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Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects
Linköping University, Department of Medicine and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
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2009 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 15, no 7-8, 228-234 p.Article in journal (Refereed) Published
Abstract [en]

Insulin resistance and type 2 diabetes (T2D) are closely linked to obesity. Numerous prospective studies have reported on weight gain, insulin resistance, and insulin signaling in experimental animals, but not in humans. We examined insulin signaling in adipocytes from lean volunteers, before and at the end of a 4-wk period of consuming a fast-food, high-calorie diet that led to weight gain. We also examined adipocytes from patients with T2D. During the high-calorie diet, subjects gained 10% body weight and 19% total body fat, but stayed lean (body mass index = 24.3 kg/m2) and developed moderate systemic insulin resistance. Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. Unlike the T2D subjects, in subjects on the high-calorie diet, likely owing to the ongoing weight-gain, phosphorylation of MAP-kinases ERK1/2 became hyperresponsive to insulin. To our knowledge this study is the first to investigate insulin signaling during overeating in humans, and it demonstrates that T2D effects on intracellular insulin signaling already occur after 4 wks of a high-calorie diet and that the effects in humans differ from those in laboratory animals.

Place, publisher, year, edition, pages
2009. Vol. 15, no 7-8, 228-234 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-20893DOI: 10.2119/molmed.2009.00037ISI: 000276043800004OAI: oai:DiVA.org:liu-20893DiVA: diva2:236727
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13
In thesis
1. Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states
Open this publication in new window or tab >>Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Increasing numbers of people world-wide develops the disease type 2 diabetes. Development of type 2 diabetes is characterized by a shift from an insulin sensitive state to an insulin resistant state in peripheral insulin responding organs, which originates from the development of insulin resistance in the adipose tissue. Insulin resistance in combination with reduced pancreatic insulin secretion lead to overt type 2 diabetes.

In this thesis, the insulin signaling network in primary adipocytes was analyzed. Key proteins and mechanisms were studied to gain deeper knowledge of signaling both in the insulin sensitive state and in the insulin resistant state produced by rapid weight gain as well as in type 2 diabetes.

The surface of the adipocyte is dotted with invaginations in the cell membrane called caveolae that act as important metabolic and signaling platforms in adipocytes, and also harbor the insulin receptor. In paper I we show that insulin stimulation of primary adipocytes results in a rapid phosphorylation of the insulin receptor and caveolin-1, and that internalization of the proteins is mediated by endocytosis of caveolae.

Weight gain due to overfeeding and obesity has been associated with the development of insulin resistance in insulin sensitive tissues such as the adipose tissue. In paper II we show that short-term overfeeding for one month of lean subjects results in an insulin resistant state. At the end of the study, the subjects had developed a mild systemic insulin resistance. Moreover, in isolated subcutaneous adipocytes we found several alterations of the insulin signaling pathway that mimicked alterations found in isolated subcutaneous adipocytes from subjects with type 2 diabetes.

In paper III we present a first dynamic mathematical model of the insulin signaling network in human adipocytes that are based on experimental data acquired in a consistent fashion. The model takes account of insulin signaling in both the healthy, insulin sensitive state and in the insulin resistant state of type 2 diabetes. We show that attenuated mTORC1-mediated positive feedback to control of phosphorylation of IRS1 at Ser307 is an essential component of the insulin resistant state of type 2 diabetes. A future application of the model is the identification and evaluation of drug targets for the treatment of insulin resistance and type 2 diabetes.

In paper IV we examine the protein kinase that catalyzes the insulin stimulated mTORC1- mediated feedback to IRS1. We find that the phosphorylation of IRS1 at Ser307 is not likely to be catalyzed by the kinases S6K1, mTOR or PKB. However, a catalyzing protein kinase for the in vitro phosphorylation of IRS1 at Ser307 was found to be associated with the complex mTORC1.

In conclusion, this thesis provide new insights and characterize mechanisms of the intrinsically complex insulin signaling network of primary adipocytes, both in insulin sensitive and insulin resistant states.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 64 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1369
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-95562 (URN)978-91-7519-577-3 (ISBN)
Public defence
2013-08-30, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Available from: 2013-07-08 Created: 2013-07-08 Last updated: 2013-10-23Bibliographically approved

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Danielsson, AnnaFagerholm, SiriÖst, AnitaFranck, NiclasKjölhede, PrebenNyström, Fredrik HStrålfors, Peter

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Danielsson, AnnaFagerholm, SiriÖst, AnitaFranck, NiclasKjölhede, PrebenNyström, Fredrik HStrålfors, Peter
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Nursing ScienceFaculty of Health SciencesCell BiologyDepartment of Medicine and Health SciencesObstetrics and gynecology Department of Gynecology and Obstetrics in LinköpingCardiology Department of Endocrinology and Gastroenterology UHL
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Molecular medicine (Cambridge, Mass. Print)
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