Diabetes Mellitus, Type 1
Conditions
Brief summary
Inhibitors of sodium-dependent glucose-transporter 2 (SGLT-2 inhibitors, including dapagliflozin) inhibit glucose reabsorption in renal tubular cells, hereby increasing glycosuria in the hyperglycemic state. Its mechanisms of action are independent of insulin, which makes SGLT-2 inhibitors a potential adjunct to insulin in type 1 diabetes mellitus (T1DM). However, a higher risk for diabetic ketoacidosis (DKA) was reported in patients with T1DM taking SGLT-2 inhibitors. DKA depends on an accumulation of ketone bodies in the blood stream, which equals an accumulation of acids that lead to acidosis. The underlying mechanisms of this observation are unknown. Ketone body production depends on the molar ratio of glucagon to insulin, with insulin suppressing but glucagon stimulating ketone body production. This translates into higher production during relative insulin deficiency, carbohydrate deficiency, and prolonged fasting, which occurs during sickness but also physical exercise. Physical exercise is a recommended cornerstone in the treatment of T1DM and current treatment guidelines recommend both, reductions of insulin doses and ingestion of additional carbohydrates to avoid hypoglycemic events. These adaptions might increase relative insulin deficiency, hyperglycemia and glycaemic variability, which might in turn promote ketone body production. The addition of SGLT-2 inhibitors further may promote ketogenesis even though there are reports of SGLT-2 inhibitors increase Glucagon-like-peptide-1 (GLP-1) in patients with T1DM. GLP-1 is a suppressor of glucagon secretion. In summary, knowledge about the effects of SGLT-2 inhibition on ketone body production is scarce, especially during exercise in patients with T1DM. The study seeks to illustrate the effect of SGLT-2 inhibition on glycemic variability and ketone body production during and after recreational exercise in patients with T1DM. The results of study 2 will provide the basis for future studies investigating the underlying mechanisms of potentially modified ketone body production during and after exercise under SGLT-2 inhibition.
Interventions
DRUGForxiga 10mg
Dapagliflozin 10mg per 24 hours, oral, for 7 consecutive days
DRUGPlacebo
Placebo 1 tablet per 24 hours, oral, for 7 consecutive days
Sponsors
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Randomized, placebo-controlled, open-label, crossover
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Diagnosis of T1DM * Duration of T1DM \> 5 years * Male or female sex * Insulin therapy via multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) * Body mass index (BMI) between 20 and 29 kg/m2 * Adherence to sufficient contraceptive measures (double barrier method combining hormonal with mechanical barriers). * Ability to perform a 60 minutes exercise session at 50% VO2max.
Exclusion criteria
* Diagnosis of renal and/or hepatic dysfunction * History of malignancy of any kind * Intake of drugs influencing glucose homeostasis during the last three months * Alcohol or drug abuse * Inadequate vein status on both forearms * Active smoker * Known pregnancy, positive plasma beta human choriogonadotropine test prior to study inclusion or intention to become pregnant during the study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Amplitude of Glucose Excursions (MAGE) after physical exercise | From completion of physical exercise at day 7 of each intervention period to 72 hours after | MAGE will be calculated via sensor glucose measurements obtained over 72 hours after physical exercise |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the curve for glucagon-like peptide I before, during and after physical exercise | From time-point 0 to 120 minutes before, during and after physical exercise session | Glucagon-like peptide I will be measured at the beginning, during and after physical exercise following each intervention period |
| Area under the curve for glucagon before, during and after physical exercise | From time-point 0 to 120 minutes before, during and after physical exercise session | Glucagon will be measured at the beginning, during and after physical exercise following each intervention period |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area under the curve for ketone bodies before, during and after physical exercise | From time-point 0 to 120 minutes before, during and after physical exercise session | Ketone bodies will be measured at the beginning, during and after physical exercise |
| Area under the curve for free fatty acids bodies before, during and after physical exercise | From time-point 0 to 120 minutes before, during and after physical exercise session | Free fatty acids will be measured at the beginning, during and after physical exercise |
| Area under the curve for somatostatin before, during and after physical exercise | From time-point 0 to 120 minutes before, during and after physical exercise session | Somatostatin will be measured at the beginning, during and after physical exercise |
Countries
Switzerland
Outcome results
None listed