The role of TRPM channels in glucose homeostasis

Khajavi, Noushafarin (2026): The role of TRPM channels in glucose homeostasis: identifying novel therapeutic strategies for diabetes treatment. Habilitationsschrift, LMU München: Faculty of Medicine

Abstract

The rising prevalence of obesity and type 2 diabetes (T2D) underscores the urgent need to understand the molecular mechanisms regulating pancreatic islet function and to develop innovative therapeutic strategies. This thesis investigates the physiological and pathophysiological roles of two transient receptor potential (TRP) channels, TRPM7 and TRPM5, in pancreatic islets, bridging mechanistic insights with translational applications. TRPM7, a bifunctional channel–kinase highly expressed in both β- and α-cells, is shown to be a master regulator of islet plasticity. In β-cells, TRPM7 kinase is critical for maintaining cell identity, transcriptional programs, proliferation, and glucose-stimulated insulin secretion (GSIS), particularly under metabolic stress. Mechanistic studies reveal that TRPM7 kinase regulates key transcription factors (e.g., Pdx1, MafA) and signaling cascades (PI3K/AKT, ERK1/2) that regulate β-cell function, establishing TRPM7 as a pivotal integrator of β-cell dynamics and glucose homeostasis under obesogenic diet. TRPM7 also regulates α-cell mass and glucagon production via the mTORC1–FoxA2 signaling axis, orchestrating adaptive responses to metabolic signals and maintaining systemic glucose homeostasis. TRPM5, a calcium (Ca2+) -activated non-selective cation channel, is identified as a crucial mediator of incretin-stimulated insulin secretion. Studies with a GLP-1/GIP/glucagon triagonist (IUB447) demonstrate that unlike classical incretin signaling, which depends on Gαs activation and cAMP accumulation, triagonist IUB447 engages a Gαq-dependent pathway that triggers protein kinase C (PKC) activation and enhances calcium influx and insulin secretion. Central to this mechanism is the TRPM5, whose pharmacological inhibition or genetic deletion abolishes the metabolic benefits of triagonist therapy. Structural modelling further suggests that additional stabilizing interactions strengthen and prolong IUB447–GLP-1R binding compared with native GLP-1, potentially explaining its superior efficacy. Collectively, this work establishes TRPM7 and TRPM5 as key molecular effectors that link nutrient and hormonal signals to islet function. It provides mechanistic insights into β- and α-cell biology, elucidates the basis for the superior efficacy of multi-agonist incretin therapies, and identifies TRP channels as promising therapeutic targets for improving β-cell function, preserving islet mass, and restoring metabolic homeostasis in T2D. This thesis connects fundamental cellular mechanisms to translational pharmacology, providing a framework for the rational design of next-generation diabetes therapies.

• Item Type: Postdoctoral Theses
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 2026
• Signature of the printed copy: 0700/UMD 22797