After a meal, insulin resistance shapes a heart hormone’s fall in high-risk patients

When people at high cardiovascular risk drink a standardized, fat-enriched test meal, the hormone MR-proANP falls measurably in their blood within two hours, and the size of that fall tracks how insulin resistant they are rather than whether they carry a diabetes diagnosis. That is the central finding of an exploratory analysis of 373 participants from the Berlin Long-term Observation of Vascular Events (BeLOVE) cohort, published in Cardiovascular Diabetology. The study is, according to its authors, the first characterization of postprandial cardiometabolic peptide changes in a population that includes people recovering from acute coronary syndrome or stroke.

The BeLOVE study is a prospective observational cohort run at Charité-Universitätsmedizin Berlin, the Max-Delbrück Center for Molecular Medicine and the Berlin Institute of Health. Between 18 July 2017 and 11 December 2020, 1,897 individuals were enrolled across five clinical arms. For this predefined sub-analysis, the researchers selected participants who completed a mixed meal test at a deep phenotyping visit: 81 with acute coronary syndrome, 186 with acute cerebrovascular disorder and 106 in a very-high-chronic-risk reference group, all of whom had type 2 diabetes. Participants with acute kidney injury or heart failure were excluded because too few had completed the nutritional challenge.

The meal itself was deliberately unconventional. Whereas standard mixed meal tests tend to be carbohydrate-rich, the BeLOVE challenge was designed as a fat-enriched liquid drink of roughly 500 kilocalories, with 15 percent protein, 45 percent fat and 40 percent carbohydrates, dissolved in 300 milliliters of still water. Participants arrived after an overnight fast of at least eight hours, consumed the meal within five minutes under supervision, and gave a second blood sample 120 minutes later, with a strict acceptance window of 90 to 150 minutes. The investigators chose the two-hour point because prior data indicated an almost maximal MR-proANP response by then, minimal NT-proBNP change over six hours after carbohydrate loading, and the lowest copeptin concentrations at 120 minutes after a mixed meal.

Three peptides were tracked: MR-proANP and NT-proBNP, both established markers of cardiac stress, and copeptin, a stable surrogate of vasopressin secretion linked to adverse cardiovascular outcomes. Fasting and postprandial concentrations of these peptides were measured alongside insulin and glucose. Across all groups, glucose and insulin rose after the meal, MR-proANP fell consistently, NT-proBNP showed little to no change, and copeptin declined slightly with considerable variability between individuals.

To disentangle the effects of disease status from starting concentrations, the team used structural equation models rather than conventional regression. Because postprandial change is inherently dependent on the fasting level, and fasting levels themselves differ between exposures, the models decompose each association into a direct path to the postprandial change and an indirect path running through the fasting concentration, with adjustment for age, sex and body mass index. The authors stress that, given the observational, cross-sectional design, the estimates are associations and not causal effects.

The acute event analysis, restricted to participants with type 2 diabetes, showed that a recent acute cardiovascular event was associated with higher fasting natriuretic peptide levels: a standardized coefficient of 0.22 for MR-proANP and 0.28 for NT-proBNP. However, once fasting concentrations were accounted for, the events were not substantially linked to the magnitude of postprandial change. Fasting concentrations were the main determinant of postprandial responses for all three peptides. In models confined to the acute event groups, type 2 diabetes showed no consistent association with either fasting or postprandial natriuretic peptide responses.

Insulin resistance told a different story. Among all participants with a recent acute cardiovascular event, higher HOMA-IR, a fasting index calculated from glucose and insulin, was associated with lower fasting MR-proANP (standardized β = −0.19) and a stronger postprandial decline (β = −0.18). The pattern was weaker for NT-proBNP, where higher HOMA-IR was linked to lower fasting concentrations (β = −0.15) but showed no clear association with postprandial change. Copeptin dynamics were largely independent of acute cardiovascular disease and metabolic status. Sensitivity analyses adjusting for atrial fibrillation, kidney function, SGLT2 inhibitor use and GLP-1 receptor agonist use, and excluding the eleven participants on insulin therapy, left these associations essentially unchanged.

The authors offer a mechanistic framing while flagging its limits. Experimental work suggests atrial natriuretic peptide stimulates lipolysis in adipocytes through the NPR-A/cGMP/PKG pathway, an effect largely absent for BNP, and hyperinsulinemia has been shown to upregulate the natriuretic clearance receptor NPR-C in human subcutaneous adipose tissue, a phenomenon contributing to the so-called natriuretic handicap of obesity. On that basis, the stronger postprandial suppression seen with higher insulin resistance might reflect reduced ANP-mediated lipolytic signaling. But the study did not measure ANP bioactivity, lipolysis or substrate oxidation, so no mechanistic link can be established from these data, and whether improved insulin sensitivity would restore postprandial MR-proANP regulation requires prospective interventional research.

The divergent behavior of the two natriuretic peptides has a plausible basis in their biology. The metabolic actions of the natriuretic peptide system are mediated mainly by ANP, whereas BNP release is driven primarily by ventricular wall stress, which changes slowly and is not affected by a single meal. NT-proBNP therefore appears to reflect chronic cardiac loading rather than acute nutrient-driven regulation, consistent with prior studies reporting minimal postprandial NT-proBNP responses. Copeptin’s modest decline, meanwhile, may not be nutrient-driven at all: the test meal delivered 300 milliliters of water, and oral fluid intake alone is known to lower copeptin, so osmoregulatory effects of fluid ingestion may have contributed. Because additional water sips during the test were not documented, their contribution cannot be quantified.

The study carries important caveats. The population had high cardiovascular risk and predominantly well-controlled diabetes, with median HbA1c between 6.3 and 6.8 percent, which may limit generalizability and could weaken associations with diabetes status. Participants had to complete the meal test, biasing the sample toward clinically stable individuals, and the stroke cohort showed predominantly mild neurological deficits. Postprandial responses were captured at a single 120-minute time point, so the full trajectory remains unresolved, and a single meal design cannot isolate the contribution of individual macronutrients. Explained variance for postprandial changes was modest, with R² values between 0.05 and 0.16, meaning the models characterize average associations rather than individual responses. The authors describe the work as exploratory and hypothesis-generating, and note that the prognostic value of postprandial peptide responses remains unproven. Planned longitudinal follow-up within BeLOVE is intended to test whether these dynamic responses carry information about future cardiovascular outcomes.

Subject of Research: Postprandial changes in natriuretic peptides and copeptin in relation to acute cardiovascular events, type 2 diabetes and insulin resistance

Article Title: Meal-induced changes in cardiometabolic peptides in the context of acute cardiovascular diseases and glucose metabolism

Article References: Lishkova, G., Schweizerhof, O., Großmann, J., von Rohr, K., Landmesser, U., Edelmann, F., Eckardt, K. U., Endres, M., Weber, J. E., Grittner, U., Pischon, T., Schulz-Menger, J., Müller, D. N., Spranger, J., Li, L., Mai, K., the BeLOVE Study Group, Ahmadi, M., Boldt, L. H., … Weber, J. E. (2026). Meal-induced changes in cardiometabolic peptides in the context of acute cardiovascular diseases and glucose metabolism. Cardiovascular Diabetology, 25(1), Article 314. https://doi.org/10.1186/s12933-026-03424-5

Image Credits: AI Generated

DOI: 10.1186/s12933-026-03424-5

Keywords: MR-proANP, NT-proBNP, copeptin, insulin resistance, type 2 diabetes, natriuretic peptides, mixed meal test, acute coronary syndrome, stroke, cardiometabolic biomarkers, BeLOVE cohort, postprandial metabolism