GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop

Ferdinando Giacco, Xue-Liang Du, Anna Carratu, Gary J. Gerfen, Maria D'Apolito, Ida Giardino, Andrea Rasola, Oriano Marin, Ajit S. Divakaruni, Anne N. Murphy, Manasi S. Shah, Michael Brownlee

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA1c, prevents microvascular complications. However, 89% of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9-36)amide reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA1c value are a major determinant of the 89% of diabetes complications risk not captured by HbA1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA1c and novel therapeutic agents, including GLP-1(9-36)amide, for the prevention and treatment of diabetes complications.

Original languageEnglish (US)
Pages (from-to)3273-3284
Number of pages12
JournalDiabetes
Volume64
Issue number9
DOIs
StatePublished - Sep 1 2015

Fingerprint

Glucagon-Like Peptide 1
Hyperglycemia
Reactive Oxygen Species
Diabetes Complications
Glucose
Albuminuria
Biomarkers
glucagon-like peptide-1 (9-36)-amide
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop. / Giacco, Ferdinando; Du, Xue-Liang; Carratu, Anna; Gerfen, Gary J.; D'Apolito, Maria; Giardino, Ida; Rasola, Andrea; Marin, Oriano; Divakaruni, Ajit S.; Murphy, Anne N.; Shah, Manasi S.; Brownlee, Michael.

In: Diabetes, Vol. 64, No. 9, 01.09.2015, p. 3273-3284.

Research output: Contribution to journalArticle

Giacco, F, Du, X-L, Carratu, A, Gerfen, GJ, D'Apolito, M, Giardino, I, Rasola, A, Marin, O, Divakaruni, AS, Murphy, AN, Shah, MS & Brownlee, M 2015, 'GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop', Diabetes, vol. 64, no. 9, pp. 3273-3284. https://doi.org/10.2337/db15-0084
Giacco, Ferdinando ; Du, Xue-Liang ; Carratu, Anna ; Gerfen, Gary J. ; D'Apolito, Maria ; Giardino, Ida ; Rasola, Andrea ; Marin, Oriano ; Divakaruni, Ajit S. ; Murphy, Anne N. ; Shah, Manasi S. ; Brownlee, Michael. / GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop. In: Diabetes. 2015 ; Vol. 64, No. 9. pp. 3273-3284.
@article{19e97389bc2640a1ac605653c534ebb4,
title = "GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop",
abstract = "The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA1c, prevents microvascular complications. However, 89{\%} of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9-36)amide reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA1c value are a major determinant of the 89{\%} of diabetes complications risk not captured by HbA1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA1c and novel therapeutic agents, including GLP-1(9-36)amide, for the prevention and treatment of diabetes complications.",
author = "Ferdinando Giacco and Xue-Liang Du and Anna Carratu and Gerfen, {Gary J.} and Maria D'Apolito and Ida Giardino and Andrea Rasola and Oriano Marin and Divakaruni, {Ajit S.} and Murphy, {Anne N.} and Shah, {Manasi S.} and Michael Brownlee",
year = "2015",
month = "9",
day = "1",
doi = "10.2337/db15-0084",
language = "English (US)",
volume = "64",
pages = "3273--3284",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "9",

}

TY - JOUR

T1 - GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop

AU - Giacco, Ferdinando

AU - Du, Xue-Liang

AU - Carratu, Anna

AU - Gerfen, Gary J.

AU - D'Apolito, Maria

AU - Giardino, Ida

AU - Rasola, Andrea

AU - Marin, Oriano

AU - Divakaruni, Ajit S.

AU - Murphy, Anne N.

AU - Shah, Manasi S.

AU - Brownlee, Michael

PY - 2015/9/1

Y1 - 2015/9/1

N2 - The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA1c, prevents microvascular complications. However, 89% of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9-36)amide reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA1c value are a major determinant of the 89% of diabetes complications risk not captured by HbA1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA1c and novel therapeutic agents, including GLP-1(9-36)amide, for the prevention and treatment of diabetes complications.

AB - The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA1c, prevents microvascular complications. However, 89% of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9-36)amide reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA1c value are a major determinant of the 89% of diabetes complications risk not captured by HbA1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA1c and novel therapeutic agents, including GLP-1(9-36)amide, for the prevention and treatment of diabetes complications.

UR - http://www.scopus.com/inward/record.url?scp=84960144959&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960144959&partnerID=8YFLogxK

U2 - 10.2337/db15-0084

DO - 10.2337/db15-0084

M3 - Article

C2 - 26294429

AN - SCOPUS:84960144959

VL - 64

SP - 3273

EP - 3284

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -