Effect of Empagliflozin Versus Placebo on Brain Insulin Sensitivity in Patients With Prediabetes

Recently, various sodium glucose cotransporter 2 (SGLT2) inhibitors have been approved for the treatment of type 2 diabetes mellitus. Empagliflozin is a preparation of this class of substances. SGLT2 inhibitors also lead to a reduction in body weight in addition to their blood glucose lowering effect. The basis for this is probably the calorie loss by the increased glucose excretion over the urine. However, this weight-reducing effect is lost after a few weeks of treatment and the body weight subsequently stabilizes at a lower level than before. However, patients continue to lose energy via the urine. Hence, the weight stabilization could be due to an increased energy intake as a possible consequence of a changed brain setpoint for the body weight. As the main weight loss is achieved during the first 6-8 weeks of treatment, the investigators assume that the underlying central nervous mechanisms will be present after this time.

Furthermore, clinical-experimental observations show that treatment with empagliflozin promotes endogenous glucose production in the liver. This presumably compensatory mechanism also occurs after only a few weeks of treatment. The common mechanism, which could be based both on energy intake and on the endogenous glucose production effect, is still unclear. The investigators suspect that regulatory circuits in the brain contribute to these observed effects.

In fact, several studies in animals as well as initial clinical studies in humans show that the brain is involved in eating behavior and peripheral metabolism. In particular, effects of the hormone insulin modulate the dietary intake via the brain, thereby affecting human body weight.

Many of the experiments on the insulin sensitivity of the human brain used a specific approach to the selective delivery of insulin into the brain: the application of insulin as a nasal spray. Although this application route has no therapeutic value, this technique allows the administration of insulin to the central nervous system with little effect on the circulating insulin levels. By combining nasal insulin administration with functional MRI, regional insulin sensitivity of the brain can be quantified. The investigators recently found that the insulin action of the brain (stimulated by nasal insulin) regulates both endogenous glucose production and peripheral glucose uptake during hyperinsulinemic euglycemic glucose clamps. The signals from the brain seem to reach the periphery via the autonomic nervous system in order to modulate metabolic processes. A central brain area in this regard is the hypothalamus. This brain region receives afferents over various systems such as the autonomic nervous system and various endocrine systems (including insulin). The investigators recently characterized the hypothalamus as an insulin-sensitive brain area in humans. The hypothalamus is the key area for homeostatic control throughout the body.

Since the dietary intake and the endogenous glucose production are modulated by a hypothalamic insulin effect in humans, we suspect that the observed effects of SGLT2 inhibitors on both processes could be due to altered insulin activity in the brain. Since the SGLT2 inhibition by empagliflozin modulates the autonomic nervous system in the kidneys, signals from the kidney may be transmitted to the brain via the autonomic nervous system, thereby changing specific setpoints, including e.g. insulin sensitivity of the brain.

In order to test this hypothesis, a precise phenotyping of prediabetic volunteers with regard to regional brain insulin sensitivity as well as the brain effect on metabolism before and after 8 weeks of treatment with empagliflozin compared to placebo is planned.