Ketosis-Prone Diabetes

Ketosis prone diabetes is a heterogeneous form of diabetes in which ketosis or ketoacidosis occurs at onset in people who lack the usual autoimmune features of type 1 diabetes, and in whom beta cell function often recovers enough to allow insulin to be reduced or stopped.

Four groups are defined by islet autoantibodies (present or absent) and beta cell reserve (preserved or poor). Reserve is preserved when fasting C-peptide is 0.33 nmol/L (1.0 ng/mL) or more and peak glucagon stimulated C-peptide is 0.5 nmol/L (1.5 ng/mL) or more.

It is most often reported in adults of sub-Saharan African, Afro-Caribbean and African American ancestry, and also in Hispanic and Asian populations. Men are affected more often than women, and obesity is common.

The autoantibody negative group with preserved reserve is the largest and has the most complete remission. A family history of type 2 diabetes is common, and glucose-6-phosphate dehydrogenase deficiency has been reported in people of African ancestry.

After the acute episode and recovery from glucotoxicity, many people with preserved reserve stay well for months to years without insulin. Ketosis can recur if glycaemia deteriorates or treatment lapses.

Pathophysiology.

Transient glucotoxicity and lipotoxicity impair insulin secretion and action. The resulting relative insulin deficiency permits unrestrained lipolysis and ketogenesis, while reserve recovers between episodes.

The cause of the reversible beta cell defect is not settled. Impaired antioxidant handling has been proposed, including in glucose-6-phosphate dehydrogenase deficiency.

• Osmotic symptoms (polyuria, polydipsia) for days to a few weeks, with weight loss, followed by ketoacidosis that often has no identifiable precipitant.
• Typical patient: adult, overweight or obese, family history of type 2 diabetes, acanthosis nigricans.
• Ketosis without acidosis may be found when hyperglycaemia is investigated.

Red flags.

• Severe ketoacidosis: pH under 7.0, bicarbonate under 5 mmol/L, ketones over 6.0 mmol/L, Glasgow Coma Scale score under 12, systolic blood pressure under 90 mmHg, serum potassium under 3.5 mmol/L.
• Persistent vomiting, abdominal pain or drowsiness.

• Diabetes: fasting glucose 7.0 mmol/L or more, random glucose 11.1 mmol/L or more, or HbA1c 48 mmol/mol (6.5%) or more.
• Ketosis: capillary beta hydroxybutyrate 3.0 mmol/L or more, or urine ketones 2+ or more. Ketoacidosis adds pH under 7.3 or bicarbonate under 15 mmol/L.
• Islet autoantibodies at presentation: glutamic acid decarboxylase, IA-2 and zinc transporter 8.
• Fasting C-peptide, with a stimulated value where available, once glycaemia is controlled (usually after several weeks), because glucotoxicity suppresses early values. Repeat at about 3 months and yearly, or if control worsens.
• Glucose-6-phosphate dehydrogenase activity in people of African, Mediterranean or Asian ancestry, because deficiency affects choice of sulphonylureas and other sulphonamide related drugs.
• Baseline urea and electrolytes, venous blood gas, ECG and a search for infection.

Differential diagnosis.

• Autoimmune type 1 diabetes: autoantibodies present, low C-peptide that does not recover.
• Type 2 diabetes with ketoacidosis triggered by infection, myocardial infarction or drugs.
• Latent autoimmune diabetes of adults: antibodies present, slower progression to insulin dependence.
• Ketoacidosis associated with sodium-glucose cotransporter 2 inhibitors, and pancreatogenic diabetes.
• Monogenic diabetes in younger patients with a strong family history.

Acute ketoacidosis (adults).

• Fluids: 0.9% sodium chloride 1000 mL over 1 hour (500 mL bolus first if systolic pressure is under 90 mmHg), then 1000 mL over 2 hours, 1000 mL over 2 hours, 1000 mL over 4 hours, 1000 mL over 4 hours and 1000 mL over 6 hours, adjusted to haemodynamics and to cardiac and kidney function.
• Insulin: fixed rate intravenous soluble insulin 0.1 units/kg/h, with the usual long acting insulin continued. Add 10% glucose at 125 mL/h once glucose is under 14 mmol/L.
• Potassium: serum potassium over 5.5 mmol/L, none; 3.5 to 5.5 mmol/L, add 40 mmol to each litre of fluid; under 3.5 mmol/L, withhold insulin and give potassium replacement with senior review.
• Aim for a ketone fall of at least 0.5 mmol/L/h, a bicarbonate rise of 3.0 mmol/L/h and a glucose fall of 3.0 mmol/L/h. If not reached, increase insulin by 1 unit/h.
• Resolution: ketones under 0.6 mmol/L and pH over 7.3. Then give subcutaneous insulin with a meal and stop the infusion 30 to 60 minutes after the first rapid acting dose.
• Bicarbonate is not used routinely and is reserved for pH under 6.9 with senior review. Give low molecular weight heparin to all admitted patients unless contraindicated.

Longer term.

• At discharge start basal bolus insulin, total daily dose about 0.5 units/kg with roughly half as basal insulin.
• If autoantibodies are negative and C-peptide shows preserved reserve, review at 4 to 12 weeks. Withdraw insulin in steps while fasting glucose stays under 7 mmol/L with no ketones, and replace with metformin (eGFR 30 or more; maximum 1000 mg daily at eGFR 30 to 44; stop under 30), with a dipeptidyl peptidase-4 inhibitor or gliclazide added if needed. Avoid sodium-glucose cotransporter 2 inhibitors because of ketoacidosis risk.
• Supply a capillary ketone meter and sick day rules: check ketones if unwell or glucose is over 15 mmol/L, and restart insulin when ketones are 0.6 mmol/L or more.

Monitoring. HbA1c every 3 months. Annual retinal screening, urine albumin to creatinine ratio, foot examination, lipids and blood pressure.

Referral and escalation. Specialist diabetes review at diagnosis. Critical care for any severe feature listed under red flags.