Renal Handling of Ketones in Response to Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 2 Diabetes.
Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes.



We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min-1· 1.73 m-2) and in control subjects without diabetes at baseline and following empagliflozin treatment.



With chronic (4 weeks) sodium-glucose cotransporter 2 inhibition, baseline fractional glucose excretion (<2%) rose to 38 ± 12% and 46 ± 11% (fasting vs. postmeal, respectively;P< 0.0001) over a range of BMIs (range 23-41 kg/m2) and creatinine clearance (65-168 mL · min-1· m-2). Excretion of β-HB (median [interquartile range]: 0.08 [0.10] to 0.31 [0.43] µmol · min-1), lactate (0.06 [0.06] to 0.28 [0.25] µmol · min-1), and sodium (0.27 [0.22] to 0.36 [0.16] mEq · min-1) all increased (P≤ 0.001 for all) and were each positively related to glycosuria (P≤ 0.001). These parameters changed in the same direction in subjects without diabetes, but changes were smaller than in the patients with diabetes. Although plasma N-terminal pro-B-type natriuretic peptide levels were unaltered, plasma erythropoietin concentrations increased by 31 (64)% (P= 0.0078).



We conclude that the sodium-glucose cotransporter 2 inhibitor-induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.
CNR Institute of Clinical Physiology, Pisa, Italy ferranni@ifc.cnr.it.
Ele
0000-0002-1384-1584
E
Ferrannini
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Simona
S
Baldi
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Silvia
S
Frascerra
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Brenno
B
Astiarraga
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Elisabetta
E
Barsotti
CNR Institute of Clinical Physiology, Pisa, Italy.
Aldo
A
Clerico
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Elza
E
Muscelli
D020155:3-Hydroxybutyric Acid / Q000652:urine; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D001786:Blood Glucose; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000652:urine*; D004921:Erythropoietin / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate; D005934:Glucagon / Q000378:metabolism; D005960:Glucosides / Q000627:therapeutic use; D006029:Glycosuria / Q000097:blood / Q000652:urine; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007659:Ketones / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D019344:Lactic Acid / Q000652:urine; D008297:Male; D008875:Middle Aged; D009318:Natriuresis; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D012964:Sodium / Q000652:urine; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D007659:Ketones; D010446:Peptide Fragments; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C109794:pro-brain natriuretic peptide (1-76); D004921:Erythropoietin; D020097:Natriuretic Peptide, Brain; D019344:Lactic Acid; D005934:Glucagon; D012964:Sodium; C570240:empagliflozin; D020155:3-Hydroxybutyric Acid