Molecular Link Between Diabetes and Pulmonary Hypertension Explored in Review

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PAH and clinical trials

In recent years, reports emerged linking diabetes to pulmonary hypertension. But news that a disease affecting our blood sugar could increase the risk, or speed the progression, of a devastating lung disease is difficult to imagine. A recent review attempts an explanation.

Titled The Role of Hyperglycemia and Insulin Resistance in the Development and Progression of Pulmonary Arterial Hypertension,” the article, published in the Journal of Diabetes Research, shows the complexity of the workings of the body. A disease state can communicate changes far beyond the organ it affects, using molecular messengers that spread havoc in other parts of the body.

It is difficult to dispute the link between the two conditions. Studies show that between around 26 percent of patients have diabetes when they are diagnosed with lung hypertension, a somewhat higher number than the 19 percent found in the U.S. population older than 45.

Since pulmonary hypertension patients are older age today than they were a few decades ago, some might argue that the link may be explained by the fact that diabetes is also more common in older people, but studies show that diabetes in patients who already have pulmonary hypertension is linked to a shorter survival.

Failure of the heart’s right ventricle to cope with changes in lung blood vessels is known to drive disease, so researchers from Virginia Commonwealth University Health System started there to look for clues.

In pulmonary hypertension, the enlargement of the heart makes it difficult for oxygen to reach the tissue, and along with fibrosis of the heart makes up two factors driving disease progression. Meanwhile, studies in diabetes patients also show that the right ventricle is affected in similar ways, contributing to ischemia (lack of blood supply causing a shortage of oxygen) and fibrosis.

Molecular factors affecting both processes are relatively well-studied. Scientists know that high blood sugar increases the levels of factors causing the profibrotic molecule TGF-β to rise. Another factor that sugar influences, endothelin-1, constricts lung blood vessels and might also contribute to fibrosis. A group of molecules belonging to the microRNA miR-29 family increases heart fibrosis when the body ends up in a state of insulin resistance.

Likewise, troponin T, signaling ischemia, is found in pulmonary hypertension patients who complain of chest pain after exertion. While no studies have looked specifically at whether diabetes can cause ischemia in the right ventricle in such patients, the general ischemic effects of diabetes are well-known, causing numerous complications in diabetes patients.

Pulmonary arterial hypertension (PAH) differs from other types of hypertension in the lungs, in that small arteries in the lungs are thickened, narrowing blood vessels and increasing blood pressure. Molecular factors triggered by a diabetic state, affect several known molecular pathways in PAH, constricting blood vessels, generating reactive oxygen species, and boosting the production of inflammatory mediators.

Studies have also shown that insulin resistance lowers the levels of PPAR-γ, a common finding in PAH patients, and predispose mice to pulmonary hypertension. Also, mice lacking the BMPR2 gene — often found to be mutated in PAH patients — developed diabetes, and if they were fed a high-fat diet, they developed PAH more often.

The examples likely provide just a fraction of possible mechanisms by which diabetes might trigger or worsen pulmonary hypertension, but clearly demonstrates the need to conduct more research studies to understand the connections — a move that would increase opportunities of finding new approaches to treatment.

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