PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity

Study Questions:

What is the effect of tumor-suppressor phosphatase and tensin homologue (PTEN) haploinsufficiency on insulin action in humans?


The investigators 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 five mutation carriers and five well-matched controls. They also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2,097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission X-ray absorptiometry and skinfold thickness.


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/L [range, 9-99] vs. 74 pmol/L [range, 22-185]; 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, 23-42] vs. 26 [range, 15-48]; p < 0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.


The authors concluded that PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic.


The study reports a monogenic cause of profound insulin sensitization that paradoxically occurs in association with adiposity. PTEN aploinsufficiency appears to result in an increased risk of obesity and cancer, but a decreased risk of type 2 diabetes, owing to enhanced insulin sensitivity. This is an example of how intimately pathways in metabolism and cell growth may be linked, and lends support to the hypothesis that the epidemiologic and genetic associations between cancer and type 2 diabetes may be based on some common signaling pathways linking tumor-suppressor genes to metabolic pathways that mediate insulin action. Additional research is indicated to assess whether genetic modification of PTEN expression may ameliorate diabetes.

Clinical Topics: Prevention, Diet

Keywords: Neoplasms, PTEN Phosphohydrolase, Microfilament Proteins, Body Weight, Diabetes Mellitus, Type 2, Genes, Suppressor, Phosphatidylinositol 3-Kinases, Insulin Resistance, Glucose, Mutation, Insulin-Secreting Cells, Body Mass Index, Cardiology, Cardiovascular Diseases, Obesity, Haploinsufficiency, Phosphoric Monoester Hydrolases, Fasting

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