Aim: To examine the mechanisms responsible for the increase in glucose and ketone production caused by SGLT2 inhibition with empagliflozin in T2DM patients. Research Design and Methods: 12 T2DM subjects (Age = 53; BMI = 31.7; HbA1c = 7.4%) participated in two studies performed in random order. At 0700h following an overnight fast subjects received an 8-hour infusion of 6,6D2-glucose to measure endogenous (hepatic) glucose production. At 0900 h an infusion of 3H-norepinephrine was started. At 1000h subjects ingested 25 mg of empagliflozin (n=8) or matching placebo (n=4) and were followed for 5 hours (1500 h) . Within 1 week subjects returned for a repeat study with pancreatic clamp to maintain plasma insulin and glucagon concentrations constant at the basal level. As per study one, subjects ingested empagliflozin 25 mg or placebo prior to the pancreatic clamp. 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%) , FFA (+29%) and β-hydroxybutyrate (β-HB) (+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 increased significantly in subjects receiving empagliflozin (+67%) compared to placebo under both fasting and pancreatic clamp conditions. No difference in plasma norepinephrine concentration was observed in either study. Conclusion: 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 explained by the increase in total-body NE turnover. Disclosure S. Abdelgani: None. J. M. Adams: None. G. Daniele: n/a. F. Almulla: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca. M. Abdul-ghani: None. M. Abu-farha: None. S. Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. Funding National Institute of Health, Boehringer Ingelheim provided empagliflozin and placebo
Aim: ANGPTL8 plays an important role in regulating lipoprotein lipase activity. Its plasma level is increased following nutrient ingestion. Its not well characterized whether insulin or glucose drive the increased ANGPTL8 after food uptake. To address this, we examined the dynamic relationship between plasma insulin level, ANGPTL8 concentration and glucose following glucose ingestion. Methods: 30 healthy subjects with impaired fasting glucose (IFG) (n=14) and normal glucose tolerance (NGT) (n=16) received 75-glucose OGTT, multistep euglycemic hyperinsulinemic clamp and pancreatic clamp. ANGPTL8 level was measured during the fasting state, OGTT and the clamp studies. Results: Subjects with IFG had significantly higher ANGPTL8 during the fasting state (80±5.6 pmol/L VS 68±4.9 pmol/L respectively, p<0.05) . During the OGTT, plasma ANGPTL8 level increased by 62% above the fasting level (from 81±8 pmol/L to 131±pmol/L, p<0.0001) . During the insulin clamp, insulin infusion caused a dose-dependent increase in ANGPTL8 level (figure 1) . Conversely, during the pancreatic clamp and in the absence of an increase in plasma insulin, the increase in plasma glucose concentration failed to cause a significant increase in plasma ANGPTL8 concentration. Conclusion: The increased ANGPTL8 expression in circulation after glucose ingestion was driven by increased insulin and not glucose. Disclosure M.Abu-farha: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. M.Abdul-ghani: None. J.Abubaker: None. I.Al khairi: None. P.T.Cherian: None. C.Agyin: None. S.Abdelgani: None. E.S.Alozairi: None. J.M.Adams: None. F.Almulla: None. Funding Kuwait Foundation for the Advancement of Sciences
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.