AZ11040: Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin

• Sponsor: The University of Texas Health Science Center at San Antonio (Other)
• Overall Status: Completed
• CT.gov ID: NCT02984644
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 26.3
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

To determine the role of plasma glucagon and insulin in the rise of endogenous glucose production (EGP) following the SGLT2 inhibition.

Condition or Disease	Intervention/Treatment	Phase
Type II; Diabetes	Drug: Dapagliflozin; Drug: Placebo	Phase 3

Detailed Description

The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to glucosuria is (are) important signal(s) responsible, at least in part, for the increase in EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will account for the majority of increase in EGP in both NGT and T2DM subjects. This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of endogenous glucose production (EGP), which is the biosynthesis of new glucose, with administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose production (HGP), which is the net release of glucose from the liver, will be measured for 5 hours after drug administration to allow sufficient time for a significant increase in HGP above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for 5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin. Study 2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose concentration stable at each subject's fasting level). This study will define whether the decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin concentrations constant at the basal level). This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16 subjects will receive placebo. Each study will be performed on a separate day, after a 10-12 hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a renal (kidney) MRI-measurement to record kidney size.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (P2)
• Actual Study Start Date: Sep 6, 2017
• Actual Primary Completion Date: Nov 16, 2018
• Actual Study Completion Date: Nov 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dapagliflozin 32 subjects will receive dapagliflozin 10mg	Drug: Dapagliflozin; Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.; Other Names: Farxiga
Placebo Comparator: Placebo 16 subjects will receive placebo	Drug: Placebo; Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.; Other Names: Placebo for Dapagliflozin

Outcome Measures

Primary Outcome Measures

1. Measurement of the Change in Plasma Glucose (mg/dL): Study 1 [Baseline to 240-300 minutes]

   Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration

2. Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2 [Baseline to 240-300 minutes]

   Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)

3. Change in Plasma Glucose Using a Pancreatic Clamp: Study 3 [Baseline to 240-300 minutes]

   Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.

4. Change in EGP: Study 1 [Baseline to 240-300 minutes]

   Change from baseline to the last hour of the study (240-300 minutes) in EGP

5. Change in EGP With Glucose Clamp: Study 2 [Baseline to 240-300 minutes]

   Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)

6. Change in EGP With Pancreatic Clamp: Study 3 [Baseline to 240-300 minutes]

   Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.

Secondary Outcome Measures

1. Change in Plasma Insulin Concentrations: Study 1 [Baseline to 240-300 minutes]

   Plasma insulin concentrations during measurement of EGP

2. Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2 [Baseline to 240-300 minutes]

   Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)

3. Change in Plasma Insulin While Using Pancreatic Clamp: Study 3 [Baseline to last hour of the study]

   Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.

4. Change in Glucagon: Study 1 [Baseline to 240-300 minutes]

   Change in glucagon concentrations during measurement of EGP

5. Change in Glucagon Using Glucose Clamp: Study 2 [Baseline to 240-300 minutes]

   Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.

6. Change in Glucagon Using Pancreatic Clamp: Study 3 [Baseline to 240-300 minutes]

   Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• T2DM according to ADA criteria-HbA1C < 8.0%

• BMI = 25-35 kg/m2

• Subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis

• Body weight has been stable (± 3 lbs) over the preceding three months

• Do not participate in an excessively heavy exercise program

• Taking stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea

Exclusion Criteria:

• Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea) will be excluded

• Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine

1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg will be excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Health Science Center	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• The University of Texas Health Science Center at San Antonio

Investigators

• Principal Investigator: Eugenio Cersosimo, MD,PhD, The University of Texas Health Science Center at San Antonio

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 18, 2017

More Information

Publications

None provided.

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT02984644
• Other Study ID Numbers: HSC20160586H
• First Posted: Dec 7, 2016
• Last Update Posted: Dec 18, 2019
• Last Verified: Nov 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.	Subjects will receive placebo Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
Period Title: Overall Study
STARTED	20	10
COMPLETED	20	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Dapagliflozin	Placebo	Total
Arm/Group Description	Subjects will receive dapagliflozin 10mg Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.	Subjects will receive placebo Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.	Total of all reporting groups
Overall Participants	20	10	30
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55 (2)	53 (2)	54 (2)
Sex: Female, Male (Count of Participants)
Female	8 40%	3 30%	11 36.7%
Male	12 60%	7 70%	19 63.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	13 65%	5 50%	18 60%
Not Hispanic or Latino	7 35%	5 50%	12 40%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Hispanic	12 60%	4 40%	16 53.3%
Caucasian	7 35%	2 20%	9 30%
African American	1 5%	2 20%	3 10%
Region of Enrollment (participants) [Number]
United States	20 100%	10 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Measurement of the Change in Plasma Glucose (mg/dL): Study 1
Description	Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)	Change in plasma glucose concentration after placebo administration
Measure Participants	20	10
Mean (Standard Deviation) [mg/dl]	-29 (4)	-17 (3)

