Ketone-prone diabetes

Dear Editor,

The concept of diabetes mellitus (DM) has evolved in recent years to encompass a broad spectrum of clinical forms that differ in pathophysiology, clinical course, and treatment, justifying the need for a specific and individualized approach.¹ We present two cases of type 2 DM with atypical presentation and progression.

Case 1: A 47-year-old male of African descent, with obesity as the only relevant medical history, presented to the Emergency Department with hyporexia, nausea, vomiting, cardinal symptoms, and altered mental status for one week. Tests led to the diagnosis of severe diabetic ketoacidosis (DKA) (Table 1), requiring intensive treatment with fluid therapy and intravenous insulin in the Intensive Care Unit. After ten days of hospitalization, with favorable evolution, he was discharged with a basal-bolus insulin regimen and flash glucose monitoring (FGM). Two weeks later, an Endocrinology follow-up showed normal glucose profiles with a tendency for postprandial hypoglycemia. Laboratory tests revealed a C-peptide level of 1.33 ng/L, with negative islet autoimmunity. Insulin was discontinued, and metformin 1 g every 12 h was initiated alongside lifestyle recommendations, achieving optimal glycemic control (time in range 10–180 mg/dL [TIR] 99%, mean glucose 92 mg/dL, and coefficient of variation [CV] 14.3%). This evolution supported a diagnosis of Flatbush diabetes or ketone-prone diabetes (KPD).

Table 1.

Laboratory analytical results.

	Case 1	Case 2
BMI (kg/m^2)	38.58	27.5
HbA1c (%) (hospital admission)	12	10.3
VBG (hospital admission)
• pH	7.00	7.31
• HCO3 (mmol/L)	7	21.1
• Gly (mg/dL)	481	>1000 mg/dl
Urinary ketones	++++	−
Insulin requirements (UI/24 h) at discharge	42	115
Anti-pancreatic islet antibodies (UI/mL)
• Anti-GAD65 Ab	<0.5	3.62
• Anti-IA2 Ab	2	2
Anti-insulin antibodies (%)	4.5	6.3
Capillary HbA1c (%) at discharge	5.5	5.3

BMI: body mass index; HbA1c: glycated haemoglobin; VBG: venous blood gas; Gly: glycemia; anti-GAD65 Ab: glutamic acid decarboxylase 65 antibodies; anti-IA2 Ab: insulinoma-associated antigen 2 antibodies.

Case 2: A 50-year-old male with hypertension treated with enalapril/hydrochlorothiazide was transferred to the Emergency Department due to altered mental status, general deterioration, and cardinal symptoms lasting one month. Initial assessment revealed acute kidney injury, metabolic acidosis, and hyperglycemia exceeding 1000 mg/dL (Table 1). Diagnosed with a hyperglycemic hyperosmolar state, he was admitted to the ICU, where acute comorbidities were ruled out, and intensive directed treatment was initiated with good improvement. After 11 days, he was discharged on a basal-bolus insulin regimen and FGM. At the 15-day Endocrinology follow-up, excellent glycemic control was observed (TIR 99%, CV 17.2%), with negative autoimmunity and preserved C-peptide levels (3.24 ng/L). Insulin therapy was discontinued, and metformin 850 mg every 12 h was started, maintaining excellent glycemic control after two months (TIR 100%, CV 12.3%). The diagnosis of type 2 DM (T2DM) with KPD-like features and hyperosmolar hyperglycemic state was established.

KPD is a form of T2DM (primarily driven by insulin resistance) with a propensity for acute hyperglycemic decompensation leading to DKA, often due to transient insulin synthesis impairment. Proposed DKA triggers include viral infections and conditions associated with increased oxidative stress.² Given the reversibility of insulinopenia, insulin therapy can often be discontinued.^2,4,5 KPD occurs more frequently in patients with obesity, family history of T2DM, and certain ethnic backgrounds (e.g., African-Americans).³

A modified Aβ classification system categorizes DM subtypes prone to DKA into four groups based on autoantibody presence and β-cell functional reserve: (1) A+β−, or type 1A KPD; (2) A−β−, or type 1B KPD; (3) A+β+, or type 2A KPD; and (4) A−β+, or type 2B KPD, also referred to as Flatbush diabetes.² Beta-cell autoimmunity and insulin reserve should be assessed after resolution of the acute episode through measurement of glutamic acid decarboxylase, tyrosine phosphatase, and zinc transporter autoantibodies, as well as C-peptide levels.^2,4,5

While the first three subgroups typically require intensive and sustained insulin therapy, patients with type 2B KPD or Flatbush diabetes exhibit excellent responsiveness to short-term insulin, with discontinuation feasible in up to 70% of cases.⁵ Sodium-glucose cotransporter-2 inhibitors (SGLT2i) should be avoided due to the increased risk of euglycemic ketoacidosis.⁵ The second case presented in this letter represents an unusual form of KPD-like DM, given the development of a hyperglycemic hyperosmolar crisis with negative ketonuria, possibly due to pronounced baseline insulin resistance. The subsequent evolution, with insulin deintensification and excellent glycemic control, supports this diagnosis.

KPD should be considered in patients presenting with DKA, regardless of prior diabetes history. Early identification and classification can prevent unnecessary prolonged insulin therapy in Flatbush diabetes patients. Monitoring C-peptide levels and assessing autoimmunity are essential for determining long-term treatment needs.³

Ethics statement

The authors declare that the present work has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments on human subjects.

Funding

The authors declare no financial support to prepare the manuscript.

Conflict of interest

The authors declare no conflict of interest.