PTEN mutations as a cause of constitutive insulin sensitivity and obesity.

Pal, A; Barber, T; Van de Bunt, M; Rudge, SA; Zhang, Q; Lachlan, K; Cooper, N; Linden, H; Levy, J; Wakelam, M; Walker, L; Karpe, F; Gloyn, A

Journal article

PTEN mutations as a cause of constitutive insulin sensitivity and obesity.

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.).

Publication status:: Published

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Share
Cite

Cite this record

APA Style

Pal, A., Barber, T., Van de Bunt, M., Rudge, S. A., Zhang, Q., Lachlan, K., Cooper, N., Linden, H., Levy, J., Wakelam, M., Walker, L., Karpe, F., & Gloyn, A. (2012). PTEN mutations as a cause of constitutive insulin sensitivity and obesity. New England Journal of Medicine, 367(11), 1002–1011.

MLA Style

Pal, A, et al. “PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity.” New England Journal of Medicine, vol. 367, no. 11, 2012, pp. 1002–11.

Chicago Style

Pal, A, T Barber, M Van de Bunt, et al. 2012. “PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity.” New England Journal of Medicine 367 (11): 1002–11.
Print