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Mekanismer for hypoglykæmi associeret autonom svigt

27. april 2026 opdateret af: Meredith Hawkins, Albert Einstein College of Medicine
Intensiv glukosekontrol ved type 1 diabetes mellitus (T1DM) er forbundet med klare sundhedsmæssige fordele (1). På trods af udvikling af insulinanaloger, pumpe-/multiposis-behandling og kontinuerlig glukosemonitorering er opretholdelse af næsten normal glykæmi dog stadig et uhåndgribeligt mål for de fleste patienter, for en stor del på grund af risikoen for hypoglykæmi. T1DM-patienter er modtagelige for hypoglykæmi på grund af defekte modregulatoriske responser (CR) karakteriseret ved: 1) mangelfuld glucagonfrigivelse under forestående/tidlig hypoglykæmi; 2) yderligere hypoglykæmi-associeret autonomt svigt (HAAF) og træningsassocieret autonomt svigt (EAAF), der sløver de sympathoadrenale reaktioner på hypoglykæmi efter gentagne episoder af hypoglykæmi eller træning samt nedbrydning af anden CR; og 3) hypoglykæmi ubevidsthed (HU), sænker tærsklen for symptomer, der udløser adfærdsmæssige reaktioner (f.eks. spise). Risikoen for hypoglykæmi ved T1DM hæmmer således ideel insulinbehandling og fører til misligholdelse af suboptimal glykæmisk kontrol (2). Der er to tilgange, der kunne løse dette vigtige kliniske problem: 1) perfektion af glucose-sensing og insulin- og glucagonleveringstilgange (biomanipuleret eller cellebaseret), der efterligner normal ø-funktion og præcist regulerer glukose kontinuerligt, eller 2) et lægemiddel til at forbedre eller normalisere mønsteret af CR til hypoglykæmi. På trods af megen forskning og vigtige fremskridt på området er hverken ø-transplantation eller biosensoranordninger dukket op som levedygtige langsigtede løsninger for størstedelen af ​​patienterne (3, 4). I løbet af de sidste mange år har vores laboratorium udforsket tilgangen til at forbedre CR ved at undersøge mekanismer, der er ansvarlige for HAAF/EAAF og søge efter potentielle farmakologiske metoder til at modulere CR til hypoglykæmi (5-11). Vores arbejde har ført til et paradigmeskifte inden for hypoglykæmi, eksemplificeret ved den nye hypotese og offentliggjorte eksperimentelle data, der understøtter en rolle for opioidsignalering, som resulterede i initieringen af ​​eksplorative kliniske forsøg fra andre forskningsgrupper.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

I den forudgående projektperiode af R01 DK079974 belyste vi den centrale rolle, som opioidsignalsystemet spiller som en mekanisme for udviklingen af ​​HAAF/EAAF. Vi har tidligere vist, at opioidreceptorblokade ved akut infusion af naloxon under forudgående hypoglykæmi kan forhindre eksperimentelt induceret HAAF hos ikke-diabetiske og T1DM-personer (JCEM 94:3372-80, 2009; JCEM 96:3424-31, 2011). Vi har også vist, at opioidreceptorblokade også ophæver EAAF, og at begge effekter reguleres af stressresponsen (henholdsvis hypoglykæmi og træning). Desuden har vi for nylig vist, at aktivering af μ-opioidreceptorer med IV-infusion af morfin reproducerer nogle af de biokemiske og kliniske nøgletræk ved HAAF hos ikke-diabetiske mennesker. Sammenlagt viser disse undersøgelser, at opioidsystemet spiller en central rolle i modregulering af hypoglykæmi og i HAAF.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

39

Fase

  • Fase 2

Kontakter og lokationer

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

Studiesteder

  • Forenede Stater
    • New York
      • The Bronx, New York, Forenede Stater, 10461
        • Albert Einstein College of Medicine / General Clinical Research 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

21 år til 60 år (Voksen)

Tager imod sunde frivillige

Ja

Beskrivelse

Inklusionskriterier:

  • Ikke-diabetikere

Ekskluderingskriterier:

  • Forhøjet blodtryk
  • Hyperlipidæmi
  • Hjerte sygdom
  • Cerebrovaskulær sygdom
  • Anfald
  • Blødningsforstyrrelser

Studieplan

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

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Grundvidenskab
  • Tildeling: Randomiseret
  • Interventionel model: Crossover opgave
  • Maskning: Dobbelt

