PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria

Phase 4

Completed

Interventions: Drug: Dapagliflozin 10mg then Placebo Oral Tablet
Drug: Placebo Oral Tablet then Dapagliflozin 10mg

Brief Summary: Purpose/Objectives: Examining the effect of SGLT2 inhibition on EGP and plasma glucose concentration in diabetic and non-diabetic subjects after kidney transplantation (i.e. renal denervation) or in subjects after renal sympathectomy (63) can add insight about the possible role of a neural arc which mediates the changes in plasma glucagon and/or insulin concentration in response to glucosuria.

Detailed Description: Purpose/Objectives: Examining the effect of SGLT2 inhibition on EGP and plasma glucose concentration in diabetic and non-diabetic subjects after kidney transplantation (i.e. renal denervation) or in subjects after renal sympathectomy (63) can add insight about the possible role of a neural arc which mediates the changes in plasma glucagon and/or insulin concentration in response to glucosuria.

Research Design/Plan: After screening, eligible subjects will receive 2 measurements of endogenous glucose production with a prime-continuous infusion of 3-3H-glucose. Each measurement will be performed on a separate day in random order after a 10-12 hour overnight fast and will last 8 hours (from 6 AM to 2 PM). After a 3-hour tracer equilibration period, each subject will receive one of the following medications in random order: (i) placebo and (ii) dapagliflozin 10 mg. Following the test medication at 9 AM, blood samples will be drawn every 20 minutes for an additional 5 hours and plasma glucose, insulin, C-peptide, glucagon, catecholamine concentrations and tritiated glucose sp act will be measured.

Methods: Visit 1: Screening Visit 2: Endogenous Glucose Production Measurement (EGP) Visit 3: After completing the first EGP measurement, subjects will return to the Diabetes Research Unit for the second study.

Recruitment & Eligibility

Inclusion Criteria

age = 18-70 years
BMI = 18.5-40 kg/m2
HbA1c ≥ 7.0% and ≤10.0% for type 2 diabetics
males or females
Must be at least 3 months post renal transplantation and be on a stable dose of prednisone (≤5 mg/day), tacrolimus, and mycophenolate mofetil
Not taking any antidiabetic medications or who are treated with metformin, sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor, thiazolidinedione or some combination
Must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis

Exclusion Criteria

Subjects who are taking insulin or SGLT2 inhibitor are excluded
Only subjects whose body weight has not been stable (± 3 lbs) over the preceding three months and/or who participate in an excessively heavy exercise program will be excluded.
Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine >1.4 females or >1.5 males (and eGFR <45ml/min.1.73m2), or 24-hour urine albumin excretion > 300 mg will be excluded.

Arm && Interventions

Group	Intervention	Description
Dapagliflozin first then placebo	Dapagliflozin 10mg then Placebo Oral Tablet	Renal transplant subjects with intact native kidneys who are non-diabetic receive placebo then dapagliflozin
Placebo first and then dapagliflozin	Dapagliflozin 10mg then Placebo Oral Tablet	Renal transplant subjects with intact native kidneys with Type 2 Diabetes Mellitus receive dapagliflozin then placebo
Placebo first and then dapagliflozin	Placebo Oral Tablet then Dapagliflozin 10mg	Renal transplant subjects with intact native kidneys with Type 2 Diabetes Mellitus receive dapagliflozin then placebo
Dapagliflozin first then placebo	Placebo Oral Tablet then Dapagliflozin 10mg	Renal transplant subjects with intact native kidneys who are non-diabetic receive placebo then dapagliflozin
Control Group	Dapagliflozin 10mg then Placebo Oral Tablet	Subjects who are type 2 diabetes mellitus who have not undergone renal transplant.

Primary Outcome Measures

Name	Time	Method
Change in Endogenous Glucose Production (EGP)	baseline and 240-300 minutes	Renal transplant subjects with native kidneys intact underwent measurement of EGP with an 8 hour infusion of 3-3H-glucose on 2 separate days with the administration in random order of either dapagliflozin 10mg or placebo after 3 hours of the tracer equilibration period. The equilibration at 3 hours was considered the baseline measurement. Measurement of change in endogenous glucose production was obtained for all subjects.

Secondary Outcome Measures

Name	Time	Method
Change in Fasting Plasma Glucose	baseline and 240-300 minutes	Change in Fasting Plasma Glucose in Type 2 Diabetes Mellitus subjects only
Change in Fasting Plasma Insulin	baseline and 240-300 minutes	Change in Fasting Plasma Insulin in Type 2 Diabetes Mellitus subjects in diabetic subjects only