What is it about?

We set out to investigate sugar and insulin metabolism in PAH using the gold-standard hyperglycemic clamp technique in individuals with idiopathic PAH and age-, BMI- and sex-matched Controls. Individuals with PAH had reduced circulating insulin levels in response to IV-induced hyperglycemia, but pancreatic insulin secretion was similar to Controls. The decrease in circulating insulin may instead be due to hepatic insulin extraction. Surprisingly, skeletal muscle in PAH is more insulin sensitive compared to Controls (contradicting the literature based on static measures of insulin resistance). Fasting lipid and ketone metabolism is upregulated.

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Why is it important?

Our data suggests, rather than overt tissue insulin resistance in PAH, it appears that peripheral tissues in PAH are insulin sensitive, but some factor/s (potentially hepatic insulin extraction) are reducing the systemic insulin response to exogenous glucose (oral or intravenous). We hypothesize this may be due to the underlying PAH physiology which prefers to utilize ketone and lipid metabolism at the expense of glucose control (perhaps to compensate for the progressive heart failure, as ketones are a more efficient fuel source).

Perspectives

These results go against a widely believed notion that insulin sensitivity is reduced in PAH, but confirms that PAH features significant metabolic abnormalities. The next logical step is to test pharmacologic or lifestyle approaches to minimize glucose excursions and/or promote ketone and lipid metabolism for improving clinical outcomes in PAH. Our group is currently investigating a lifestyle intervention, involving aerobic exercise (60 min/day, 5 days/week, 12 weeks) and the Mediterranean diet, in individuals with PAH.

Gustavo Heresi
Cleveland Clinic

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This page is a summary of: Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study, European Respiratory Journal, February 2020, European Respiratory Society (ERS),
DOI: 10.1183/13993003.01700-2019.
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