Effect of Empagliflozin Versus Placebo on Brain Insulin Sensitivity in Patients With Prediabetes
Condition: PreDiabetes; Body Weight
MeSH terms: Insulin Resistance; Prediabetic State; Glucose Intolerance; Body Weight
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    


Intervention name(s): Empagliflozin 25mg; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): Once daily over 8 weeks; Once daily over 8 weeks
Intervention MeSH terms: Empagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science