Is ketone production during fasting a concern for a healthy individual versus a diabetic patient, particularly those with type 1 diabetes (T1D)?

Ketone Production During Fasting: Critical Distinction Between Healthy Individuals and Diabetic Patients

Ketone production during fasting is a normal, protective physiological response in healthy individuals, but represents a potentially life-threatening emergency in patients with type 1 diabetes, particularly when insulin-deficient. 1, 2

Physiological Ketosis in Healthy Individuals

Normal Metabolic Response

• During fasting, healthy individuals develop "physiological ketosis" with ketone levels typically ranging from 0.3 to 4 mmol/L, characterized by normal pH, normal blood glucose, and serum bicarbonate usually not lower than 18 mEq/L. 1, 3

• As fasting extends beyond several hours, glycogen stores deplete and low insulin levels trigger fatty acid release from adipocytes, with oxidation generating ketones that serve as alternative fuel for skeletal muscle, cardiac muscle, liver, kidney, and adipose tissue, sparing glucose for the brain and erythrocytes. 1

• Up to 30% of first morning urine specimens show positive ketones even in healthy individuals, and this increases substantially during fasting states—this is completely benign. 2, 3

Safety Profile in Non-Diabetics

• Starvation ketosis from reduced caloric intake is the most common benign explanation when patients feel unwell and eat less, causing the body to shift to fat metabolism for energy. 2

• In keto-adapted healthy individuals, prolonged fasting with ketone levels up to 7.5 mmol/L during extended exercise (5 days, 100 miles) was well-tolerated with no adverse effects on physical or mental function. 4

Pathological Ketosis in Type 1 Diabetes

Critical Differences from Physiological Ketosis

• Pathological ketosis in decompensated diabetes is characterized by low systemic pH, absent or severely deficient insulin, hyperglycemia, and very high ketone body levels (>7-8 mmol/L), representing diabetic ketoacidosis (DKA)—a medical emergency. 1

• The EPIDIAR study demonstrated a threefold increase in severe hyperglycemia with or without ketoacidosis in type 1 diabetes patients during fasting (from 5 to 17 events per 100 people per month). 1

Accelerated Ketosis During Fasting in T1D

• Short-term fasting (32 hours) in insulin-deficient type 1 diabetes patients dramatically accelerates ketone production (8.82 vs. 6.23 μmol/L/min) and worsens metabolic acidosis (serum bicarbonate nadir 15.4 vs. 18.6 mmol/L) compared to the postprandial state. 5

• Fasting predisposes type 1 diabetes patients to euglycemic ketoacidosis during insulin deficiency, where plasma glucose may be only mildly elevated (13.3 mmol/L or ~240 mg/dL) despite severe ketoacidosis. 5

• This occurs because fasting reduces hepatic glucose production while ketone production continues progressively, accelerated by elevated glucagon and catecholamine levels. 5

Clinical Decision Algorithm

Immediate Risk Stratification

High-risk patients requiring immediate evaluation: 2, 3

• Known type 1 diabetes
• History of prior DKA
• Currently on SGLT2 inhibitors (which increase DKA risk and can cause euglycemic DKA with glucose <250 mg/dL)
• Unexplained hyperglycemia or symptoms of ketosis (abdominal pain, nausea, Kussmaul respirations)

Lower-risk patients (likely starvation ketosis): 2, 3

• No diabetes history
• Normal or low blood glucose
• Recent decreased oral intake
• No abdominal pain or altered mental status

Diagnostic Testing Recommendations

• Blood beta-hydroxybutyrate measurement is strongly preferred over urine testing for all clinical decision-making, as urine dipsticks only detect acetoacetate and significantly underestimate total ketone concentration. 1, 2, 3

• The American Diabetes Association recommends checking blood glucose immediately to distinguish between DKA and benign starvation ketosis, with glucose >250 mg/dL indicating a medical emergency requiring immediate DKA evaluation. 3

Blood Ketone Action Thresholds (American College of Clinical Endocrinologists)

• <0.5 mmol/L: No intervention needed 3
• 0.5-1.5 mmol/L: Initiate sick-day rules 3
• ≥1.5 mmol/L: Immediate medical attention required 3

DKA Diagnostic Criteria (American Diabetes Association)

All of the following must be present: 3

• Plasma glucose >250 mg/dL
• Arterial pH <7.30
• Serum bicarbonate <15 mEq/L
• Positive urine or serum ketones
• Anion gap >10 mEq/L

Critical Pitfalls and Special Considerations

SGLT2 Inhibitor Complications

• SGLT2 inhibitors exaggerate ketone production and partially reduce compensatory urinary excretion, particularly in women, increasing plasma ketone concentrations even during mild hyperglycemia. 6

• These medications decrease the hyperglycemia that typically accompanies DKA, making diagnosis more challenging and enabling euglycemic DKA. 3

Testing Limitations

• Urine dipsticks using the nitroprusside method do NOT measure beta-hydroxybutyrate, the predominant ketone body in DKA, leading to significant underestimation of ketosis severity. 1, 3

• False-positive ketones can occur with sulfhydryl drugs like captopril, while false-negatives occur with prolonged air exposure of test strips or highly acidic urine. 2

Type 1 Diabetes Fasting Considerations

• Individuals with type 1 diabetes who are prone to ketosis should measure ketones in urine or blood if they have unexplained hyperglycemia or symptoms of ketosis and implement sick day rules and/or seek medical advice if ketones are increased. 1

• Even mild hyperglycemia (9-11 mmol/L or ~160-200 mg/dL) in type 1 diabetes is associated with greater ketone production, normally compensated by urinary excretion, but this compensation fails during insulin deficiency. 6

• In properly managed, keto-adapted type 1 diabetes patients with adequate insulin, nutritional ketosis (ketone levels similar to non-diabetics) can be well-tolerated without progressing to DKA, but this requires careful monitoring and insulin adjustment. 4