Why Some Obese May Not Develop Diabetes

A lone genetic mutation appears to simultaneously enhance insulin sensitivity while increasing the risk of obesity….

According to Anna Golyn, DPhil, of the University of Oxford, in England, and colleagues, in a small matched cohort study, patients with a mutation in the phosphate and tensin homologue (PTEN) gene had significantly lower levels of insulin resistance than controls (P=0.001).

At the same time, PTEN mutation carriers were more obese than their healthy counterparts (P<0.001), the researchers reported.

This "profound insulin sensitization … paradoxically occurs in association with adiposity," they wrote. Typically insulin resistance, which is considered a precursor of type 2 diabetes, is a hallmark of obesity. Moreover, mutation carriers had higher levels of adiponectin than controls — a finding that is expected in patients with increased insulin sensitivity, but is unexpected in obese patients, they said.

Recent work has suggested that cancer and type 2 diabetes may result from defects in the same pathway. Some have suspected that insulin and insulin-like growth factor 1 (IGF-1) — both of which are growth factors — were the main drivers of this association.

But newer evidence points to other causes, particularly enzymes and signaling pathways common to both the cell life cycle and metabolism, the researchers said. One example could be the tumor suppressor PTEN gene, which plays a role in both of those functions. Germline PTEN mutations cause Cowden syndrome, which puts patients at high risk for a number of cancers while at the same time lowering their risk of type 2 diabetes.

Golyn and colleagues assessed insulin sensitivity in 15 carriers of the mutation and 15 matched controls from the Oxford BioBank in the U.K.

They found that measures of insulin resistance were significantly lower in patients with a PTEN mutation than in controls:

• Mean fasting plasma insulin: 60% lower (P=0.001)
• AUC for insulin: 67% lower (P<0.001)
• HOMA-IR: 59% lower (P=0.001)

The findings were confirmed with hyperinsulinemic euglycemic clamping, which showed a glucose infusion rate among carriers that was twice as high as normal controls (P=0.009), they found.

This insulin sensitivity could be explained by enhanced insulin signaling through the PI3K-AKT pathway, as seen by increased AKT phosphorylation, they reported. Yet the mutation carriers were far more obese than controls, with a significantly higher mean body mass index (BMI) (32 versus 26, P<0.001).

Practice Pearls:

• Note that mutation carriers had higher levels of adiponectin than controls — a finding that is expected in patients with increased insulin sensitivity but is unexpected in obese patients.
• A lone genetic mutation in the phosphatase and tensin homologue (PTEN) gene appears to simultaneously enhance insulin sensitivity while increasing the risk of obesity.

Pal A, et al "PTEN mutations as a cause of constitutive insulin sensitivity and obesity" N Engl J Med 2012; 367(11): 1002-1011.