Inhibitors of sodium-dependent glucose-transporter 2 (including dapagliflozin) represent intensively investigated drugs in the field of diabetes. SGLT-2 inhibition limits glucose reabsorption in renal tubular cells, hereby increasing the amount of glucose excreted via urine in the hyperglycemic state. Its mechanisms of action are independent of insulin, the indispensable standard of care in Type 1 Diabetes (T1D). Several international diabetes experts highlighted the need for adjunct therapies in T1D. Subcutaneous application of insulin is non-physiological. Most significant, subcutaneous insulin substitution does not address the bi-hormonal character of T1D. The loss of pancreatic beta cells and subsequent endogenous insulin production uncouples alpha cell derived glucagon secretion from its paracrine suppressor. Consequently, excess glucagon concentrations occur in the fasting and the postprandial state, which promotes hyperglycemia, requires higher doses of subcutaneous insulin, and promotes glycaemic variability. Recent studies on SGLT-2 inhibition in T1D showed better glycemic control compared to placebo, whereas a higher risk for the development of diabetic ketoacidosis was observed. Knowledge about the underlying mechanisms is scarce. Studies showed that SGLT-inhibition increased Glucagon-like-peptide 1 (GLP-1) in T1D, an incretin hormone capable of suppressing glucagon. On the other side, total concentrations of ketone bodies were higher following SGLT-2 inhibition, irrespective of ongoing subcutaneous or intravenous insulin substitution. The present study aims to investigate the effect of SGLT-2 inhibitor dapagliflozin on hormonal regulators of glucose homeostasis and ketogenesis in T1D. The primary endpoint is the difference of GLP-1 during oral glucose tolerance test clamps (OGGTc). Secondary endpoints comprise total ketone body concentrations, free fatty acids, glucagon, and somatostatin during OGTTc and hyperinsulinemic, euglycemic clamps (HEC) following dapagliflozin and placebo. The study recruits male and female patients with T1DM in a randomized, open label, cross-over intervention study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
13
Forxiga™ 10mg, dapagliflozin 10mg, oral, once daily for 7 days (70 mg total)
Placebo tablets, starch, oral, once daily for 7 days (7 tablets total)
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Bern, Switzerland
Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
Glucagon-like peptide I will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
Glucagon-like peptide I will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: During visit 3 (day 7): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Area under the curve for glucagon-like peptide I in oral glucose tolerance test clamp
Glucagon-like peptide I will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: During visit 5 (day 31): From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Area under the curve for glucagon-like peptide I in euglycemic, hyperinsulinemic clamp
Glucagon-like peptide I will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Area under the curve for ketone body concentrations in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Ketone bodies will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Area under the curve for ketone body concentrations in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Ketone bodies will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Area under the curve for free fatty acids in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Free fatty acids will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Area under the curve for free fatty acids in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Free fatty acids will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Area under the curve for glucagon in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Glucagon will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Area under the curve for glucagon in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Glucagon will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
Area under the curve for somatostatin in euglycemic, hyperinsulinemic clamp following dapagliflozin compared with placebo
Somatostatin will be measured in euglycemic, hyperinsulinemic clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during euglycemic, hyperinsulinemic clamp, measurement every 15 minutes
Area under the curve for somatostatin in oral glucose tolerance test clamp following dapagliflozin compared with placebo
Somatostatin will be measured in oral glucose tolerance test clamp following dapagliflozin and will be compared with concentrations measured following placebo. Active and inactivated glucagon like peptide I will be measured.
Time frame: From time-point 0 to 120 minutes during oral glucose tolerance test clamp, measurement every 15 minutes
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