| Autor: |
Jensen-Cody S; Merck & Co., Inc., South San Francisco, California., Coyne ES; Merck & Co., Inc., South San Francisco, California., Ding X; Merck & Co., Inc., South San Francisco, California., Sebin A; Merck & Co., Inc., South San Francisco, California., Vogel J; Merck & Co., Inc., South San Francisco, California., Goldstein J; Merck & Co., Inc., South San Francisco, California., Rosahl TW; Merck & Co., Inc., West Point, Pennsylvania., Zhou HH; Merck & Co., Inc., Kenilworth, New Jersey., Jacobs H; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, Université de Strasbourg, CNRS, INSERM, Illkirch, France., Champy MF; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, Université de Strasbourg, CNRS, INSERM, Illkirch, France., About GB; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, Université de Strasbourg, CNRS, INSERM, Illkirch, France., Talukdar S; Merck & Co., Inc., South San Francisco, California., Zhou Y; Merck & Co., Inc., South San Francisco, California. |
| Abstrakt: |
Insulin resistance is a major public health burden that often results in other comorbidities including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. An insulin sensitizer has the potential to become a disease-modifying therapy. It remains an unmet medical need to identify therapeutics that target the insulin signaling pathway to treat insulin resistance. Low-molecular-weight protein tyrosine phosphatase (LMPTP) negatively regulates insulin signaling and has emerged as a potential therapeutic target for insulin sensitization. Genetic studies have demonstrated that LMPTP is positively associated with obesity in humans and promotes insulin resistance in rodents. A recent study showed that pharmacological inhibition or genetic deletion of LMPTP protects mice from high-fat diet-induced insulin resistance and diabetes. Here, we show that loss of LMPTP by genetic deletion has no significant effects on improving glucose tolerance in lean or diet-induced obese mice. Furthermore, our data demonstrate that LMPTP deficiency potentiates cardiac hypertrophy that leads to mild cardiac dysfunction. Our findings suggest that the development of LMPTP inhibitors for the treatment of insulin resistance and type 2 diabetes should be reevaluated, and further studies are needed to characterize the molecular and pathophysiological role of LMPTP. NEW & NOTEWORTHY Inhibition of LMPTP with a small-molecule inhibitor, Cmpd23, improves glucose tolerance in mice as reported earlier. However, genetic deficiency of the LMPTP-encoding gene, Acp1 , has limited effects on glucose metabolism but leads to mild cardiac hypertrophy in mice. The findings suggest the potential off-target effects of Cmpd23 and call for reevaluation of LMPTP as a therapeutic target for the treatment of insulin resistance and type 2 diabetes. |
