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.

Inclusion Criteria:

• Fasting blood glucose between 100 and 125 mg/dl and/or 2-hour post load glucose between 140 and 199 mg/dl during a 75 g oral glucose tolerance test.
• Body mass index (BMI) between 25 and 40 kg/m².
• Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
• Ability to adhere to the study visit schedule and other protocol requirements.
• Females of childbearing potential (FCBP1) must agree
• to utilize two reliable forms of contraception simultaneously or practice complete abstinence from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 28 days after study treatment discontinuation and must agree to pregnancy testing during this timeframe
• to abstain from breastfeeding during study participation and 28 days after study drug discontinuation.
• Males must agree
• to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study, even if he has undergone a successful vasectomy
• to refrain from donating semen or sperm while participating in this study and for 28 days after discontinuation from this study treatment.
• All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
• All subjects must agree not to share medication.

Exclusion Criteria:

• Women during pregnancy and lactation.
• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal products. This includes empagliflozin, placebo and human insulin.
• Participation in other clinical trials or observation period of competing trials up to 30 days prior to this study.
• Diabetes mellitus
• Known malformation of the central nervous system
• Persons working nightshift
• Treatment with glucose lowering drugs, drugs with central nervous actions or systemic steroid therapy
• Any relevant (according to investigator's judgment) cardiovascular disease, e.g. myocardial infarction, acute coronary syndrome, unstable angina pectoris, Percutaneous transluminal coronary angioplasty (PTCA), heart failure (NYHA II-IV), stroke or transient ischemic attack (TIA), within 12 months prior to screening.
• Indication of liver disease, as per medical history or defined by serum levels of either Alanine Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (AST [SGOT]), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening.
• Alcohol abuse, defined as more than 20 gr/day
• Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min (MDRD formula) as determined during screening.
• Known structural and functional urogenital abnormalities, that predispose for urogenital infections.
• Subjects with a haemoglobin (Hb) ≤ 11.5 g/dl (for males) and Hb ≤ 10.5 g/dl (for females) at screening.
• Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption within the last 5 years.
• Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years.
• Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight.
• Known autoimmune disease (except autoimmune disease of the thyroid gland) or chronic inflammatory condition.
• Claustrophobia
• Any other clinically significant major organ system disease at screening such as relevant gastrointestinal, neurologic, psychiatric, endocrine (i.e. pancreatic), hematologic, malignant, infection or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult.
• Presence of any contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc.
• Refusal to get informed of unexpected detected pathological MRI findings

Any other clinical condition that would jeopardize subjects' safety while participating in this clinical trial.