Cover Story Current Issue

Maternal nutrition exerts profound and lasting effects on infant development, with implications extending beyond somatic growth to long-term brain function and metabolic health. For example, newborns from mothers with obesity or diabetes exhibit increased susceptibility to metabolic disorders, including insulin resistance (IR) and type 2 diabetes (T2D), often emerging in childhood or adolescence. While genetic inheritance contributes to this intergenerational risk, early-life nutritional exposures are increasingly recognized as primary drivers of persistent metabolic programming. Among key classes of nutrients, branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—have emerged as potent modulators of metabolic health in human adults. Elevated circulating BCAAs are among the most accurate predictors of future insulin resistance (IR) and T2D, with a two-fold increase in serum levels conferring a 2.5-fold risk of diabetes onset within 6–10 years. This elevation can directly cause organ toxicity, exacerbating metabolic deficits in a feed-forward loop. However, the extent to which maternal BCAA overnutrition during gestation and lactation impacts offspring metabolic programming and predisposes to dysfunction remains unclear.

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Current Issue

TRPM7 kinase regulates α-cell proliferation and glucagon production in mice

Severin Boulassel, Pascale C.F. Schreier, Andreas Beck, Hyeri Choi, ... Noushafarin Khajavi

TRPM7 kinase regulates α-cell proliferation and glucagon production in mice

Objectives

Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway.

Methods

Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (Trpm7R/R). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor.

Results

Ex vivo analysis revealed impaired mTOR signaling in Trpm7R/R islets. Trpm7R/R islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including Gcg and Mafb. Morphological analysis identified reduced proliferation and enhanced apoptosis of Trpm7R/R α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells.

Conclusions

Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.

Articles in Press

TRPM7 kinase regulates α-cell proliferation and glucagon production in mice

Severin Boulassel, Pascale C.F. Schreier, Andreas Beck, Hyeri Choi, ... Noushafarin Khajavi

TRPM7 kinase regulates α-cell proliferation and glucagon production in mice

Objectives

Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway.

Methods

Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (Trpm7R/R). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor.

Results

Ex vivo analysis revealed impaired mTOR signaling in Trpm7R/R islets. Trpm7R/R islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including Gcg and Mafb. Morphological analysis identified reduced proliferation and enhanced apoptosis of Trpm7R/R α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells.

Conclusions

Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.

SAVE THE DATE!

13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

2024 impact factor: 6.6

You are what you eat

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