Title of project

DiaSpax: Adipose Tissue Heterogeneity and Its Link to Type 2 Diabetes: A Randomized Open Treatment Trial comparing Empagliflozin, Pioglitazone, and Semaglutide

Abstract

Overweight is tightly linked to insulin resistance and type 2 diabetes (T2D), though the causal mechanisms are largely unknown. Dysfunctional adipose tissue function contributes to the development of T2D, and even small increases in white adipose tissue (WAT) mass have been shown to be associated with measured changes in adipocyte gene expression and function. In a recent study using spatial transcriptomics it has been demonstrated, how human white adipose tissue (WAT) can be categorised into at least three different adipocyte subtypes with distinct differences in their transcriptional response to insulin. However, the pathophysiological relevance of these subtypes in relation to T2D is unknown. We hypothesize that the proportion and/or function of these specific adipocyte subtypes may explain the large inter-individual variations in response to changes in WAT mass and/or interventions including diet, exercise, and pharmacotherapy. To test this, we are conducting a multi-site open randomised trial including 90 individuals with newly diagnosed T2D, who have not yet attained a goal of HbA1c<42mmol/mol using Metformin. Recruitment of the first 60 participants has begun at the Karolinska Institute, and this PhD project will include the recruitment of the following 30 participants to be examined at SDCC. Subjects are randomized to 6 months of treatment with oral Empagliflozin, Pioglitazone or Semaglutide. Clinical examinations including Dual X-ray Absorptiometry (DXA) and hyperinsulinemic euglycemic clamps are performed as well as subcutaneous WAT biopsies before and after the intervention. Our results will give insights to how different anti-hyperglycemic treatments affect lipolysis, insulin sensitivity, and through lipidomics how these may contribute to or explain changes of the WAT lipidome. We hope to create greater understanding of WAT heterogeneity and function, including how it is affected by pharmacotherapy and thus to differential T2D treatment responses, thereby enabling future development of risk markers and therapies targeting WAT.