Mothers with type 1 diabetes may unknowingly shape their sons’ cardiovascular health long before birth. New research suggests that young men exposed to maternal type 1 diabetes in the womb can already show signs of blood-vessel dysfunction – years before any traditional risk factors appear.
Heart disease is usually framed as the end result of decades of unhealthy habits. But a study published in Cell Reports Medicine indicates a different starting-point: risk that may be programmed during pregnancy and that can be visible in the blood vessels long before classic risk factors appear.
If confirmed, the findings suggest that cardiovascular vulnerability can exist in young adults who appear entirely healthy by every conventional measure.
Qiaolin Deng, principal researcher at Karolinska Institutet and Stockholm University, Stockholm, Sweden, says that the project grew out of a longstanding interest in how early development shapes later disease. She also points to earlier Nordic evidence that maternal type 1 diabetes can leave long-term traces in offspring.
“The human evidence is there, showing very strongly that mothers with type 1 diabetes leave a long-term effect in the offspring,” she says.
But that evidence left key questions open – particularly about mechanism. “Human studies have a lot of confounding factors,” Deng explains. “We really wanted to dissect it out.” That motivation placed controlled animal experiments at the centre of the study.
First author Allan Zhao, an MD, PhD student at Karolinska Institutet, says that the team initially expected metabolic effects but became increasingly interested in cardiovascular signals that pointed toward the vessel lining itself.
“The prevailing assumption was that cardiovascular complications arise downstream of metabolic disease,” Zhao says. “But we asked if vascular dysfunction could appear earlier – even when metabolism looks normal.” When the researchers revisited registry outcomes, many of the associated diagnoses were linked to endothelial dysfunction.
A modern model — and an unexpected sex signal
That shift led the team to focus on endothelial function as an early readout, enabling them to test whether vascular vulnerability could emerge before any signs of metabolic disease.
To reflect today’s clinical reality, the researchers also moved away from animal models based on severe diabetes. Modern type 1 diabetes care enables many women to enter pregnancy with well-controlled glucose levels, and Deng emphasises that the study was designed to mirror that context:
“We are mimicking the current patient context – they do not have severe hyperglycaemia, because they are well treated.”
What they did not anticipate was the magnitude – and specificity – of the sex difference.
“We did not expect there to be such a strong sex dimorphism,” Zhao says, referring to the fact that the signal appeared among sons but not daughters. That surprise ultimately drove the decision to test the finding across mouse experiments, Nordic registries and direct clinical measurements among young adult men.
When young hearts defy risk profiles
Cardiovascular disease is increasingly diagnosed at younger ages, even though classic prevention efforts have improved outcomes later in life. Lifestyle factors such as obesity, smoking, inactivity and diabetes remain major drivers but do not explain everything, especially among young adults who do not fit the classic risk profile.
For Qiaolin Deng, that mismatch is exactly why early-life biology matters. She describes the broader framework as developmental origins of health and disease: “From my background, I am a developmental biologist, and I have been very interested in this concept of development and later health and disease.”
Maternal type 1 diabetes has been a recurring signal in that field, particularly in Scandinavian populations, in which studies have established associations but not mechanisms. Zhao says that the team also began from that landscape but with an emerging sense that something else might be going on.
“In the beginning, mainly, we knew that metabolic disease was affected by maternal diabetes, but cardiovascular disease was a bit newer,” he says, adding that “no one had really looked into it” in the way they wanted to.
Registry clues: vessel walls react first
Zhao describes how they revisited those outcomes and noticed something more specific: “We looked at that, and we found that a lot of the diseases mentioned were actually linked to endothelial dysfunction.”
That mattered because the endothelium is the ultrathin inner lining of blood vessels, and when it stops responding properly, vessels become worse at relaxing and regulating blood flow – changes that are often seen early on the road to cardiovascular disease.
Their key question was whether this kind of vascular dysfunction might show up even when metabolic health still looks normal.
“The prevailing assumption was that cardiovascular complications arise downstream of metabolic disease,” Zhao says. “But we thought it might be different.” That reasoning led the team to use endothelial function as an early readout, enabling them to test vascular vulnerability before metabolic disease emerged.
A second motivation was that many animal models of maternal diabetes are extremely severe and do not reflect modern care in type 1 diabetes.
“We are mimicking the current patient context,” Deng says. “These women are well treated and do not have severe hyperglycaemia.” That milder reality, she adds, has been largely overlooked in experimental models.
