The menopause-related decline in estradiol exposure interferes with glucose and energy homeostasis, translating into a 20 - 30% increased risk of type 2 diabetes, independent of the effect of ageing. In people with preexisiting diabetes, the onset of menopause can challenge blood glucose control. Conversely, menopausal hormonal therapy in women with diabetes exerts benefits in on glucose control. 

Estradiol acts on organs involved in glucose-insulin and energy homeostasis – namely the pancreas and the brain. The same organs are targeted by glucagon-like peptide 1 (GLP-1), building the foundation for powerful obesity and diabetes medications. Parallelism in target organ effects, sex differences in responses to GLP-1 receptor agonist (GLP-1RA) drugs (greater in women than men), and findings of preclinical studies indicate that the menopausal decline in estradiol influences the GLP-1 gut-pancreas/brain axis. The exact mechanisms are scarcely investigated to date. 

In the collaborative and translational DECLARED project – supported by the Swiss National Science Foundation –, we test the overarching research hypothesis whether the menopausal decline in estradiol disrupts the GLP-1 gut-pancreas/brain axis, predisposing to or worsening type 2 diabetes. To this end, we are combining preclinical experiments in an animal model with clinical research and mechanistic modelling. 

In the DECLARED clinical trial, we are investigating, whether a menopausal hormone therapy can augment the benefits of GLP-1RA therapy on glucose and energy homeostasis in overweight women with (pre)diabetes and how menopausal hormonal therapy interacts with the endogenous GLP-1 axis. In complementary animal experiments, we explore in detail the interplay between estradiol and GLP-1 on the level of the target organs (pancreas and brain). 

Experimental work is supported by strong bioanalytical research partners focusing on analytics of gut hormones, GLP-1RA and sex hormone profiling. Mechanistic modelling are performed in collaboration with experts in biomedical engineering. Collaborating with partners in digital health, we will perform numerous digital measurements and developments of digital biomarkers. 

Insights from the DECLARED project will:

• close knowledge gaps in menopause-related changes in metabolic physiology.
• help performing risk/benefit evaluations of menopausal hormone therapy in women with metabolic risks.
• contribute to more targeted preventive and therapeutic strategies to improve metabolic health in postmenopausal women.