Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: A new mechanism of insulin resistance in humans

A. Monroy, S. Kamath, A. O. Chavez, V. E. Centonze, M. Veerasamy, A. Barrentine, J. J. Wewer, D. K. Coletta, C. Jenkinson, R. M. Jhingan, D. Smokler, S. Reyna, N. Musi, R. Khokka, M. Federici, D. Tripathy, R. A. Defronzo, F. Folli

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Aims/hypothesis: TNF-α levels are increased in obesity and type 2 diabetes. The regulation of TNF-α converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. Methods: We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-α, TNF-α-receptor 1 (TNFR1), TNF-α-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. Results: TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-α, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. Conclusions/interpretation: TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-α and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.

Original languageEnglish (US)
Pages (from-to)2169-2181
Number of pages13
JournalDiabetologia
Volume52
Issue number10
DOIs
StatePublished - Oct 2009
Externally publishedYes

Fingerprint

Tissue Inhibitor of Metalloproteinase-3
Enzyme Inhibitors
Type 2 Diabetes Mellitus
Insulin Resistance
Skeletal Muscle
Interleukin-6 Receptors
Tumor Necrosis Factor Receptors
Glucose
Palmitates
Skeletal Muscle Fibers
Lipids
Glucose Clamp Technique
Vascular Cell Adhesion Molecule-1
Cell Adhesion Molecules
Confocal Microscopy
Proteolysis
Obesity
Western Blotting
Insulin
Gene Expression

Keywords

  • Human type 2 diabetes mellitus
  • Insulin resistance
  • TACE
  • TIMP3

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients : A new mechanism of insulin resistance in humans. / Monroy, A.; Kamath, S.; Chavez, A. O.; Centonze, V. E.; Veerasamy, M.; Barrentine, A.; Wewer, J. J.; Coletta, D. K.; Jenkinson, C.; Jhingan, R. M.; Smokler, D.; Reyna, S.; Musi, N.; Khokka, R.; Federici, M.; Tripathy, D.; Defronzo, R. A.; Folli, F.

In: Diabetologia, Vol. 52, No. 10, 10.2009, p. 2169-2181.

Research output: Contribution to journalArticle

Monroy, A, Kamath, S, Chavez, AO, Centonze, VE, Veerasamy, M, Barrentine, A, Wewer, JJ, Coletta, DK, Jenkinson, C, Jhingan, RM, Smokler, D, Reyna, S, Musi, N, Khokka, R, Federici, M, Tripathy, D, Defronzo, RA & Folli, F 2009, 'Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: A new mechanism of insulin resistance in humans', Diabetologia, vol. 52, no. 10, pp. 2169-2181. https://doi.org/10.1007/s00125-009-1451-3
Monroy, A. ; Kamath, S. ; Chavez, A. O. ; Centonze, V. E. ; Veerasamy, M. ; Barrentine, A. ; Wewer, J. J. ; Coletta, D. K. ; Jenkinson, C. ; Jhingan, R. M. ; Smokler, D. ; Reyna, S. ; Musi, N. ; Khokka, R. ; Federici, M. ; Tripathy, D. ; Defronzo, R. A. ; Folli, F. / Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients : A new mechanism of insulin resistance in humans. In: Diabetologia. 2009 ; Vol. 52, No. 10. pp. 2169-2181.
@article{f6607c1963944a938d830ca37eb668cb,
title = "Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: A new mechanism of insulin resistance in humans",
abstract = "Aims/hypothesis: TNF-α levels are increased in obesity and type 2 diabetes. The regulation of TNF-α converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. Methods: We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-α, TNF-α-receptor 1 (TNFR1), TNF-α-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. Results: TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-α, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25{\%} with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. Conclusions/interpretation: TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-α and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.",
keywords = "Human type 2 diabetes mellitus, Insulin resistance, TACE, TIMP3",
author = "A. Monroy and S. Kamath and Chavez, {A. O.} and Centonze, {V. E.} and M. Veerasamy and A. Barrentine and Wewer, {J. J.} and Coletta, {D. K.} and C. Jenkinson and Jhingan, {R. M.} and D. Smokler and S. Reyna and N. Musi and R. Khokka and M. Federici and D. Tripathy and Defronzo, {R. A.} and F. Folli",
year = "2009",
month = "10",
doi = "10.1007/s00125-009-1451-3",
language = "English (US)",
volume = "52",
pages = "2169--2181",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "10",

}

TY - JOUR

T1 - Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients

T2 - A new mechanism of insulin resistance in humans

AU - Monroy, A.

AU - Kamath, S.

AU - Chavez, A. O.

AU - Centonze, V. E.

AU - Veerasamy, M.

AU - Barrentine, A.

AU - Wewer, J. J.

AU - Coletta, D. K.

AU - Jenkinson, C.

AU - Jhingan, R. M.

AU - Smokler, D.

AU - Reyna, S.

AU - Musi, N.

AU - Khokka, R.

AU - Federici, M.

AU - Tripathy, D.

AU - Defronzo, R. A.

AU - Folli, F.

PY - 2009/10

Y1 - 2009/10

N2 - Aims/hypothesis: TNF-α levels are increased in obesity and type 2 diabetes. The regulation of TNF-α converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. Methods: We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-α, TNF-α-receptor 1 (TNFR1), TNF-α-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. Results: TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-α, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. Conclusions/interpretation: TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-α and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.

AB - Aims/hypothesis: TNF-α levels are increased in obesity and type 2 diabetes. The regulation of TNF-α converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. Methods: We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-α, TNF-α-receptor 1 (TNFR1), TNF-α-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. Results: TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-α, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. Conclusions/interpretation: TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-α and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.

KW - Human type 2 diabetes mellitus

KW - Insulin resistance

KW - TACE

KW - TIMP3

UR - http://www.scopus.com/inward/record.url?scp=69949130225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69949130225&partnerID=8YFLogxK

U2 - 10.1007/s00125-009-1451-3

DO - 10.1007/s00125-009-1451-3

M3 - Article

C2 - 19633828

AN - SCOPUS:69949130225

VL - 52

SP - 2169

EP - 2181

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 10

ER -