Postdoc Fellowships 2026 - Project 1

Summary 

Insulin resistance in skeletal muscle is a core defect in type 2 diabetes, resulting in reduced glucose disposal and hyperglycaemia. Insulin resistance is also linked to altered muscle remodelling, reduced metabolic flexibility, and impaired adaptation to diet and exercise. We have recently taken an unbiased approach to deconvolute insulin signalling in skeletal muscle. Specifically, we  applied deep proteomics and phosphoproteomics in human skeletal muscle during fasting and during hyperinsulinaemic euglycaemic clamps in a large, well phenotyped cohort across the insulin sensitivity spectrum. Strikingly, a key and unexpected pattern emerged. Several insulin-stimulated mTORC1 substrates tracked tightly with insulin sensitivity, whereas many AKT substrates remained insulin responsive even in insulin resistant muscle (Cell, 2025). This points to selective uncoupling of insulin signalling to mTORC1 rather than global proximal insulin signalling failure. Thus the aim of this post-doctoral project is to: 

1.  Define an insulin responsive mTORC1 signature in human skeletal muscle across insulin sensitivity.
2. Identify upstream regulators reducing mTORC1 signalling in insulin resistance
3. Test causality in primary human skeletal muscle cells from insulin sensitive and insulin resistant donors.

mTORC1 is a central integrator of insulin, nutrients, growth factors, energy status, and cellular stress. It controls translation initiation, ribosomal biogenesis, autophagy, and aspects of intermediary metabolism. In skeletal muscle, mTORC1 also contributes to protein turnover and thus to muscle quality and function. In insulin resistant states, mTORC1 may be altered in two nonexclusive ways. First, insulin may fail to engage mTORC1 due to impaired coupling between AKT and the TSC complex, altered RPTOR based scaffolding, or altered localisation of the complex. Second, stress and nutrient sensing inputs may dominate over insulin input, shifting the operating point of the pathway. In vivo data from human studies that resolve these possibilities are scarce. One of mTOR’s key roles is to regulate protein synthesis. Interestingly we have recently identified reduced expression of TMEM9-AS1 in skeletal muscle from people with type 2 diabetes, a lncRNA that appears necessary for adequate protein synthesis.