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Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (AZ11040)

2. december 2019 opdateret af: The University of Texas Health Science Center at San Antonio

Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (P2)

To determine the role of plasma glucagon and insulin in the rise of endogenous glucose production (EGP) following the SGLT2 inhibition.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to glucosuria is (are) important signal(s) responsible, at least in part, for the increase in EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will account for the majority of increase in EGP in both NGT and T2DM subjects. This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of endogenous glucose production (EGP), which is the biosynthesis of new glucose, with administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose production (HGP), which is the net release of glucose from the liver, will be measured for 5 hours after drug administration to allow sufficient time for a significant increase in HGP above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for 5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin. Study 2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose concentration stable at each subject's fasting level). This study will define whether the decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin concentrations constant at the basal level). This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16 subjects will receive placebo. Each study will be performed on a separate day, after a 10-12 hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a renal (kidney) MRI-measurement to record kidney size.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

30

Fase

  • Fase 3

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Forenede Stater
    • Texas
      • San Antonio, Texas, Forenede Stater, 78229
        • University of Texas Health Science Center

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 70 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

Inclusion Criteria:

  • T2DM according to ADA criteria-HbA1C < 8.0%
  • BMI = 25-35 kg/m2
  • Subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis
  • Body weight has been stable (± 3 lbs) over the preceding three months
  • Do not participate in an excessively heavy exercise program
  • Taking stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea

Exclusion Criteria:

  • Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea) will be excluded
  • Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine >1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg will be excluded

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Enkelt

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Aktiv komparator: Dapagliflozin
32 subjects will receive dapagliflozin 10mg
Medicin: Dapagliflozin
Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.
Andre navne:
  • Farxiga
Placebo komparator: Placebo
16 subjects will receive placebo
Medicin: Placebo
Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
Andre navne:
  • Placebo for Dapagliflozin

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Measurement of the Change in Plasma Glucose (mg/dL): Study 1
Tidsramme: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration
Baseline to 240-300 minutes
Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2
Tidsramme: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Baseline to 240-300 minutes
Change in Plasma Glucose Using a Pancreatic Clamp: Study 3
Tidsramme: Baseline to 240-300 minutes
Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Baseline to 240-300 minutes
Change in EGP: Study 1
Tidsramme: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in EGP
Baseline to 240-300 minutes
Change in EGP With Glucose Clamp: Study 2
Tidsramme: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Baseline to 240-300 minutes
Change in EGP With Pancreatic Clamp: Study 3
Tidsramme: Baseline to 240-300 minutes
Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Baseline to 240-300 minutes

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Change in Plasma Insulin Concentrations: Study 1
Tidsramme: Baseline to 240-300 minutes
Plasma insulin concentrations during measurement of EGP
Baseline to 240-300 minutes
Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2
Tidsramme: Baseline to 240-300 minutes
Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Baseline to 240-300 minutes
Change in Plasma Insulin While Using Pancreatic Clamp: Study 3
Tidsramme: Baseline to last hour of the study
Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Baseline to last hour of the study
Change in Glucagon: Study 1
Tidsramme: Baseline to 240-300 minutes
Change in glucagon concentrations during measurement of EGP
Baseline to 240-300 minutes
Change in Glucagon Using Glucose Clamp: Study 2
Tidsramme: Baseline to 240-300 minutes
Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
Baseline to 240-300 minutes
Change in Glucagon Using Pancreatic Clamp: Study 3
Tidsramme: Baseline to 240-300 minutes
Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Baseline to 240-300 minutes

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

The University of Texas Health Science Center at San Antonio

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

6. september 2017

Primær færdiggørelse (Faktiske)

16. november 2018

Studieafslutning (Faktiske)

16. november 2019

Datoer for studieregistrering

Først indsendt

30. november 2016

Først indsendt, der opfyldte QC-kriterier

2. december 2016

Først opslået (Skøn)

7. december 2016

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

18. december 2019

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

2. december 2019

Sidst verificeret

1. november 2019

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • HSC20160586H

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

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Kliniske forsøg med Type II; Diabetes

Kliniske forsøg med Dapagliflozin

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