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

Study Overview
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Brief Summary
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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
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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.

Official Title
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SGLT2 INHIBITION AND STIMULATIION OF ENDOGENOUS GLUCOSE PRODUCTION Significance - PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Dapagliflozin 10mg then Placebo Oral Tablet
* Drug: Placebo Oral Tablet then Dapagliflozin 10mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Post renal transplant type 2 diabetes mellitus patients and non-diabetic mellitus patients after renal transplant with a control group of type 2 diabetes mellitus who have not undergone renal transplant
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo first and then dapagliflozin<br>Renal transplant subjects with intact native kidneys with Type 2 Diabetes Mellitus receive dapagliflozin then placebo | Drug: Dapagliflozin 10mg then Placebo Oral Tablet<br>* SGLT2 inhibitor - Dapagliflozin then Placebo<br>* Other names: Farxiga then placebo;Drug: Placebo Oral Tablet then Dapagliflozin 10mg<br>* Placebo then SGLT2 inhibitor - Dapagliflozin<br>* Other names: Placebo then Farxiga;|
| Active Comparator: Dapagliflozin first then placebo<br>Renal transplant subjects with intact native kidneys who are non-diabetic receive placebo then dapagliflozin | Drug: Dapagliflozin 10mg then Placebo Oral Tablet<br>* SGLT2 inhibitor - Dapagliflozin then Placebo<br>* Other names: Farxiga then placebo;Drug: Placebo Oral Tablet then Dapagliflozin 10mg<br>* Placebo then SGLT2 inhibitor - Dapagliflozin<br>* Other names: Placebo then Farxiga;|
| Other: Control Group<br>Subjects who are type 2 diabetes mellitus who have not undergone renal transplant. | Drug: Dapagliflozin 10mg then Placebo Oral Tablet<br>* SGLT2 inhibitor - Dapagliflozin then Placebo<br>* Other names: Farxiga then placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Endogenous Glucose Production (EGP) | 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. | baseline and 240-300 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Plasma Glucose | Change in Fasting Plasma Glucose in Type 2 Diabetes Mellitus subjects only | baseline and 240-300 minutes | 
| Change in Fasting Plasma Insulin | Change in Fasting Plasma Insulin in Type 2 Diabetes Mellitus subjects in diabetic subjects only | baseline and 240-300 minutes |