Lightning Talk + Poster ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Tirzepatide treatment improves glycaemic outcomes and attenuates renal injury in a mouse model of insulin-deficient diabetes with obesity (143772)

Amanda R Purcell 1 2 3 , Natassia Rodrigo 1 3 4 , Matilda SG Longfield 1 2 3 , Sarah J Glastras 1 3 4
  1. The Kolling Institute, St Leonards, New South Wales, Australia
  2. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  3. Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, St Leonards, NSW, Australia
  4. Northern Precinct, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Obesity and insulin resistance are increasingly common in people with type 1 diabetes and may increase the risk of diabetes-related kidney disease1. Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, produces substantial weight loss and glycaemic improvement, with emerging evidence of kidney benefit in type 2 diabetes2. Whether these metabolic benefits translate into renal protection in insulin-deficient diabetes remains understudied. We therefore examined the structural and functional renal effects of tirzepatide initiated at diabetes onset or after established diabetes and obesity. Eight-week-old male C57BL/6 mice were assigned to four groups. CON mice remained free of diabetes and received standard chow. In the remaining groups, insulin-deficient diabetes was induced using streptozotocin (55 mg/kg/day for five days), with concurrent obesity promoted by high-fat feeding, creating a model of double diabetes. These mice received saline vehicle (DD), tirzepatide from diabetes onset (DD-eTZP), or tirzepatide after 12 weeks of high-fat feeding (DD-lTZP). Tirzepatide was dose-escalated to 40 nmol/kg and administered subcutaneously three times weekly. Mice were followed for 24 weeks (n=8/group). Kidney weights, serum and urinary analyses, and renal histopathology were assessed at endpoint. Data was analysed using one-way ANOVA with Bonferroni correction and is presented as mean ± SEM. At study end, DD-eTZP and DD-lTZP had reduced body weight versus DD (27.7±0.4 and 26.8±0.5 vs 32.5±0.4 g; both p<0.0001) and lowered blood glucose (10.3±0.4 and 14.2±1.8 vs 31.4±0.9 mmol/L; both p<0.0001). Both regimens reduced kidney-to-body-weight ratios by 22–34% and improved tubular vacuolation, casts and glycogenated nuclei (all p<0.05 versus DD). Only early treatment significantly reduced tubular dilation and urinary albumin-to-creatinine ratio compared with DD (both p<0.05). Tubulointerstitial fibrosis and glomerulosclerosis were unchanged by tirzepatide treatment. Both early and delayed tirzepatide improved glycaemia and attenuated renal injury, with benefits evident even when treatment commenced after established disease.

  1. 1. Van der Schueren, B., Ellis, D., Faradji, R. N., Al-Ozairi, E., Rosen, J., & Mathieu, C. (2021). Obesity in people living with type 1 diabetes. The Lancet Diabetes & Endocrinology, 9(11), 776-785. https://doi.org/10.1016/S2213-8587(21)00246-1
  2. 2. Heerspink, H. J. L., Sattar, N., Pavo, I., Haupt, A., Duffin, K. L., Yang, Z., Wiese, R. J., Tuttle, K. R., & Cherney, D. Z. I. (2022). Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol, 10(11), 774-785. https://doi.org/10.1016/s2213-8587(22)00243-1