poor prognostic sign) 2
• Relying on WBC count alone to diagnose infection (stress response in DKA causes leukocytosis; consider procalcitonin and obtain cultures if infection suspected) 2
• Failing to identify and treat the precipitating cause (most commonly infection) 5