Targeting type 2 diabetes via PDE4D-dependent amelioration of insulin resistance

• Applicant: Gencer Sancar, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562635405

Type 2 diabetes (T2D) is one of the most prevalent chronic diseases globally, affecting approximately 10% of the population. Projections indicate that by 2040, up to 12 million individuals in Germany alone will be diagnosed with T2D. A primary driver of T2D is insulin resistance, characterized by the failure of cells to respond to insulin, impairing glucose and lipid homeostasis. While the causes of whole-body insulin resistance are multifactorial, a major contributing factor is the dysregulation of adipose tissue function, which leads to impaired adipokine secretion, chronic inflammation, elevated basal lipolysis and lipotoxicity. Understanding the factors that trigger adipose tissue dysfunction and insulin resistance is crucial for the prevention and treatment of T2D. Normally, post-prandial insulin regulates hepatic glucose production (HGP) by suppressing adipose tissue lipolysis; however, in insulin-resistant adipose tissue, this suppression fails, leading to increased lipolysis, elevated HGP, and higher blood glucose levels. Current therapeutic approaches, such as the use of metformin, SGLT-2 inhibitors, incretin analogs, and exogenous insulin, aim to compensate for the impaired insulin response. However, the underlying insulin resistance is often not adequately corrected. Fibroblast growth factor (FGF-1) has been identified as a potent antidiabetic agent. Recently, we discovered that the antidiabetic function of FGF-1 depends on phosphodiesterase-4 (PDE4D) in adipose tissue. The phosphorylation of PDE4D at a specific site leads to its activation, which reduces lipolysis in adipocytes and suppresses HGP. Overexpression of wild-type PDE4D, but not the phospho-mutant reduces blood glucose levels and lipolysis in diabetic mice, indicating a potential therapeutic target for T2D. Our preliminary data show that not only FGF-1, but also insulin and IGF-1 (insulin-like growth factor 1), induce specific phosphorylation of PDE4D in adipocytes. PDE4D appears to function as a convergence point for metabolic signals. We observed that, insulin resistance inhibits PDE4D phosphorylation, while overexpression of PDE4D in adipocytes in vitro or in adipose tissue in vivo can improve insulin resistance. Based on our findings, we aim to uncover new mechanisms of insulin sensitivity by decoding the signaling cascade leading to adipose tissue PDE4D activation and its effect on insulin action. The proposal will address three main questions: What are the FGF1 and insulin signaling cascades leading to PDE4D activation and regulation of lipolysis? How do compartmentalized cAMP signaling and PDE4D interactome regulate lipolysis? What is the contribution of the PDE4D pathway to insulin resistance in vivo? The successful completion of this project will identify novel molecular factors that regulate lipolysis and specifically address insulin resistance, potentially opening new therapeutic possibilities for the treatment of type 2 diabetes.

• DFG Programme: Research Grants