The role of hsp70 on enpp1 expression and insulin-receptor activation

The goal of this review is to discuss the potential role of ENPP1 as a determinant of systemic insulin resistance and risk for its complications in humans.

The majority of animal studies to date have been consistent on the effects of ENPP1 impairing insulin stimulation of insulin receptor IR activation and downstream signaling. Early studies by Goldfine et al. However, Adipose ENPP1 -Tg mice developed fatty liver in association with changes in adipose tissue, characterized by smaller adipocyte size, decreased phosphorylation of insulin receptor Tyr and Akt Ser These changes in adipose tissue function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose and insulin during Intra-Peritoneal Glucose Tolerance Test IPGTT and impaired glucose suppression during Insulin Tolerance Test ITT.

Thus, over-expression of ENPP1 in an adipose tissue AT -selective transgenic model can play a role in adipose tissue dysfunction, with systemic consequences on glucose and lipid metabolism typically found in the metabolic syndrome: induced adipocyte insulin resistance, elevated plasma free fatty acid levels, ectopic fat distribution fatty liver and systemic insulin resistance.

A study by Zhou et al. Taken together, these results demonstrate that suppression of ENPP1 expression improves insulin sensitivity, supporting the hypothesis that ENPP1 inhibition is a potential therapeutic target for the treatment of type 2 diabetes.

Despite the existing evidence from animal studies, the effect of ENPP1 on complications of insulin resistance in humans remains controversial. Many previous studies showed positive association between the Q genetic variant and risk for type 2 diabetes and cardiovascular disease [ 4 — 12 ], whereas other studies have been negative [ 16 ].

The largest meta-analysis in type 2 diabetes to date [ 10 ] conducted on European populations showed a modest increase in risk for type 2 diabetes of the ENPP1 Q allele.

These interactions could explain some of the apparent discrepancies among genetic association studies conducted in various populations. To better define the effect of ENPP1 in humans, we [ 18 ] recently conducted a study on the relationship of ENPP1 expression level and insulin resistance in young normoglycemic volunteers.

Body composition studies, hyperinsulinemic-euglycemic clamps and adipose tissue biopsy were obtained to test the overall hypothesis that ENPP1 over-expression contributes to AT dysfunction and systemic insulin resistance. When compared to those who had low expression, the men but not the women with high ENPP1 expression had larger reductions in Rd-values during hyperinsulinemic clamps with increasing body fat content. Plasma fatty acid was higher in the high-ENPP1. These data support the notion that ENPP1 should be considered both a marker and a novel potential target of therapy, to improve AT function and systemic glucose metabolism.

Recent study by Goldfine et al. Interestingly, this association was significant in the men but not women. Furthermore, the most widely studied variant, the KQ was not found to associate with hypertriglyceridemia in any group or subgroup analysis.

It is important to note that the hypertriglyceridemic subjects recruited in this study had BMI values in the overweight range, whereas the normolipidemic controls had lower BMI Both study groups were recruited from lipid clinic, which could have enriched the study population with metabolically abnormal subjects.

A prospective study of average duration of 37 months was conducted by Trischitta et al. Results showed incidence of cardiovascular events per person—years was 4. In the diabetic patients, the Q variant predicted cardiovascular events among obese, but not among non-obese individuals HR 5.

An additional important result of this study is that the effect of the Q variant was modulated by obesity in diabetic patients, among whom the risk of incident events was five times higher in Q than in KK genotype carriers. Genomics Proteomics Bioinformatics — J Mol Med — J Clin Endocrinol Metab — Diabetes Care — Clin Chim Acta — Science — Download references. M C R. Watip Boonyasrisawat, Jose C. You can also search for this author in PubMed Google Scholar.

Reprints and Permissions. Marucci, A. J Mol Med 87, — Download citation. Received : 29 April Biochim Biophys Acta , 3 , 22 Oct Cited by: 2 articles PMID: Eur J Pharmacol , , 22 Jan Cited by: 16 articles PMID: Cited by: 24 articles PMID: Endocr Rev , 29 1 , 16 Jan Review Free to read. Contact us. Europe PMC requires Javascript to function effectively. Recent Activity. Search life-sciences literature Over 39 million articles, preprints and more Search Advanced search. Marucci A 1 ,.

Search articles by 'Giuseppe Miscio'. Miscio G 1 ,. Search articles by 'Libera Padovano'. Padovano L 1 ,. Search articles by 'Watip Boonyasrisawat'. Boonyasrisawat W 2 ,. Search articles by 'Jose C Florez'. Florez JC 3 ,. Doria A 2 ,. Trischitta V 1 ,. Search articles by 'Rosa Di Paola'. Paola RD 1. Affiliations 5 authors 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Ectonucleotide pyrophosphatase phosphodiesterase 1 ENPP1 inhibits insulin-receptor IR signaling and, when over-expressed, induces insulin resistance in vitro and in vivo.

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Associated Data Supplementary Materials 1. Introduction Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease [ 1 ]. Open in a separate window. Supplementary Material 1 Click here to view. Footnotes Electronic supplementary material The online version of this article doi References 1.

Reaven GM. Banting lecture Role of insulin resistance in human disease. Endocr Rev. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Increased adipose tissue PC-1 protein content, but not tumour necrosis factor-alpha gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine—kinase activity.

Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Am J Physiol Endocrinol Metab.