Impaired regulation of the TNF-alpha 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-alpha levels are increased in obesity and type 2 diabetes. The regulation of TNF-alpha 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-alpha, TNF-alpha-receptor 1 (TNFR1), TNF-alpha-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-alpha, 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-alpha 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.

• Authors: 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
• Journal: Diabetologia (Diabetologia) Vol. 52 Issue 10 Pg. 2169-81 (Oct 2009) ISSN: 1432-0428 [Electronic] Germany
• PMID: 19633828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Interleukin-6
• Tissue Inhibitor of Metalloproteinase-3
• ADAM Proteins
• ADAM17 Protein
• ADAM17 protein, human

Topics

• ADAM Proteins (genetics, metabolism)
• ADAM17 Protein
• Adult
• Blotting, Western
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Gene Expression Regulation
• Humans
• Insulin Resistance (genetics, physiology)
• Male
• Muscle, Skeletal (metabolism)
• Receptors, Interleukin-6 (genetics, metabolism)
• Tissue Inhibitor of Metalloproteinase-3 (genetics, metabolism)