Introduction and Objective: Despite promising incretin therapies for type 2 diabetes (T2D), many humans with T2D respond poorly to incretins, and the underlying mechanism is unclear.Methods: Human islets with GPT2 silencing and β-cell-specific Gpt2 knockout mice (Gpt2βKO) were used to study incretin response and β-cell survival.Results: We report that mitochondrial transaminase GPT2 was induced in glucolipotoxicity (GLT)-exposed non-diabetic (ND) islets and T2D islets (1.8 and 13.8-fold, respectively, P ≤0.01). Silencing GPT2 enhanced β-cell sensitivity to the GLP-1 receptor agonist Exendin4 (Ex4) (1.6 and 2.6-fold in ND and T2D islets, respectively, P≤0.01). Gpt2βKO mice had improved oral, but not intraperitoneal (IP), glucose tolerance and in vivo GSIS, highlighting improved incretin effect. Ex4 had a greater impact on IP GTT and GSIS in Gpt2βKO than Gpt2f/f mice (P≤0.05). Gpt2βKO islets showed enhanced response to Ex4 and GIP but not acetylcholine in static GSIS and in perifusion with 8 mM glucose and stepwise increase in [Ex-4] (EC50=169 nM vs 356 nM). Random blood glucose was lower in high-fat diet (HFD) fed Gpt2βKO mice (P≤0.01). HFD fed Gpt2βKO mice exhibited mildly improved IP GTT with no change in acute GSIS whereas OGTT and oral GSIS were markedly improved. After IP Ex4, HFD-fed Gpt2βKO mice exhibited lower glucose excursion than HFD-fed Gpt2f/f mice (-37%, P≤0.05). RNASeq revealed a reversal of metabolic stress-induced gene expression and upregulation of pro-survival genes in Gpt2βKO islets. β-cell silencing of human GPT2 reduced %TUNEL+ β-cells under GLT (1.3±0.2 vs 0.5±0.1, P ≤ 0.05) and T2D (1.2±0.2 vs 0.6±0.1, P≤0.05) conditions. Similarly, %TUNEL+ β-cells were reduced in GLT-exposed Gpt2βKO comparedto Gpt2f/f islets (0.15±0.06 vs. 0.05±0.01, P ≤ 0.01) and Gpt2βKO mice showed improved β-cell mass (3.8±0.9 mg vs. 2.5±0.4 mg, P≤0.05) after HFD.Conclusion: GPT2 depletion enhances incretin sensitivity and supports β-cell survival, raising it as a therapeutic target to mitigate β-cell dysfunction in T2D
S. Sen: None. A.V. Rozo: None. M.W. Haemmerle: None. J. Roman: None. C. Juliana: None. S.A. Tersey: None. C.B. Newgard: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Boehringer-Ingelheim. D.A. Stoffers: Other Relationship; Amylyx.
National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK121175-03)
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