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Healthy
Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Medicin: naloxon
Indgivelse af naloxon på dag 1 og kvantificering af de modregulatoriske reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Narcan
Kosttilskud: fruktose
Indgivelse af fruktose på dag 1 og kvantificering af de modregulerende reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Insulin
Adfærdsmæssigt: dyrke motion
Administrering af træning på dag 1 og kvantificering af de modregulerende reaktioner på hypoglykæmi på dag 2.
Medicin: Morfinsulfat
Indgivelse af morfin på dag 1 og kvantificering af de modregulatoriske reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Morfin
Medicin: Adrenalin
Administration af epinephrin på dag 1 og kvantificering af de modregulerende reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Adrenalin
Eksperimentel: Type 1 Diabetes
T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Medicin: naloxon
Indgivelse af naloxon på dag 1 og kvantificering af de modregulatoriske reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Narcan
Kosttilskud: fruktose
Indgivelse af fruktose på dag 1 og kvantificering af de modregulerende reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Insulin
Adfærdsmæssigt: dyrke motion
Administrering af træning på dag 1 og kvantificering af de modregulerende reaktioner på hypoglykæmi på dag 2.
Medicin: Morfinsulfat
Indgivelse af morfin på dag 1 og kvantificering af de modregulatoriske reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Morfin
Medicin: Adrenalin
Administration af epinephrin på dag 1 og kvantificering af de modregulerende reaktioner på hypoglykæmi på dag 2.
Andre navne:
  • Adrenalin

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study
Tidsramme: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
EGP response after antecedent morphine administration was assessed in the Morphine Sulfate vs Matched Placebo study. EGP response is a measure of how the body produces glucose from substrates to maintain blood sugar levels, particularly during fasting. Morphine was administered on Day 1 followed by a stepped hypoglycemia clamp (i.e., euglycemia → 90 mg/dl → 80 mg/dl → 70 mg/dl → 60 mg/dl) on Day 2. EGP response rate is reported in milligrams/kilograms/minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported.
Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
Endogenous Glucose Production (EGP) Via Glucose Infusion Rate - Naloxone Study
Tidsramme: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~5 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.
For the Naloxone vs Matched Placebo study, EGP, a measure of the body's production of sugar, was assessed by determining the Glucose Infusion Rate (GIR) an indirect measure of endogenous glucose production, during the first and third hypoglycemic clamp episodes. GIR is reported in cubic centimeters/minute (cc/min) and results are summarized and reported by study arm using basic descriptive statistics.
Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~5 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.
Endogenous Glucose Production (EGP) Response Rate - Epinephrine Study
Tidsramme: Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~19 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
EGP response after antecedent epinephrine administration was assessed in the Epinephrine vs Matched Epinephrine study. EGP response, a measure of how the body produces glucose from substrates to maintain blood sugar levels, was assessed during the final hypoglycemic clamp episode. EGP at the major nadir at the 60 mg/dL, during the last 10 minutes of the 3rd clamp episode, is reported in milligrams per kilogram per minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported
Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~19 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
Counterregulatory Response to Hypoglycemia - Morphine Sulfate Study
Tidsramme: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~7 months apart.
Counterregulatory response to hypoglycemia was assessed for the Morphine Sulfate study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Morphine Sulfate arm and Matched Placebo arm.
Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~7 months apart.
Counterregulatory Response to Hypoglycemia - Naloxone Study
Tidsramme: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~5 months apart.
Counterregulatory response to hypoglycemia was assessed for the Naloxone study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. The second challenge on Day 1 was conducted to assess the impact of the third episode for informational purposes only but was not reported. Group mean results are summarized for the 1st and 3rd episodes in the Naloxone arm and Matched Placebo arm.
Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~5 months apart.
Counterregulatory Response to Hypoglycemia - Epinephrine Study
Tidsramme: Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~19 months apart.
Counterregulatory response to hypoglycemia was assessed for the Epinephrine study by quantifying peak plasma epinephrine level responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 60 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Epinephrine arm and Matched Placebo arm.
Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~19 months apart.
Hypoglycemic Symptom Scores - Morphine Sulfate Study
Tidsramme: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all" to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores - Naloxone Study
Tidsramme: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores - Epinephrine Study
Tidsramme: Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 7-point Likert scale ranging from 1 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.
Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Symptomscore
Tidsramme: Målt hvert 15. minut på tidspunkterne 0, 15, 30, 45...120 gennem studieafslutning
Symptomer på hypoglykæmi vil blive taget under undersøgelsen
Målt hvert 15. minut på tidspunkterne 0, 15, 30, 45...120 gennem studieafslutning

Samarbejdspartnere og efterforskere

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

Sponsor

Albert Einstein College of Medicine

Samarbejdspartnere

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health (NIH)

Efterforskere

  • Ledende efterforsker: Meredith Hawkins, M.D., M.S., Albert Einstein College of Medicine

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

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)

1. marts 2008

Primær færdiggørelse (Faktiske)

1. august 2018

Studieafslutning (Faktiske)

1. august 2018

Datoer for studieregistrering

Først indsendt

14. maj 2008

Først indsendt, der opfyldte QC-kriterier

14. maj 2008

Først opslået (Anslået)

15. maj 2008

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

19. maj 2026

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

27. april 2026

Sidst verificeret

1. april 2026

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 2012-665
  • R01DK079974 (U.S. NIH-bevilling/kontrakt)

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

INGEN

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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