How being overweight leads to diabetes

According to the WHO, over 64 million adults and 300,000 children and adolescents in Europe are currently living with diabetes. In 90 percent of cases, excess weight is the primary trigger. At the Max Planck Institute for Metabolism Research in Cologne, Jens Brüning is investigating the mechanisms through which obesity leads to insulin resistance.

Text: Catarina Pietschmann

Nearly 9 to 10 percent of German adults already have diabetes, and this rate is on the rise. Around 8.5 million people have been diagnosed with this blood sugar disorder, while another two million remain unaware they are affected. Unfortunately, Type 2 diabetes and prediabetes—the condition that often precedes diabetes—can go undetected for years. This is concerning, as prolonged high blood sugar can lead to a cascade of complications. This is serious, as high blood sugar can lead to a cascade of complications. "Sugar molecules attach to structural proteins in the tiny blood vessels throughout the body, damaging them," explains Jens Brüning. This includes vessels supplying the nerves, but also those in the retina and kidneys. Diabetes-related complications can therefore lead to blindness, high blood pressure, and severe kidney damage that may require dialysis." Additionally, the risk of heart attacks and strokes is significantly increased.

Since excess weight is the primary trigger for diabetes, preventing weight gain in the first place is essential. "We know that if individuals with prediabetes reduce their body weight by 10–15 percent, they can cut their risk of developing diabetes by half," explains the researcher.

 Brüning’s research examines the processes that take place even before fat storage begins. He wants to understand how food intake is regulated in the brain. Recently, his team discovered that in mice, certain nerve cells activate immediately after they smell of food, signalling to the liver that food is on the way. "Within five minutes, the mitochondria—the cell’s powerhouses—in the liver alter their shape and function. It’s essentially like a Pavlovian reflex." This prepares the body to ramp up its metabolism even before eating begins

But why does being overweight lead to diabetes in the first place? A key factor appears to be a phenomenon called lipotoxicity. When there is an excessive intake of calories, the surplus is normally stored as fat in adipose tissue. "But fat cells have limited capacity. Once they reach  their maximum capacity, fatty acids are released and begin to accumulate in muscles and the liver," Brüning explains. These tissues are not designed to handle this fat overflow, and This "spillover"  leads to insulin resistance by activating pathways that block the effects of insulin in the liver and muscles. 

Jens Brüning has been researching for years which of the thousands of different fat molecules are particularly damaging to the liver. He identified a specific class of ceramides produced in the body by the enzyme ceramide synthase 6, which is found  both mice and humans. "In obese mice, we’ve shown that inhibiting this enzyme prevents the development of diabetes, even in the presence of excess weight." Now, researchers are working to find inhibitors of this enzyme as a potential third new option in diabetes therapy.   

How weight loss injections work

The other two emerging therapies target the brain rather than belly fat, and they are already available on the market. One example is GLP-1 receptor agonists, such as semaglutide (Ozempic, Wegovy). While these drugs have sparked controversy, they are highly sought after as "weight loss injections." These medications enhance insulin release in the pancreas and also act on GLP-1 receptors in certain brain cells that regulate food intake, improving glucose metabolism and promoting weight loss. Dual agonists like tirzepatide (Mounjaro) take it a step further by also binding to the GIP receptor, making them even more effective at boosting metabolism and encouraging weight loss.

The relevant nerve cells are located in the hypothalamus, a brain region that regulates not only food intake but also body temperature, sleep patterns, and sexual behaviour. In 2022, Jens Brüning, along with colleagues from Cambridge, published a cell atlas of the mouse hypothalamus in Nature Metabolism, identifying around 250 distinct  classes of neurons. Among these are certain neurons known to regulate food intake in mice. However, mice are not humans, so the team has also mapped the human hypothalamus. "We found that most neurons are very similar —essentially identical in both mice and humans.  B But there are subtle differences, particularly in GLP-1 receptors," Brüning explains. This insight is crucial, as overlooking these differences could lead to the development of drugs based on mouse models that target receptors absent in critical human cell types.

The second new therapy option is a class of drugs called gliflozins, or SGLT-2 inhibitors, which block the reabsorption of sugar from the urine filtered by the kidneys back into the body. "Both GLP-1 receptor agonists and SGLT-2 inhibitors  are true breakthroughs in diabetes treatment because they reduce overall mortality in patients. Most importantly, they significantly lower cardiovascular risk!" says Jens Brüning. 

Although Type 2 diabetes predominantly affects middle-aged and older adults, the most effect approach  is to monitor blood sugar and prevent obesity from an early age. "Prevention should start in schools," says Jens Brüning, "and education on healthy nutrition should be supported at the political level." This includes ensuring that school meals are nutritious.