2. Primary Outcome

Title	Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2
Description	Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production) using a glucose clamp	Change in plasma glucose concentration after placebo administration using a glucose clamp
Measure Participants	20	10
Mean (Standard Deviation) [mg/dl]	3 (1)	1 (1)

3. Primary Outcome

Title	Change in Plasma Glucose Using a Pancreatic Clamp: Study 3
Description	Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Change in plasma glucose concentration to show effect of Dapagliflozin on plasma glucose concentration	Change in plasma glucose concentration after placebo administration
Measure Participants	20	10
Mean (Standard Deviation) [mg/dl]	-30 (4)	-7 (5)

4. Primary Outcome

Title	Change in EGP: Study 1
Description	Change from baseline to the last hour of the study (240-300 minutes) in EGP
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.	Subjects will receive placebo Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
Measure Participants	20	10
Mean (Standard Deviation) [mg/kg.min]	0.10 (0.1)	-0.56 (0.11)

5. Primary Outcome

Title	Change in EGP With Glucose Clamp: Study 2
Description	Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Change in EGP (endogenous glucose production) after dapagliflozin administration	Change in EGP concentration after placebo administration
Measure Participants	20	10
Mean (Standard Deviation) [mg/kg.min]	-0.57 (0.12)	-1.28 (0.172)

6. Primary Outcome

Title	Change in EGP With Pancreatic Clamp: Study 3
Description	Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Change in EGP (endogenous glucose production) after dapagliflozin administration using a pancreatic clamp	Change in EGP concentration after placebo administration using a pancreatic clamp
Measure Participants	20	10
Mean (Standard Deviation) [mg/kg.min]	-0.23 (0.09)	-0.48 (0.05)

7. Secondary Outcome

Title	Change in Plasma Insulin Concentrations: Study 1
Description	Plasma insulin concentrations during measurement of EGP
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg. Change in plasma insulin level is measured at baseline minus the last hour of the study.	Subjects will receive placebo. Change in plasma insulin level is measured at baseline minus the last hour of the study.
Measure Participants	20	10
Mean (Standard Deviation) [microUnits/mL]	5 (1)	3 (1)

8. Secondary Outcome

Title	Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2
Description	Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg. Change in plasma insulin level is measured at baseline minus the last hour of the study while using glucose clamp.	Subjects will receive placebo. Change in plasma insulin level is measured at baseline minus the last hour of the study while using glucose clamp.
Measure Participants	20	10
Mean (Standard Deviation) [microUnits/mL]	0 (1)	0 (1)

9. Secondary Outcome

Title	Change in Plasma Insulin While Using Pancreatic Clamp: Study 3
Description	Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Time Frame	Baseline to last hour of the study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg. Change in plasma insulin level is measured at baseline minus the last hour of the study while using pancreatic clamp.	Subjects will receive placebo. Change in plasma insulin level is measured at baseline minus the last hour of the study while using pancreatic clamp.
Measure Participants	20	10
Mean (Standard Deviation) [microUnits/mL]	2 (1)	0 (1)

10. Secondary Outcome

Title	Change in Glucagon: Study 1
Description	Change in glucagon concentrations during measurement of EGP
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg. Change in plasma glucagon level is measured at baseline minus the last hour of the study.	Subjects will receive placebo. Change in plasma glucagon level is measured at baseline minus the last hour of the study.
Measure Participants	20	10
Mean (Standard Deviation) [ng/ml]	5 (2)	-1 (2)

11. Secondary Outcome

Title	Change in Glucagon Using Glucose Clamp: Study 2
Description	Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a glucose clamp.	Subjects will receive placebo. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a glucose clamp.
Measure Participants	20	10
Mean (Standard Deviation) [ng/ml]	-6 (2)	-7 (3)

12. Secondary Outcome

Title	Change in Glucagon Using Pancreatic Clamp: Study 3
Description	Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
Time Frame	Baseline to 240-300 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin	Placebo
Arm/Group Description	Subjects will receive dapagliflozin 10mg. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a pancreatic clamp.	Subjects will receive placebo. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a pancreatic clamp.
Measure Participants	20	10
Mean (Standard Deviation) [ng/ml]	-1 (1)	-2 (2)

Adverse Events

Time Frame	On each study day: Study start at 6am until study ends at 2pm.
Arm/Group Title	Dapagliflozin		Placebo
Arm/Group Description	20 subjects will receive dapagliflozin 10mg Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.		10 subjects will receive placebo Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
All Cause Mortality
	Dapagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/10 (0%)
Serious Adverse Events
	Dapagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Dapagliflozin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.