Pal, Aparna, Barber, T. M., Van de Bunt, Martijn, Rudge, Simon A., Zhang, Qiang, Lachlan, Katherine L., Cooper, Nicola S., Linden, Helen, Levy, Jonathan C., Wakelam, Michael J. O., Walker, Lisa, Karpe, Fredrik and Gloyn, Anna L. (2012) PTEN mutations predisposing to monogenic cancer syndrome cause constitutive insulin sensitivity and obesity in humans. The New England Journal of Medicine, Volume 367 (Number 11). pp. 1002-1011. ISSN 0028-4793.

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Abstract

BACKGROUND:
Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.
METHODS:
We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.
RESULTS:
Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients' insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.
CONCLUSIONS:
PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.).

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Non-insulin-dependent diabetes -- Treatment, Obesity , Cancer
Journal or Publication Title:	The New England Journal of Medicine
Publisher:	Massachusetts Medical Society
ISSN:	0028-4793
Official Date:	13 September 2012
Dates:	Date Event 13 September 2012 Published
Volume:	Volume 367
Number:	Number 11
Page Range:	pp. 1002-1011
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Wellcome Trust (London, England), Medical Research Council (Great Britain) (MRC), National Institute for Health Research (Great Britain) (NIHR), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Seventh Framework Programme (European Commission) (FP7)
Grant number:	095101/Z/10Z (Wellcome Trust), G0700222 G0800467 (MRC), 202272 (FP7)

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