Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Tirzepatide improves adverse liver outcomes in a mouse model of concurrent type 1 diabetes and obesity (128398)

April Foster-Powell 1 2 , Amanda R Purcell 1 2 , Matilda S G Longfield 1 2 3 , Carys Campbell 1 2 3 , Cameron J F Evans 1 2 , Natassia Rodrigo 1 2 3 4 , Sarah J Glastras 1 2 3
  1. Kolling Institute, St Leonards, NSW, Australia
  2. Northern Precinct, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  3. Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, St Leonards, NSW, Australia
  4. Department of Diabetes and Endocrinology, Nepean Hospital, Kingswood, NSW, Australia

The incidence of obesity in people with type 1 diabetes (T1D) is rising at an alarming rate, and obesity is associated with insulin resistance and poorer glycaemic control. The enhanced metabolic dysfunction, coupled with lipid accumulation, increases the risk of metabolic dysfunction-associated fatty liver disease (MAFLD), which is already increased in T1D. MAFLD can progress to severe stages of liver disease such as fibrosis and cirrhosis. Given weight loss is the gold-standard treatment for MAFLD, there is a need for therapies beyond lifestyle intervention, often particularly challenging in the setting of T1D. This study aimed to assess the effect of tirzepatide, an incretin-based therapy which facilitates weight loss, on liver outcomes in a mouse model of concurrent T1D and obesity.

C57BL/6J mice received intraperitoneal 55mg/kg/day injections for 5 days of vehicle-matched control (CON) or streptozotocin (STZ) to achieve beta cell depletion and insulin-dependent diabetes. After 2 weeks, once hyperglycaemia was established (≥14 mmol/L), mice that received STZ were split into: chow diet (DM), high-fat diet (HFD; DMO) or HFD with tirzepatide (DMO-TZP). Tirzepatide was administered thrice weekly at maximum dose of 40nmol/kg s.c. for 24 weeks. Mice were sacrificed and livers harvested for histology and immunohistochemistry.

Total histological scoring for liver steatosis, inflammation and ballooning was elevated in the DMO group, compared to DM (P < 0.01), indicating a MAFLD phenotype. Tirzepatide significantly reduced scores (DMO vs DMO-TZP, P < 0.01). Hepatic lipid accumulation was significantly lowered in tirzepatide-treated mice (DMO vs DMO-TZP, P < 0.05). There were no differences in fibrosis between groups.

These findings underscore the potential of tirzepatide to promote weight loss and improve MAFLD-related liver outcomes in individuals with T1D and obesity. Our T1D and obesity mouse model resembled early-stage MAFLD; longer studies are needed to assess whether tirzepatide can prevent progression to advanced liver disease.