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| Name | Class |
|---|---|
| Eli Lilly and Company | INDUSTRY |
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In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and in response to ingestion of glucose or a mixed meal.glucagon, glucagon concentrations fail to decrease appropriately and may even increase. This diabetic hyperglucagonaemia may therefore contribute importantly to the hyperglycaemia of the patients.
Several glucose-lowering treatment modalities have been shown to affect glucagon levels in patients with type 2 diabetes, but the role of glucagon in the glucose-lowering effects of these treatment modalities has been difficult to discern. By using a glucagon receptor antagonist (GRA) the investigators will exploit glucagon receptor antagonism to delineate the role of glucagon during treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to increase and decrease plasma glucagon levels, respectively.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A1: GRA-placebo + MEAL + DPP4-placebo | Placebo Comparator | LY2409021 placebo + 4 hour standardised liquid mixed-meal test + linagliptin placebo |
|
| A2: GRA-active + MEAL + DPP4-placebo | Placebo Comparator | 300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + linagliptin placebo |
|
| A3: GRA-placebo + MEAL + DPP4-active | Active Comparator | LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta) |
|
| A4: GRA-active + MEAL + DPP4-active | Active Comparator | 300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 5 mg linagliptin (Trajenta) |
|
| B1: GRA-placebo + MEAL + SGLT2-placebo | Placebo Comparator | LY2409021 placebo + 4 hour standardised liquid mixed-meal test + empagliflozin placebo |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LY2403021 | Drug | Glucagon receptor antagonist |
|
| Measure | Description | Time Frame |
|---|---|---|
| Difference in postprandial glucose excursions (linagliptin) | Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values). | Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with linagliptin (A1, A2, A3, A4) |
| Difference in postprandial glucose excursions | Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve | Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with empagliflozin (B1, B2, B3, B4) |
| Measure | Description | Time Frame |
|---|---|---|
| Endogenous glucose production | Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique. | Plasma concentration of 6,6^2 H2-glucose and U-13C^6-glucose at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes. |
| Lipolysis |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Diabetes Research, Gentofte Hospital, Copenhagen University | Hellerup | DK-2900 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33004472 | Derived | Haedersdal S, Lund A, Nielsen-Hannerup E, Maagensen H, van Hall G, Holst JJ, Knop FK, Vilsboll T. The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition. Diabetes. 2020 Dec;69(12):2619-2629. doi: 10.2337/db20-0369. Epub 2020 Oct 1. | |
| 32994273 | Derived | Cox AR, Chernis N, Bader DA, Saha PK, Masschelin PM, Felix JB, Sharp R, Lian Z, Putluri V, Rajapakshe K, Kim KH, Villareal DT, Armamento-Villareal R, Wu H, Coarfa C, Putluri N, Hartig SM. STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity. Diabetes. 2020 Dec;69(12):2630-2641. doi: 10.2337/db20-0384. Epub 2020 Sep 29. |
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|
| B2: GRA-active + MEAL + SGLT2-placebo | Placebo Comparator | 300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + empagliflozin placebo |
|
| B3: GRA-placebo + MEAL + SGLT2-active | Active Comparator | LY2409021 placebo + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance) |
|
| B4: GRA-active + MEAL + SGLT2-active | Active Comparator | 300 mg LY2409021 + 4 hour standardised liquid mixed-meal test + 25 mg empagliflozin (Jardiance) |
|
| LY2403021 placebo | Drug |
|
| Standardised liquid meal | Procedure |
|
| Linagliptin | Drug | DPP-4-inhibitor |
|
|
| Linagliptin placebo | Drug |
|
| Empagliflozin | Drug | SGLT2-inhibitor |
|
|
| Empagliflozin placebo | Drug |
|
Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique. |
| Plasma concentration of 1,1,2,3,3-^2-H5 - glycerol measured at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes. |
| Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1. | : 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes |
| Appetite | Appetite will be evaluated with a visual analogue scale (VAS). | VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes. |
| Energy intake (kcal/kJ) | At the end of the standardised liquid meal test, food intake will be examined with an ad libitum meal. The weight of the food will be measured in grams and calculated to the energy intake in kcal/kJ | At time 240 to 270, the participants will eat an ad libitum meal. |
| Changes in blood pressure (mmHg) | Measured at time 0 and time 210 minutes. |
| Changes in pulse rate (beat per minute) | Measured at time 0 and at time 210 minutes. |
| Differences in gastric emptying | Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC) | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes |
| Free fatty acids | Serum values of free fatty acids | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes |
| Plasma Fibroblast growth factor-21 | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes |
| Resting energy expenditure | Resting energy expenditure evaluated by 10 minutes of indirect calorimetry. | -60 to -50 and 35 to 45 |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000069476 | Linagliptin |
| C570240 | empagliflozin |
| ID | Term |
|---|---|
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011799 | Quinazolines |
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