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Herring et al Diabetes Care May 2020.pdf (463.74 kB)

Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes.

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posted on 2020-07-27, 14:10 authored by Roselle A Herring, Fariba Shojaee-Moradie, Robert Garesse, Mary Stevenage, Nicola Jackson, Barbara A Fielding, Agampodi Mendis, Sigurd Johnsen, A Margot Umpleby, Melanie Davies, David L Russell-Jones
OBJECTIVE:To determine the effect of sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes.
RESEARCH DESIGN AND METHODS:A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose Ra, Rd, and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate <15 mmol/L, venous pH <7.35, or capillary ketones >5.0 mmol/L.
RESULTS:At baseline, glucose Ra was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose Rd area under the curve (AUC)0-180 min and β-hydroxybutyrate (BOHB) AUC0-180 min were significantly higher. There was a small but significantly higher glycerol Ra (measure of lipolysis) AUC0-180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and <27 kg/m2, basal glucose Ra, BOHB, and glycerol Ra AUC0-180 min were significantly higher in the low-BMI group with dapagliflozin treatment versus the low-BMI group with placebo. CONCLUSIONS:During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role.

History

Citation

Diabetes Care 2020 Jul; dc192579, https://doi.org/10.2337/dc19-2579

Author affiliation

Diabetes Research Centre, College of Life Sciences

Version

  • AM (Accepted Manuscript)

Published in

Diabetes care

Volume

73

Issue

8

Pagination

dc192579

Publisher

American Diabetes Association

issn

0149-5992

eissn

1935-5548

Acceptance date

2020-05-30

Copyright date

2020

Available date

2020-07-08

Spatial coverage

United States

Language

eng

Publisher version

https://care.diabetesjournals.org/content/early/2020/07/03/dc19-2579

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