Renal and Peripheral Hemodynamic Function in Patients With Type 1 Diabetes Mellitus
Renal and Peripheral Hemodynamic Function in Patients With Type 1 Diabetes Mellitus
Protein kinase C (PKC), an enzyme in the body, has been implicated in the process of diabetic
 microvascular complications. The purpose of this study will be to evaluate the renal
 hemodynamic and peripheral vascular effects of PKC inhibition with ruboxistaurin mesylate (an
 inhibitor of PKC) in patients with Type 1 diabetes mellitus and evidence of early
 nephropathy. In this pilot study, 21 patients with type 1 diabetes were planned to be
 randomized to LY333531 or placebo in a 2:1 fashion, after an initial period of testing. After
 8 weeks of study drug, patients were retested.
This is a pilot study with 3 parts. Twenty-one patients with type 1 diabetes will be
 randomized to LY333531 or placebo in a 2:1 fashion. Each patient will be studied on four
 occasions, while euglycemic and while hyperglycemic without PKC inhibition and while
 euglycemic and hyperglycemic after an eight-week period of PKC inhibition.

 Study Part 1: The impact of PKC inhibition on the renal and peripheral hemodynamic response
 to hyperglycemia On the evening prior to the first study day, the study participants will be
 admitted to an in-patient research facility with overnight plasma glucose levels maintained
 at 4-6 mmol/L using a modified glucose clamp technique. The next day, baseline measures of
 endothelial function and vascular compliance, mean arterial pressure (MAP), and renal
 function, including glomerular filtration rate (GFR), effective renal plasma flow (ERPF),
 renal blood flow (RBF), filtration fraction (FF) and renal vascular resistance (RVR) will be
 obtained using inulin and para-aminohippurate. In all diabetic subjects, euglycemia or
 hyperglycemia will be maintained by modified overnight glucose clamping techniques. During
 the second day of the study, capillary blood glucose will be maintained at 9-11 mmol/l
 overnight, and the renal and peripheral vascular hemodynamic measurements will be repeated
 the following day. The subjects will then be given the PKC-inhibitor LY333531 (or placebo)
 for 6 weeks, after which the study will be repeated. The first dose of LY333531 will be taken
 at 0800 hrs the day after the completion of Study 1 The dose will consist of 32 mg PO OD.
 Study participants will monitor their capillary blood glucose levels on a four times daily
 schedule.

 Study Part 2: The impact of PKC inhibition on the response to Ang II On the evening prior to
 the first study day, the study participants will be admitted to an in-patient research
 facility with overnight plasma glucose levels maintained at 4-6 mmol/L using a modified
 glucose clamp technique. The next day, baseline measures of renal function, including GFR,
 ERPF, RBF, FF and RVR will be obtained. Graded Ang II infusion will be administered, and the
 response of MAP, GFR, RPF, RBF, FF and RVR will be measured. The subjects will then be given
 the PKC-inhibitor LY333531 (or placebo) for 8 weeks, as previously described, after which the
 study will be repeated.

 Study Part 3: The impact of PKC inhibition on proteinuria . Subjects will collect a 24 hour
 urine sample for protein / albumin excretion. They will subsequently be randomized to receive
 either the PKC inhibitor LY333531 or placebo, using a table of random numbers. After 8 weeks
 treatment, the 24 hour urine sample will again be collected.
Inclusion Criteria:

 -  have type 1 diabetes mellitus

 -  hemoglobin A1C between 6 and 10%

 -  have evidence of early diabetic renal disease as determined by creatinine clearance
 more than 80 ml/minute, urine albumin to creatinine ratio of more than 3.0 and urinary
 albumin levels consistent with the diagnosis of diabetic nephropathy (more than 20
 mg/mmol for men and more than 28 mg/mmol for women)

 -  are without language barrier, cooperative, expected to return for all follow-up
 visits, and who give informed consent before entering the study's randomization phase
 and after being informed of the study medications and procedures.

 Exclusion Criteria:

 -  Have poorly controlled diabetes, chronic liver disease, clinical jaundice, and/or
 elevation of liver-related laboratory results, have chronic renal failure on dialysis,
 have received a kidney transplant or have a moderate to severe kidney disease, have
 previous history of myocardial infarction, stroke, claudication or amputation, have
 cancer and are currently receiving chemotherapy or plan to receive chemotherapy in the
 next 6 months and woman of childbearing potential despite actively practicing birth
 control by using a medically accepted device or therapy.

 -  are being treated or intending to start treatment during the trial with excluded
 drugs: topical or oral carbonic anhydrase inhibitors and require more than 2 weeks of
 treatment with drugs known to strongly inhibit cytochrome P450 3A4 (CYP3A4), including
 but not limited to, delavirdine, fluconazole, itraconazole, indinavir, ketoconazole
 mibefradil, nelfinavir, ritonavir, and saquinavir.

 -  consume alcohol, tobacco and nicotine products within 48 hours before the study and
 have any condition that, in the investigator's opinion, would preclude meaningful
 participation in the study, including, but not limited to, abnormal laboratory values
 the investigator considers clinically significant, patients who are poor medical or
 psychiatric risks for treatment with an investigational drug, patients who are
 unlikely to complete the study.

 -  suspected or proven to have a kidney disease other than diabetic related albuminuria
 and/or renal insufficiency.