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Hyperinsulinemic-Euglycemic Clamp in the Conscious Rat
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Hyperinsulinemic-Euglycemic Clamp in the Conscious Rat

Published on: February 7, 2011

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Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated

Rachel J Perry1,2, Aviva Rabin-Court1, Joongyu D Song1

  • 1Departments of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, TAC S269, New Haven, CT, 06519, USA.

Nature Communications
|February 3, 2019
PubMed

Insights

Sodium-glucose transport protein 2 (SGLT2) inhibitors can cause ketoacidosis. In rats, dapagliflozin-induced ketoacidosis resulted from insulinopenia and dehydration, not increased glucagon.

Area of Science:

  • Endocrinology
  • Metabolic Disorders
  • Pharmacology

Background:

  • Sodium-glucose transport protein 2 (SGLT2) inhibitors are used to treat type 2 diabetes.
  • Concerns exist regarding their potential to cause euglycemic ketoacidosis and alter glucose/glucagon levels.
  • The underlying mechanisms for these effects are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms by which SGLT2 inhibitors induce ketoacidosis.
  • To determine the role of insulinopenia, dehydration, and glucagon in SGLT2 inhibitor-associated ketoacidosis.

Main Methods:

  • Experiments were conducted on healthy and type 2 diabetic rats under insulinopenic conditions.
  • Dapagliflozin was administered to induce SGLT2 inhibition.
  • Effects on plasma catecholamines, corticosterone, lipolysis, hepatic glucose production, and ketogenesis were measured.
  • Furosemide (a loop diuretic) was used to model volume depletion.

Main Results:

  • Dapagliflozin induced ketoacidosis in insulinopenic rats, linked to increased catecholamines and corticosterone due to volume depletion.
  • These changes promoted white adipose tissue lipolysis and hepatic ketogenesis.
  • Hepatic glucose production also increased.
  • Furosemide mimicked dapagliflozin's effects under insulinopenic conditions.
  • SGLT2 inhibition's ketoacidogenic effects were independent of hyperglucagonemia.

Conclusions:

  • In rats, SGLT2 inhibitor-induced ketoacidosis under insulinopenia is driven by volume depletion, leading to hormonal changes and altered metabolism.
  • The findings suggest that insulinopenia combined with dehydration are key factors in SGLT2 inhibitor-associated euglycemic ketoacidosis.
  • These conditions may represent a therapeutic target for prevention.

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