GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice
Ricardo J. Samms, Michael E. Christe, Kyla A.L. Collins, Valentina Pirro, Brian A. Droz, Adrienne K. Holland, Jessica L. Friedrich, Samantha Wojnicki, Debra L. Konkol, Richard Cosgrove, Ellen P.S. Conceição Furber, Xiaoping Ruan, Libbey S. O’Farrell, Annie M. Long, Mridula Dogra, Jill A. Willency, Yanzhu Lin, Liyun Ding, Christine C. Cheng, Over Cabrera, Daniel A. Briere, Jorge Alsina-Fernandez, Ruth E. Gimeno, Julie S. Moyers, Tamer Coskun, Matthew P. Coghlan, Kyle W. Sloop, William C. Roell
Ricardo J. Samms, Michael E. Christe, Kyla A.L. Collins, Valentina Pirro, Brian A. Droz, Adrienne K. Holland, Jessica L. Friedrich, Samantha Wojnicki, Debra L. Konkol, Richard Cosgrove, Ellen P.S. Conceição Furber, Xiaoping Ruan, Libbey S. O’Farrell, Annie M. Long, Mridula Dogra, Jill A. Willency, Yanzhu Lin, Liyun Ding, Christine C. Cheng, Over Cabrera, Daniel A. Briere, Jorge Alsina-Fernandez, Ruth E. Gimeno, Julie S. Moyers, Tamer Coskun, Matthew P. Coghlan, Kyle W. Sloop, William C. Roell
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Research Article Metabolism

GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice

Abstract

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r–null mice. In the absence of GLP-1R–induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.

Authors

Ricardo J. Samms, Michael E. Christe, Kyla A.L. Collins, Valentina Pirro, Brian A. Droz, Adrienne K. Holland, Jessica L. Friedrich, Samantha Wojnicki, Debra L. Konkol, Richard Cosgrove, Ellen P.S. Conceição Furber, Xiaoping Ruan, Libbey S. O’Farrell, Annie M. Long, Mridula Dogra, Jill A. Willency, Yanzhu Lin, Liyun Ding, Christine C. Cheng, Over Cabrera, Daniel A. Briere, Jorge Alsina-Fernandez, Ruth E. Gimeno, Julie S. Moyers, Tamer Coskun, Matthew P. Coghlan, Kyle W. Sloop, William C. Roell

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Figure 6

LAGIPRA improves insulin sensitivity in obese insulin-resistant mice.

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LAGIPRA improves insulin sensitivity in obese insulin-resistant mice. Hi...
High-fat diet–fed obese insulin-resistant mice dosed daily with either vehicle (n = 8–14) or a long-acting glucose-dependent insulinotropic polypeptide receptor agonist (LAGIPRA, n = 8–14) for 14 days. (A) Daily body weight and food intake. (B) Fasting blood glucose and plasma insulin following 14 days of treatment. Hyperinsulinemic-euglycemic clamp following 14 days of treatment. (C) Average glucose infusion rates throughout and during the final 30 minutes of clamp (GIR). (D) Endogenous glucose production (EGP). Insulin-stimulated glucose disposal in (E) soleus, (F) red, and (G) white gastrocnemius skeletal muscle and (H) epididymal white adipose tissue (eWAT) and (I) inguinal white adipose tissue (iWAT). Data are presented as mean ± SEM. *P < 0.05 compared with vehicle. Statistical analyses performed included Student’s unpaired t test, 2-way ANOVA, or Kruskal-Wallis test, where appropriate.