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Factors in serum from type 2 diabetes patients can cause cellular insulin resistance.
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
2009 (English)In: Hormone and Metabolic Research, ISSN 0018-5043, Vol. 41, no 10, 767-772 p.Article in journal (Refereed) Published
Abstract [en]

This pilot study was aimed to investigate whether there are humoral factors in serum from type 2 diabetic subjects that, in addition to glucose, insulin and free fatty acids are able to induce or contribute to peripheral insulin resistance with respect to glucose transport. Isolated subcutaneous adipocytes from 11 type 2 diabetic subjects and 10 nondiabetic controls were incubated for 24-h in medium supplemented with 25 % serum from a control or a type 2 diabetic donor, in the presence of a low (5 mM) or a high (15 mM) glucose concentration, respectively. After the incubation period glucose uptake capacity was assessed. Serum from type 2 diabetic donors, compared to serum from controls, significantly reduced the maximal insulin eff ect to stimulate glucose uptake (approximately 40 %, p < 0.05) in adipocytes from control subjects, independent of surrounding glucose concentrations. Glucose uptake capacity in adipocytes isolated from type 2 diabetic subjects was similar regardless of culture condition. No significant alterations were found in cellular content of key proteins in the insulin signaling cascade (insulin receptor substrate-1 and -2, and glucose transporter 4) that could explain the impaired insulin-stimulated glucose transport in control adipocytes incubated with serum from type 2 diabetic donors. The present findings indicate the presence of biomolecules in the circulation of type 2 diabetic subjects, apart from glucose, insulin, and free fatty acids with the ability to induce peripheral insulin resistance. This further implies that even though normoglycemia is achieved other circulating factors can still negatively aff ect insulin sensitivity in type 2 diabetic patients.

Place, publisher, year, edition, pages
2009. Vol. 41, no 10, 767-772 p.
Keyword [en]
glucose transport, insulin signaling, human fat cells
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-32396DOI: 10.1055/s-0029-1220751PubMedID: 19764108OAI: diva2:303083
Available from: 2010-03-11 Created: 2010-03-11 Last updated: 2010-06-17Bibliographically approved
In thesis
1. Fat cell insulin resistance: an experimental study focusing on molecular mechanisms in type 2 diabetes
Open this publication in new window or tab >>Fat cell insulin resistance: an experimental study focusing on molecular mechanisms in type 2 diabetes
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of the present thesis was to further increase our understanding of mechanisms contributing to and maintaining cellular insulin resistance in type 2 diabetes (T2D). For this reason, the effects of high glucose and insulin levels on glucose transport capacity and insulin signaling, with emphasis on insulin receptor substrate 1 (IRS-1) were assessed in fat cells. Altered levels of IRS-1 have previously been observed in adipose tissue from insulin-resistant and T2D subjects.

A high glucose level (≥15 mM) for 24 h exerted only a minor impairment on glucose transport capacity in human adipocytes, as opposed to rat adipocytes. However, when combined with a high insulin level (104 µU/ml), basal and insulin-stimulated glucose transport was significantly impaired in both human and rat adipocytes. This was associated with a depletion of IRS-1 and IRS-2 protein levels in rat adipocytes, as a result of post-translational changes and altered gene transcription, respectively. In human adipocytes was only IRS-1 protein levels reduced. The high glucose/high insulin setting achieved maximal impairment of glucose transport within 6 h. Subsequent incubations of rat adipocytes under physiological conditions could partially restore insulin sensitivity. Interestingly, in both human and rat fat cells, decreased levels of IRSs occurred after the establishment of impaired glucose transport, suggesting that the observed depletion of IRSs is a consequence rather than a cause of insulin resistance. Nonetheless, IRS depletion is likely to further aggravate insulin resistance.

Tyrosine phosphorylation of IRS-1 upon insulin stimulation activates the signaling pathway that mediates glucose transport. Pre-treatment of human adipocytes with high glucose and insulin levels was not associated with any alterations in the total IRS-1 Tyr612 phosphorylation following 10 min insulin stimulation. However, a significant increase in basal Tyr612 phosphorylation was observed. Furthermore, a rise in basal IRS-1 Ser312 phosphorylation was found. This is associated with reduced IRS-1 function and is considered to target IRS-1 to degradation pathways, and thus could potentially explain the observed decrease in IRS-1 protein levels. Our results imply an enhanced activation of insulin’s negative-feedback control mechanism that inhibit IRS-1 function. This could potentially have contributed to the observed impairment of insulin action on glucose transport in these cells. Accordingly, we have also shown that the downstream activation of protein kinase B upon insulin-stimulation is significantly impaired in human adipocytes exposed to the high glucose/high insulin setting, indicating a defect in the signaling pathway mediating glucose transport.

We also investigated whether there are humoral factors in the circulation of T2D patients that contribute to peripheral insulin resistance. Human adipocytes cultured for 24 h in medium supplemented with 25% serum from T2D subjects, as compared to serum from non-diabetic subjects, displayed significantly reduced insulin-stimulated glucose uptake capacity. The effect could neither be attributed to glucose, insulin, FFA, TNF-α or IL-6 levels in the serum, but other circulating factor(s) seem to be of importance.

In conclusion, chronic conditions of elevated glucose and/or insulin levels all impair insulin action on glucose turnover, but to different extents. A clear distinction between rat and human fat cells in the response to these different milieus was also observed. Alterations in the function of the key insulin signaling protein IRS-1 might be involved in the mechanisms underlying the impaired glucose uptake capacity. IRS-1 reduction however, occurs after but probably aggravates the existing insulin resistance. The effects of high glucose and/or insulin levels may be of importance in T2D, but additional novel factors present in the circulation of T2D patients seem to contribute to cellular insulin resistance.

Place, publisher, year, edition, pages
Umeå: Folkhälsa och klinisk medicin, 2007. 60 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1088
adipocyte, insulin signaling, insulin, glucose, IRS-1, glucose uptake, insulin resistance, typ 2 diabetes, serum
National Category
Clinical Science
urn:nbn:se:umu:diva-1078 (URN)978-91-7264-268-3 (ISBN)
Public defence
2007-04-27, Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2007-04-05 Created: 2007-04-05 Last updated: 2010-06-17Bibliographically approved

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