Distinct Mechanisms Responsible for the Increase in Glucose Production and Ketone Formation Caused by Empagliflozin in T2DM Patients.

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  • Additional Information
    • Source:
      Publisher: American Diabetes Association Country of Publication: United States NLM ID: 7805975 Publication Model: Print Cited Medium: Internet ISSN: 1935-5548 (Electronic) Linking ISSN: 01495992 NLM ISO Abbreviation: Diabetes Care Subsets: MEDLINE
    • Publication Information:
      Publication: Alexandria Va : American Diabetes Association
      Original Publication: New York, American Diabetes Assn.
    • Subject Terms:
      Glucose*/therapeutic use ; Diabetes Mellitus, Type 2*/drug therapy; Humans ; Glucagon ; Insulin/therapeutic use ; Ketones/therapeutic use ; Norepinephrine/therapeutic use ; Blood Glucose ; Fatty Acids, Nonesterified
    • Abstract:
      Objective: To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM).
      Research Design and Methods: Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions.
      Results: When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dL) and insulin (-52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study.
      Conclusions: The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover.
      (© 2023 by the American Diabetes Association.)
    • Grant Information:
      R01 DK097554 United States DK NIDDK NIH HHS
    • Accession Number:
      IY9XDZ35W2 (Glucose)
      HDC1R2M35U (empagliflozin)
      9007-92-5 (Glucagon)
      0 (Insulin)
      0 (Ketones)
      X4W3ENH1CV (Norepinephrine)
      0 (Blood Glucose)
      0 (Fatty Acids, Nonesterified)
    • Publication Date:
      Date Created: 20230301 Date Completed: 20230517 Latest Revision: 20240502
    • Publication Date:
      20240502
    • Accession Number:
      PMC10154659
    • Accession Number:
      10.2337/dc22-0885
    • Accession Number:
      36857415