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Peptide Predicts Diabetes, CV Disease in Women

High levels of the peptide proneurotensin are associated with an increased risk of diabetes, cardiovascular disease, and death in women, but not necessarily in men….

If this relationship is shown to be causal, proneurotensin and the related peptide neurotensin could become new targets for drug therapy as well as new markers for risk prediction.

The study was conducted by a team led by Dr. Olle Melander (Lund University, Malmo, Sweden). They assessed proneurotensin levels in a population-based study in 4600 healthy individuals at the beginning of the 1990s and followed them for 13 to 15 years.

Results showed a significant relationship between higher levels of proneurotensin and increased incidence of diabetes, cardiovascular disease (MI and stroke), breast cancer, and mortality (almost exclusively cardiovascular mortality). Increased levels of proneurotensin preceded these diseases by several years, indicating that it is "a marker of underlying disease susceptibility rather than being an expression of subclinical disease," the researchers write. However, the association with all the conditions was seen only in women.

Relation of Proneurotensin Level to Risk of Various Events in Women

Event
HR (95% CI)
p
Onset of diabetes
1.41 (1.12–1.77)
0.003
CV disease
1.33 (1.17–1.51)
<0.001
Breast cancer
1.44 (1.21–1.71)
<0.001
Total mortality
1.13 (1.01–1.27)
0.03
CV mortality
1.50 (1.20–1.87)
<0.001

Melander stated that, the focus of their investigations was actually the peptide neurotensin, but because neurotensin is quite unstable, they measured levels of the more stable related peptide, proneurotensin, which they say is produced in the same quantities as neurotensin.

Melander said their interest in neurotensin was driven by the finding that it is the ligand for a receptor known as sortilin-1 (also known as the NT3 receptor) which has been implicated in cardiovascular disease. A common gene variant of sortilin-1 was associated with an increased risk of MI in a study published in 2010. Melander noted that sortilin sorts cholesterol-containing particles in the liver and is also involved in glucose transport. "We think the association of proneurotensin with diabetes and cardiovascular disease may be driven through the NT3/sortilin-1 receptor."

Another receptor for neurotensin — the NT1 receptor — is highly expressed in breast-cancer tumors, and studies in mice have shown that blockade of this receptor slows tumor growth, he added.

Melander stated that, "We don’t really know why neurotensin appears to predict risk only in women, but it probably has something to do with the fact that cells producing neurotensin are stimulated by estrogen."

Melander said the next step is to "investigate whether the relationship between neurotensin and diabetes/cardiovascular disease is causal or if neurotensin is just increased in parallel with something else that is causal." They hope to do this with genetic studies that have already started.

He explained: "Assuming a certain proportion of neurotensin is genetically defined, we can look for genetic markers across the whole genome and hope to identify variants that are associated with increased neurotensin levels. Then we will look to see if these variants are associated with diabetes and cardiovascular disease in large case-control studies."

On the neurotensin results, he says: "We do need our findings to be replicated in other studies. But if it is confirmed to have an effect size as large as we showed, it could make a useful new marker for predicting risk of diabetes and cardiovascular death in women, particularly as it appears to be independent from traditional markers. There would also be opportunities for drugs targeting neurotensin as new treatments for diabetes and cardiovascular disease."

Melander O, Maisel AS, Almgren P, et al. Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality. JAMA 2012; 308:1469-1475.