Three linked tests: mice, nationwide registries and young men
The researchers built the study in three linked steps: first mice to probe biology under controlled conditions, then nationwide registry data to test whether the same signal appears at population scale and, finally, direct clinical measurements among young adult men to see whether it can be detected in people.
The experimental core was a mouse model of mild maternal hyperglycaemia, designed to resemble contemporary pregnancies among women with type 1 diabetes.
Unlike older models that induce severe diabetes and widespread illness, this approach produces only modestly elevated blood glucose while preserving fertility.
Deng emphasises why that mattered: “We are really mimicking nowadays the human patient context – they do not have severe hyperglycaemia, because they are well treated.”
Female mice with this mild hyperglycaemia were mated with healthy males, and their offspring were followed into adulthood. Before any vascular testing, the team confirmed that the offspring showed no signs of metabolic disease – enabling the researchers to isolate vascular effects from later disease.
To assess blood-vessel function directly, the researchers used wire myography, a technique in which tiny isolated vessels are mounted on wires and then challenged with signals that should make them relax. This enabled the problems in the endothelial lining to be separated from problems in the underlying smooth muscle – a critical distinction when probing early vascular dysfunction.
To uncover molecular drivers, the team combined RNA sequencing of aortic tissue with targeted biochemical and histological analysis. These experiments focused on pathways linked to oxidative stress, mitochondrial activity and nitric oxide signalling. Importantly, they did not stop at correlations. As Deng puts it: “We did not want to just describe something – we wanted to know what is driving it.” The researchers therefore tested causality directly by treating blood vessels with antioxidants and arginase inhibitors, both outside the body and in living animals.
From registries to clinic: is the signal visible?
In parallel, the team turned to nationwide registry data from Denmark and Sweden to ask a simple question at scale: do sons of mothers with type 1 diabetes show higher cardiovascular risk in real life? By linking birth records to long-term health outcomes, they followed more than 4.3 million individuals and adjusted for factors such as parental cardiovascular disease, socioeconomic background, maternal body-mass index, smoking and the offspring’s own diabetes.
Deng highlights the strength of this approach: “Both Sweden and Denmark have very good registries, and by combining them, we could get better power.”
Finally, the researchers carried out a clinical case–control study among young adult men whose mothers have type 1 diabetes – a step Zhao describes as essential. “We do not study mouse disease – we study human disease,” he says.
Using peripheral arterial tonometry, they measured endothelial function directly and paired this with blood-based markers of oxidative stress.
Sons show early dysfunction — daughters do not
Across mouse experiments, population data and direct clinical measurements, the results converged on a clear and highly specific pattern: early vascular dysfunction develops among the sons – but not daughters – of mothers with type 1 diabetes.
In the mouse model, offspring exposed to mild maternal hyperglycaemia showed no detectable metabolic abnormalities across a broad range of measures. Deng notes how misleading that could have been: “From a metabolic perspective, they look completely normal.” Had the analysis stopped there, she adds, “we might have thought that there was no effect at all at this early age.”
That conclusion changed once vascular function was examined. Using wire myography, the researchers found that male offspring showed a pronounced impairment in endothelium-dependent relaxation – a defining feature of endothelial dysfunction. Even strong vasodilatory signals failed to trigger a normal response. Female offspring, by contrast, showed fully intact endothelial function, both in early adulthood and later.
The sex difference proved to be striking. “We did not expect such a strong sex dimorphism,” Zhao says. Because results like this can be fragile, the team repeatedly validated the finding in animals. “We redid the experiments several times, across four or five different cohorts, to make sure that this was not being driven by some external factor.”
Mechanism: oxidative stress weakens blood vessels
Importantly, the defect was specific to the endothelial layer. Smooth muscle–driven responses were normal, and vessel structure was intact, indicating a functional and molecular disturbance rather than anatomical damage at the early stage. This distinction became crucial when the researchers looked for mechanisms.
Gene-expression analysis of aortic tissue from male offspring pointed clearly toward oxidative stress, with changes in pathways linked to mitochondrial activity and reactive oxygen species. Histological analysis confirmed oxidative damage in the vessel wall.
When the researchers treated the vessels with antioxidants, endothelial function recovered – demonstrating that oxidative stress was not merely associated with the phenotype but causally involved in driving it.
