Why does hyperglycemia cause metabolic acidosis (diabetic ketoacidosis)?

Why High Blood Sugar Leads to Acidosis

High blood sugar itself does not directly cause acidosis—rather, the underlying insulin deficiency that causes hyperglycemia simultaneously triggers uncontrolled fat breakdown and ketone production, which generates the metabolic acidosis seen in diabetic ketoacidosis (DKA). 1

The Core Mechanism: Insulin Deficiency Drives Both Problems

The fundamental issue is absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), which together create a perfect storm for both hyperglycemia and acidosis 1, 2:

Why Hyperglycemia Occurs

• Insulin deficiency impairs glucose uptake by cells in insulin-dependent tissues because insulin normally governs the translocation of glucose-transporter proteins to the cell membrane 3
• Glucose accumulates in the extracellular space (blood) because cells cannot utilize it effectively, creating hyperglycemia that serves as a "marker" of insulin deficiency 3
• Increased hepatic and renal glucose production further worsens hyperglycemia as counterregulatory hormones stimulate gluconeogenesis and glycogenolysis 1

Why Acidosis Occurs (The Critical Part)

• The same insulin deficiency triggers uncontrolled lipolysis—elevated counterregulatory hormones combined with lack of insulin cause massive release of free fatty acids from adipose tissue 1, 2
• Hepatic ketone production becomes unregulated—the liver converts these fatty acids through beta-oxidation into ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) 2, 4
• Ketone bodies are organic acids that accumulate in the blood, overwhelming the body's buffering systems and causing metabolic acidosis with an increased anion gap 5, 4
• Mitochondrial dysfunction from insulin deficiency specifically increases susceptibility to ketone generation—the more severe the insulin deficiency, the greater the ketosis 3

The Triad: Hyperglycemia, Ketosis, and Acidosis

DKA is characterized by the triad of uncontrolled hyperglycemia, metabolic acidosis, and increased total body ketone concentration 5, 4. These three features occur simultaneously because:

• Hyperglycemia reflects the inability to use glucose for cellular energy 3
• Ketosis and acidosis reflect the body's shift to fat metabolism in the absence of effective insulin action 1, 2
• Both are markers of the same underlying problem: insulin deficiency 3

Important Clinical Caveat: Euglycemic DKA

Not all DKA presents with severe hyperglycemia—SGLT2 inhibitors can cause euglycemic DKA with blood glucose as low as 177-180 mg/dL or even lower, yet still produce severe metabolic acidosis with elevated anion gap and positive ketones 1. This occurs because:

• SGLT2 inhibitors increase urinary glucose excretion, lowering blood glucose 1
• They simultaneously trigger increased glucagon levels and enhanced lipolysis, driving ketone production 1
• Renal clearance of ketones is decreased, allowing accumulation 1
• The traditional teaching of "glucose >250 mg/dL" for DKA does not apply in these cases 1

Type 1 vs Type 2 Diabetes Distinction

• Type 1 diabetes: Absolute insulin deficiency makes patients highly susceptible to both hyperglycemia and ketosis; both respond to insulin administration 3
• Type 2 diabetes: Usually has residual beta-cell function adequate to prevent lipolysis and ketosis under normal circumstances, but can develop DKA under stress (infection, trauma, surgery) when insulin becomes relatively insufficient 2, 4

Common Precipitating Factors

Infection is the single most common trigger for DKA, occurring in 30-50% of cases 1, 4. Other precipitants include:

• Insulin omission (most common cause of recurrent DKA) 1
• Acute illness or stress that increases counterregulatory hormones 1
• SGLT2 inhibitor use (now a leading cause, including in non-diabetic patients) 1
• Reduced caloric intake (particularly dangerous with SGLT2 inhibitors) 1

Bottom Line

Hyperglycemia and acidosis are parallel consequences of insulin deficiency, not a cause-and-effect relationship between the two. The high blood sugar indicates cells cannot use glucose for energy; the acidosis results from the body's compensatory shift to burning fat, which produces acidic ketones when insulin is insufficient to regulate the process 1, 2. Both require insulin administration for correction 3.