Towards novel therapeutics – importance of brain insulin action for the regulation of postprandial metabolism in humans

• Applicant: Professor Dr. Martin Heni
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518749683

The brain has been characterized as an insulin-sensitive organ. Studies in rodents identified insulin action in the brain to regulate whole body energy homeostasis and metabolism as well as food intake and cognition. Translation into humans is much more complicated, since the brain is difficult to access. Administration of insulin as nasal spray allows selective stimulation of insulin action in the human brain. This tool enabled studies that demonstrated the ability of brain insulin to modulate peripheral insulin sensitivity, including suppression of endogenous glucose production, stimulation of peripheral glucose uptake and second phase insulin secretion from the pancreas. Of note, studies from our group as well as from others have shown sex-specific differences in brain insulin action. We recently observed that the menstrual cycle has a significant impact on brain insulin sensitivity in young, healthy and lean women. In addition, there is a close relationship between insulin sensitivity of the brain and body adiposity, and more importantly, body fat distribution. Insulin resistance in the brain, as often observed in obesity, is linked to an unhealthy body fat distribution pattern. Of note, insulin sensitivity is predictive for the success of lifestyle intervention and for subsequent development of body fat distribution over many years. The next step is to evaluate the therapeutic potential of treating brain insulin resistance. Recently, our group was able to show that brain insulin resistance is a modifiable condition, but a detailed understanding of the underlying mechanisms and brain-derived outflows to the periphery is still needed. We aim to use oral glucose tolerance tests to induce the dynamic nature of the postprandial period when direct signals in the organs and central inputs from the brain allocate energy fluxes in the body. This will be combined with the application of intranasal insulin in comparison to placebo spray. With this approach the major postprandial regulatory pathways can be addressed in an integrative manner to clarify to what extent brain insulin action contributes to the orchestration of postprandial signals. In detail, the contribution of the brain to the regulation of endogenous glucose production and glucose disappearance will be assessed as well as its impact on the secretion of incretins and insulin and the regulation of lipolysis. Post-absorptive energy expenditure and sex-specific differences will also be investigated. The results of the planned project will be the basis to elucidate the molecular mechanisms of this regulation further. Major regulatory pathways for postprandial metabolism will be subsequently addressed in diseased humans to clarify their potential contribution to the pathogenesis of diabetes and identify the most promising organs that could be targeted by novel therapies.

• DFG Programme: Research Grants