Massive global study rewrites what we know about Type 2 diabetes biology

A large global genetics study shows Type 2 diabetes is driven by complex, tissue-specific biology across organs and populations, challenging blood-focused research and treatment strategies

Type 2 diabetes is usually tracked through blood sugar levels, but a new global study suggests that much of the disease unfolds far beyond the bloodstream. By analysing genetic data from more than 2.5 million people worldwide, researchers have found that many key biological drivers of Type 2 diabetes act inside organs such as the pancreas, liver, fat, and muscles, which often do not show up in blood tests.

 

The study, titled Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues and published in Nature Metabolism, shows that relying only on blood-based research can miss crucial signals. Its findings help explain why Type 2 diabetes behaves differently across individuals and populations, and why treating it remains so challenging.

 

Using a method called Mendelian randomisation, the researchers examined how genetic variants influenced gene activity and protein levels in seven diabetes-relevant tissues, including pancreatic islets, liver, skeletal muscle, and different fat depots.

Why blood tests may miss key drivers of Type 2 diabetes

The study found that 85 per cent of genetic effects seen in key diabetes tissues were completely absent in blood-based analyses. Even in core organs like the pancreas, fewer than one in five causal genes showed up in the blood.

 

This means a blood test may look “normal” while critical disease-driving processes are already unfolding elsewhere, particularly in insulin-producing cells, fat tissue, and muscle.  ALSO READ | How type 2 diabetes physically alters the heart and drives failure

Which genes and proteins were linked to diabetes risk

The analysis identified 676 genes whose activity in disease-relevant tissues had a causal impact on Type 2 diabetes risk. In blood-based analyses alone, 335 genes and 46 proteins were linked to the disease.

 

Some genes increased risk when more active, while others were protective. Crucially, the same gene could behave very differently depending on the tissue. A gene that lowers diabetes risk in fat tissue might raise risk in the pancreas, highlighting how context-dependent diabetes biology is.

 

The study underlined that Type 2 diabetes is not a single-organ problem. It involves insulin resistance in muscle, fat dysfunction, liver glucose overproduction and failure of pancreatic beta cells. The findings show that collapsing all this biology into a single blood signal oversimplifies the disease.

 

This tissue-level insight also helps explain why many promising drug targets fail when tested broadly. A treatment that helps one tissue could inadvertently harm another if tissue context is ignored.

 

The findings suggest that two people with similar blood sugar levels may have very different underlying biology, and may respond differently to the same treatment.