DECipher the gLp-1 estrAdiol cRosstalk to tackle postmEnopausal Diabetes (DECLARED)
Description: Background and rationale: Menopause is an important turning point in a woman’s life of declining estradiol (E2) levels that translate into a 30% increased risk of type 2 diabetes, independent of age. Conversely, menopausal hormone therapy (MHT) reduces the risk of type 2 diabetes and improves glycaemic control in women with pre-existing diabetes. E2 acts on key organs that are involved in glucose homeostasis (pancreas) and eating behaviour/energy homeostasis (brain). The same regions are targeted by glucagon-like peptide 1 (GLP-1) providing powerful foundations to treat type 2 diabetes and obesity. This parallelism and first preclinical findings suggest a crosstalk between GLP-1 and E2 in the brain and pancreas. However, clinical studies are currently lacking. Hypothesis/aim: The overarching hypothesis is that the menopause related E2 deprivation disrupts the GLP-1 gut-pancreas/brain axis, predisposing to or worsening type 2 diabetes. In this context, we will explore the following specific hypotheses, combining clinical with preclinical research:I)E2 deprivation decreases secretion of GLP-1 in the gutII)E2 deprivation decreases sensitivity to GLP-1 and/or GLP-1 action in the brain and pancreas, III)GLP-1 receptor agonism (GLP-1RA) compensates for the metabolic effects of E2 deprivation on the brain and pancreasIV)E2 potentiates the effects of GLP-1RA on the brain and pancreasV)GLP-1RA reduce the procoagulant effect of E2 (safety hypothesis)Methods and design: Using a collaborative and translational approach, experts in endocrinology/metabolism, gynaecology and animal physiology (applicants) will partner with specialists in biomedical engineering, bioanalytical chemistry and digital health (partners) in a four-year project entailing the following work packages (WPs):WP1: Development of a digital biomarker framework for the collection of cardiometabolic, behavioural, and patient-reported data in response to altered E2/GLP-1 exposure (WP3)WP2: Development of a mathematical modelling and control algorithm approach for in-vivo quantification of E2/GLP-1 effects on the gut-pancreas axis (WP3+WP4)WP3: Mechanistic clinical trial in early postmenopausal (STRAW1a-c, FSH>25U/L), symptomatic women with BMI=27kg/m2 and pre-/early type 2 diabetes (n=3x32), naïve to MHT and GLP-1RA. Following two weeks of run-in, participants will randomly be assigned (stratified for HbA1c, BMI, menopausal stage, concomitant agent) to one of the following three treatments over 12 weeks: i) MHT (standard-dose continuously combined transdermal E2±oral micronized progesterone); ii) GLP-1RA; ii) GLP-1RA+MHT. After the treatment period, all women will receive the GLP1RA+MHT combination for another 12 weeks. Outcome measures of glucose (HbA1c, insulin sensitivity, ß-cell function, incretin effect, GLP-1/E2 action on insulin secretion) and energy homeostasis (body composition, physical activity, energy expenditure), eating behaviour and patient-reported metrics will include in-clinic metabolic testing at 0, 12 and 24 weeks and continuous outpatient digital monitoring. WP4: Complementary animal experiments using (sham) ovarectomized Zucker Diabetic-Sprague Dawley rats (±MHT) as a model of postmenopausal (pre)diabetes. Specific effects of the GLP-1 gut-brain/pancreas axis in E2 replete/deplete states will be investigated by intracerebral/peripheral GLP-1 receptor blockade (Exendin9-39) and target organ histology/immunohistochemistry using a 4-stage experimental design.Relevance and impact:Menopause-related decline in E2 challenges glucose homeostasis, which likely involves a disruption of the GLP-1 gut-pancreas/brain axis. The proposed mechanistic exploration and therapeutic exploitation of the GLP-1/E2 crosstalk addresses currently unmet needs in the cardiometabolic management of postmenopausal women by i) closing knowledge gaps, ii) refining risk/benefits evaluation for MHT, iii) proposing more targeted preventive and therapeutic strategies.
Amount: CHF 1,645,000
Funding type: research
Funder scheme: Project funding
Start date: 2024-07-01
End date: 2028-06-30
Investigator: Bally, Lia
Institution: University of Berne – BE
Funded outputs count: 2
Funder award ID: 10000574
OpenAlex ID: G5917960908