Clinical trial NCT03168295: PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2017-05-30
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Endogenous Glucose Production (EGP)
timeFrame: baseline and 240-300 minutes
Secondary outcomes:
measure: Change in Fasting Plasma Glucose
timeFrame: baseline and 240-300 minutes
measure: Change in Fasting Plasma Insulin
timeFrame: baseline and 240-300 minutes
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: The University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: The University of Texas Health Science at San Antonio
name: Ralph A DeFronzo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Daniele G, Solis-Herrera C, Dardano A, Mari A, Tura A, Giusti L, Kurumthodathu JJ, Campi B, Saba A, Bianchi AM, Tregnaghi C, Egidi MF, Abdul-Ghani M, DeFronzo R, Del Prato S. Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy. Diabetologia. 2020 Nov;63(11):2423-2433. doi: 10.1007/s00125-020-05254-w. Epub 2020 Aug 22.
citation: Solis-Herrera C, Daniele G, Alatrach M, Agyin C, Triplitt C, Adams J, Patel R, Gastaldelli A, Honka H, Chen X, Abdul-Ghani M, Cersosimo E, Del Prato S, DeFronzo R. Increase in Endogenous Glucose Production With SGLT2 Inhibition Is Unchanged by Renal Denervation and Correlates Strongly With the Increase in Urinary Glucose Excretion. Diabetes Care. 2020 May;43(5):1065-1069. doi: 10.2337/dc19-2177. Epub 2020 Mar 6.