A second mechanistic layer involved arginase 1. Elevated arginase activity reduced nitric oxide availability, a key signal required for normal vessel relaxation. Blocking arginase activity restored endothelial function both in isolated vessels and in living animals, establishing a causal link between oxidative stress, nitric oxide signalling and vascular dysfunction.
The population-level data reinforced the experimental findings. In combined Danish and Swedish registry cohorts, the sons of mothers with type 1 diabetes had a 63% higher risk of early-onset cardiovascular diseases linked to endothelial dysfunction, even after accounting for their own diabetes and other confounders. No such increase was seen in daughters or in offspring of fathers with type 1 diabetes. For Deng, that asymmetry was telling: “That strongly suggests this is not only genetic inheritance – it is something about the intrauterine environment.”
The same signal emerged in the clinical case–control study. Young adult men born to mothers with type 1 diabetes showed impaired endothelial function, accompanied by elevated markers of oxidative stress, directly mirroring the biology observed in mice.
The convergence of findings across animal models, nationwide registries and direct measurements in young adults convinced the researchers that the effect is robust and clinically meaningful.
A new risk question in the clinic
Taken together, the findings shift how cardiovascular risk is understood – not only what drives it but when it may begin. Rather than emerging solely from adult lifestyle or later metabolic disease, the study suggests that vascular vulnerability can be shaped during fetal development and remain silent for decades – without implying that disease is inevitable.
“In that sense, cardiovascular risk is not always an adult problem,” says Qiaolin Deng. “It can already be embedded before birth.”
One immediate implication is the identification of a previously invisible risk group: men who appear metabolically healthy but whose cardiovascular vulnerability may have been set before birth. Under current screening practices, these individuals would not raise concern despite carrying early signs of vascular dysfunction.
Allan Zhao argues that the findings may warrant a shift in how cardiovascular risk is assessed. “This should be considered a risk factor,” he says – noting that the message is already reaching clinical practice. “I have talked to cardiologists who told me they will start asking this question.”
That question – whether a patient’s mother had type 1 diabetes – could become a simple way to flag risk that would otherwise go unnoticed. Zhao stresses that this is about increased risk, not certainty: endothelial dysfunction can sit silently for years, and it may not progress to disease in everyone.
“We still do not know which early changes will actually turn into disease later in life,” Zhao says. “That is something that can only be answered with longer-term follow-up.”
Early signals, not destiny
Because endothelial dysfunction represents an early and potentially reversible state, the findings also open the door to earlier intervention – even if clinical disease lies decades in the future. The work highlights a broader challenge in pregnancy care for women with type 1 diabetes.
“We have always had the hypothesis that glycaemic management for the mothers is not enough,” Zhao says.
Deng is careful not to overpromise. “We are not proposing treatment tomorrow,” she says. “But once you understand what is driving the dysfunction, you have a rational starting point.”
In mouse experiments, both antioxidant treatment and arginase inhibition restored vascular function, demonstrating that the phenotype is modifiable under controlled conditions. Whether similar strategies can translate into prevention or early intervention among humans remains an open question – one that will require long-term follow-up.
The study may also have implications far beyond type 1 diabetes. Deng notes that her group and others are already seeing cardiovascular effects linked to other pregnancy conditions: “Mothers with obesity also affects cardiovascular function in the offspring.” Zhao adds that similar patterns are emerging across very different maternal exposures: “We think different environments converge on a similar kind of long-lasting memory.”
That memory may not be purely genetic. Instead, the researchers suspect durable biological programming – possibly involving oxidative stress, placental hypoxia or epigenetic changes – that alters how tissues respond throughout life. “Even if people live the same lifestyle,” Zhao says, “they may still have different outcomes because they carry this extra vulnerability.”
Pregnancy as a critical window
The pronounced sex difference raises another set of unanswered questions. Female offspring appeared to be protected in this study but why remains unclear. Zhao acknowledges the limits of the current data: “We have ideas of how to explore sex differences further, but it is complicated – and it is probably a second project.” Understanding that protection, Deng adds, could be as informative as understanding male vulnerability.
Finally, the findings reinforce a broader public-health message: pregnancy is not only about immediate outcomes at birth. “It is a critical window,” Deng says, “that can shape health decades later.”
"That makes early recognition – not alarm, but awareness – increasingly important. Zhao sees this as part of where medicine is heading: “All of these small factors – maternal and also paternal – will be an important part of precision medicine.”
