The VALDIATE-D Study

This study aims to evaluate whether vitamin D receptor agonist therapy (calcitriol) in
diabetes lowers renin-angiotensin system (RAS) activity in a manner similar to an ACE
inhibitor. This is a physiology study, focused on evaluating hormonal changes in the
circulating and tissue RAS when compared to placebo.

Subjects with type 2 diabetes and obesity and normal kidney function will undergo evaluation
of their circulating and renal-vascular RAS activity and urinary protein at baseline, after
withdrawing interfering medications, while on a controlled electrolyte diet, and in
controlled posture settings. They will then randomly receive a study medication (calcitriol
or placebo) for 3 weeks followed by a re-assessment of their RAS parameters. The main
outcomes that will be evaluated following calcitriol/placebo include measures of the
circulating RAS (primary), as well as measures of the renal-vascular RAS, urine protein,
adipocytokine levels, and adipose-tissue RAS activity (secondary)

In an extension phase, Lisinopril will be added to the study drug for another 2 weeks
followed by another assessment of the primary and secondary outcome parameters, and subjects
will continue lisinopril+study drug for 3 additional months for one final assessment of RAS
parameters and urinary protein.

Inclusion Criteria:

1. Type-Two Diabetes (treated with diet alone, with oral hypoglycemic agents, or with a
single injection of basal insulin daily)

2. Normal blood pressure, or Mild (Stage 1) Hypertension that is either untreated, or
adequately treated with a single anti-hypertensive drug.

3. Age >18 years and <70 years

4. Estimated GFR > 60ml/min

5. Normal laboratory values for: Complete blood count, sodium, potassium, glucose, liver
enzymes, urinalysis

6. Electrocardiogram without any signs of prior infarction, ventricular conduction
abnormality, or supraventricular arrhythmia.

Exclusion Criteria:

1. Chronic Kidney Disease or eGFR<60

2. History of nephrolithiasis (kidney stones)

3. Multiple (more than one) insulin injections daily (since insulin can alter the RAS)

4. Poorly controlled type 2 diabetes (That may require more aggressive therapy) as
defined by an HbA1c>8.5%

5. Type 1 diabetes

6. Stage 2 or Stage 3 hypertension or the use of more than 1 antihypertensive drug

7. Chronic inflammatory conditions (such as inflammatory bowel disease or arthritis)
that are treated with prescribed doses of NSAIDs by a physician.

8. The use of prescribed doses of potassium supplements.

9. History of liver failure

10. History of parathyroid or granulomatous disorders

11. History of heart failure, cerebrovascular disease or coronary heart disease

12. History of known microvascular complications of diabetes (including retinopathy,
neuropathy, nephropathy)

13. Illness requiring overnight hospitalization in the past 6 months

14. Active tobacco or recreational drug use

15. Pregnancy or current breast feeding