Sodium DL-3-hydroxybutyrate powder

BACKGROUND: Dapagliflozin (DAPA) has shown major nephroprotective effects, improving kidney metabolism and oxigenation. Lipidomics and metabolomics are powerful tools for understanding such effects, providing a comprehensive look at how SGLT2 inhibitors might change the metabolic landscape beyond their primary glucose-lowering action. We investigated changes in plasma metabolomic/lipidomic profile and urinary excretion of metabolites that could occur independent of increased diuresis. METHODS: A two-armed, parallel-design, randomized clinical trial was conducted in subjects with type 2 diabetes and hypertension who received treatment with DAPA 10 mg/day or hydrochlorothiazide 12.5 mg/day for four weeks. Lipidomics and metabolomics were performed by high resolution mass spectrometry in fasting plasma and 24-hour urine samples collected before and after treatment. RESULTS: Compared to hydrochlorothiazide, DAPA significantly increased plasma isoleucine, methionine, citrate, β-hydroxybutyrate and decreased lactate. DAPA induced plasma lipid remodeling towards a significant raise in free fatty acids (FFAs) and some sphingomyelins and lysophosphatidylcholines containing these fatty acids. A significant change was observed in plasma medium- and short-chain acylcarnitines, positively correlated with changes in plasma FFAs and β-hydroxybutyrate. In addition, DAPA, but not hydrochlorothiazide, significantly increased 24-h urinary excretion of several amino-acids, lactate, TCA cycle metabolites, β-hydroxybutyrate and electrolytes, except for a decrease in malate excretion. CONCLUSIONS: DAPA treatment has major effects on the plasma lipidomic and the urine metabolomic profiles, with significant increased renal excretion of several metabolites, especially amino-acids, independently of increased diuresis. These data offer insights into the complex metabolic pathways leading to kidney protection by SGLT2 inhibitors. CLINICAL TRIAL INFORMATION: European Union Drug Regulating Authorities Clinical Trials No. 2015-004164-11.

Abstract licence: CC BY-NC-ND

Metformin-associated lactic acidosis (MALA) and euglycemic diabetic ketoacidosis (euDKA) are distinct causes of high anion gap metabolic acidosis, but their simultaneous occurrence is rare and may be overlooked when severe hyperlactatemia dominates the presentation. We report the case of a 68-year-old man with type 2 diabetes mellitus treated with basal-bolus insulin, metformin, and linagliptin who presented with vomiting, confusion, fatigue, hypotension, and reduced level of consciousness. Initial evaluation revealed profound acidemia (arterial pH 6.75), severe high anion gap metabolic acidosis (anion gap 51 mEq/L, bicarbonate <2 mEq/L), marked hyperlactatemia (19 mmol/L), significant ketonemia (beta-hydroxybutyrate >9.60 mmol/L), near-normal glucose (9.1 mmol/L), hyperkalemia (6.5 mEq/L), and severe acute kidney injury (creatinine 516 µmol/L). Ongoing metformin exposure in the setting of acute kidney injury supported MALA, while marked ketonemia with near-normal glucose supported concurrent euDKA, likely precipitated by vomiting and reduced oral intake. The patient was treated with intravenous fluids, vasopressors, sodium bicarbonate, insulin with concurrent dextrose, and sustained low-efficiency dialysis, with subsequent hemodynamic, metabolic, and renal recovery. This case emphasizes that marked hyperlactatemia does not exclude a concurrent ketotic process and that early ketone measurement can materially change management in metformin-treated patients with persistent high anion gap acidosis.

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Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.

Abstract licence: CC BY