PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity

Pal, Aparna; Barber, Thomas M.; Van de Bunt, Martijn; Rudge, Simon A.; Zhang, Qifeng; Lachlan, Katherine L.; Cooper, Nicola S.; Linden, Helen; Levy, Jonathan C.; Wakelam, Michael J.O.; Walker, Lisa; Karpe, Fredrik; Gloyn, Anna L.
September 2012
New England Journal of Medicine;9/13/2012, Vol. 367 Issue 11, p1002
Academic Journal
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 con- firmed 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.)


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