Growing focus on ‘beginner’ as type 2 diabetes

Research targeting the inhibitory insulin receptor, called an inceptor, uncovers promising pathways for beta cell protection, offering hope for a causal treatment of diabetes. A new study in mice with diet-induced obesity demonstrates that inactivation of the inceptor improves glucose regulation, prompting further exploration as a drug target for the treatment of type 1 diabetes. 2. These discoveries, made by Helmholtz Munich in collaboration with the German Center for Diabetes Research, the Technical University of Munich and the Ludwig-Maximilians-University of Munich, are driving progress in diabetes research.

Targeting the inceptor to combat insulin resistance in beta cells

Insulin resistance, often linked to abdominal obesity, presents an important health dilemma in our time. More importantly, insulin resistance of beta cells contributes to their dysfunction and the transition from obesity to overt type 2 diabetes. Currently, all drug therapies, including insulin supplementation, focus on the management high blood sugar levels rather than the underlying cause of diabetes: beta cell failure or loss. Therefore, research into beta cell protection and regeneration is crucial and offers promising prospects for addressing the root cause of diabetes, thereby providing potential avenues for causal treatment.

With the recent discovery of the inceptor, the research group of beta cell expert Professor Heiko Likerkt has discovered an interesting molecular target. Upregulated in diabetes, inhibitory insulin receptor receptor may contribute to insulin resistance by acting as a negative regulator of this signaling pathway. Conversely, inhibition of inceptor function could enhance insulin signaling, which in turn is necessary for overall beta cell function, survival, and compensation under stress.

In collaboration with Professor Timo Müller, an expert in the molecular pharmacology of obesity and diabetes, the researchers explored the effects of receptor inactivation in diet-induced obese mice. Their study aimed to determine whether inhibiting receptor function could also improve glucose tolerance in diet-induced obesity and insulin resistance, two critical preclinical steps in the progression to diabetes. . The results were published in Natural metabolism.

Inceptor removal improves Blood sugar levels in obese mice

The researchers studied the effects of removing the inceptor from all cells in the body in diet-induced obese mice. Interestingly, they found that mice lacking the receptor had better glucose regulation without experiencing weight loss, which was linked to increased insulin secretion in response to glucose. Next, they studied the distribution of the inceptor in the central nervous system and discovered its widespread presence in neurons. Deletion of the neuronal cell receptor also improved glucose regulation in obese mice. Ultimately, the researchers selectively removed the receptor from the mice’s beta cells, leading to better glucose control and a slight increase in beta cell mass.

Search for receptor blocking drugs

“Our results support the idea that improving insulin sensitivity by targeting the inceptor holds promise as a pharmacological intervention, particularly with regard to beta cell health and function,” explains Timo Muller. In contrast to intensive early insulin treatments, the use of an inceptor to improve beta cell function shows promise in mitigating the adverse effects on blood glucose and metabolism induced by diet-induced obesity. This approach avoids the associated risks of hypoglycemia-associated unconsciousness and unwanted weight gain typically seen with intensive insulin therapy.

“Since the inceptor is expressed on the surface of pancreatic beta cells, it becomes an accessible drug target. Currently, our laboratory is actively investigating the potential of several classes of inceptor-blocking drugs to improve beta cell health in pre-diabetic and diabetic mice. Looking ahead, the inceptor emerges as a new and intriguing molecular target to improve beta cell health, not only in obese prediabetic individuals, but also in patients diagnosed with type 2 diabetes,” explains Heiko Lickert.

About scientists

Teacher. Heiko Lickert, Director of the Institute for Diabetes and Regeneration Research at Helmholtz Munich, Professor of Beta Cell Biology at the Technical University of Munich (TUM), Researcher at the German Diabetes Research Center (DZD)

Teacher. Timo Müller, director of the Helmholtz Institute for Diabetes and Obesity Munich, professor at the Walther-Straub Institute for Pharmacology and Toxicology at the Ludwig-Maximilians-University Munich (LMU), researcher at the German Center for diabetes research (DZD)

Contact

heiko.lickert@helmholtz-munich.de

timodirk.mueller@helmholtz-munich.de