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

Siham Abdelgani, Ahmed Khattab, John Adams, Mohamed Abu-Farha, Guisepe Daniele, Fahd Al-Mulla, Stefano Del Prato, Ralph A. Defronzo, Muhammad Abdul-Ghani

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 with3H-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 (234 mg/dL) and insulin (252%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and b-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.

Original languageEnglish (US)
Pages (from-to)978-984
Number of pages7
JournalDiabetes care
Volume46
Issue number5
DOIs
StatePublished - May 2023

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

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