β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats

Impairment in adipocyteβ-cell relationships

Young H Lee, Hiroshi Hirose, Makoto Ohneda, J. H. Johnson, J. Denis Mcgarry, Roger H Unger

Research output: Contribution to journalArticle

626 Citations (Scopus)

Abstract

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hy perglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 ± 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and β-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 ± 0.07 mM by pair feeding with lean littermates reduced all β-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of β cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

Original languageEnglish (US)
Pages (from-to)10878-10882
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number23
StatePublished - Nov 8 1994

Fingerprint

Nonesterified Fatty Acids
Adipocytes
Type 2 Diabetes Mellitus
Glucose
Insulin
Hyperglycemia
Hyperinsulinism
Insulin Resistance
Facilitative Glucose Transport Proteins
Age of Onset
Vascular Resistance
Triglycerides

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats : Impairment in adipocyteβ-cell relationships. / Lee, Young H; Hirose, Hiroshi; Ohneda, Makoto; Johnson, J. H.; Mcgarry, J. Denis; Unger, Roger H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 23, 08.11.1994, p. 10878-10882.

Research output: Contribution to journalArticle

@article{51c1f8937b8b4119acd4df90f6d66a4d,
title = "β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyteβ-cell relationships",
abstract = "Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hy perglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 ± 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and β-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 ± 0.07 mM by pair feeding with lean littermates reduced all β-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68{\%}; in prediabetic islets, first-phase GSIS was reduced by 69{\%} by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of β cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.",
author = "Lee, {Young H} and Hiroshi Hirose and Makoto Ohneda and Johnson, {J. H.} and Mcgarry, {J. Denis} and Unger, {Roger H}",
year = "1994",
month = "11",
day = "8",
language = "English (US)",
volume = "91",
pages = "10878--10882",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "23",

}

TY - JOUR

T1 - β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats

T2 - Impairment in adipocyteβ-cell relationships

AU - Lee, Young H

AU - Hirose, Hiroshi

AU - Ohneda, Makoto

AU - Johnson, J. H.

AU - Mcgarry, J. Denis

AU - Unger, Roger H

PY - 1994/11/8

Y1 - 1994/11/8

N2 - Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hy perglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 ± 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and β-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 ± 0.07 mM by pair feeding with lean littermates reduced all β-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of β cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

AB - Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hy perglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 ± 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and β-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 ± 0.07 mM by pair feeding with lean littermates reduced all β-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of β cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

UR - http://www.scopus.com/inward/record.url?scp=0027947379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027947379&partnerID=8YFLogxK

M3 - Article

VL - 91

SP - 10878

EP - 10882

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 23

ER -