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

72 Scopus citations

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 1 2009
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    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. (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, 52(10), 2169-2181. https://doi.org/10.1007/s00125-009-1451-3