Study of Keto Acid (KA) on Insulin Resistance in Peritoneal Dialysis (PD) Patients
Condition: Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Interventional
Phase: Phase 3

Summary: 
      The overarching aim of this proposal is to examine the effects of usual protein diet
      supplemented with keto acid (KA) on insulin sensitivity in patients on peritoneal dialysis
      (PD). The investigators will achieve this goal through a randomized controlled trial of
      administration of usual protein diet plus KA versus usual protein diet alone in patients on
      peritoneal dialysis (PD) over a period of 6 months. If successful, the results of this study
      will provide potential avenues for improvement of metabolic profile of patients on PD and
      possibly improve long-term outcomes such as cardiovascular disease risk and death.
    

Detailed description: 
      Specific Aims and Significance:

      To evaluate the effects of KA plus usual protein diet on basal and stimulated insulin
      sensitivity in PD patients.

      Hypothesis: Administration of KA plus usual protein diet will improve insulin resistance in
      peritoneal dialysis patients.

      To evaluate the influence of KA plus usual protein diet on non-traditional cardiovascular
      disease (CVD) markers (markers of inflammation and oxidative stress) in PD patients.

      Hypothesis: Administration of KA plus usual protein diet will improve markers of inflammation
      and oxidative stress in PD patients.

      Background and Rationale:

      Insulin Resistance in Peritoneal Dialysis Patients. Insulin resistance (IR), the reciprocal
      of insulin sensitivity, describes a state of reduced biological effect for any given
      concentration of insulin in the plasma. Insulin resistance plays a major pathophysiological
      role in glucose intolerance and Type 2 diabetes mellitus (T2DM) and is tightly associated
      with major public health problems including obesity, hypertension, dyslipidemia, and
      atherosclerotic cardiovascular disease. Insulin resistance, measured by homeostatic model
      assessment (HOMA-IR), is reported to be common in chronic kidney disease (CKD) patients,
      including ones on PD and hemodialysis (HD). HOMA-IR is also shown to be an independent
      predictor of cardiovascular mortality in non-diabetic maintenance HD patients although the
      pathophysiological link has not been clearly delineated.

      A unique aspect of PD that predisposes patients to IR is the inevitable glucose load from the
      dialysate required for ultrafiltration. Consequently, the prevalence of metabolic syndrome
      such as hyperglycemia, dyslipidemia and weight gain is increased in PD patients. As an
      individual component of metabolic syndrome, IR is significantly higher in PD patients than in
      HD or pre-dialysis patients (47% vs 21% or 26%). Accordingly, improvement of IR could be a
      potential intervention to decrease the CVD risk and mortality in PD patients. However, only a
      few investigations have centered on interventions to ameliorate IR in these patients.

      Low Protein Diet Supplemented with Keto Acid as a Potential Strategy to Ameliorate Insulin
      Resistance in PD Patients. Several small scale studies exploring the effects of low protein
      diet (LPD) plus KA on glucose metabolism indicated that LPD-KA could improve liver and
      peripheral tissue insulin sensitivity in CKD patients not yet on maintenance dialysis. There
      are no studies exploring such effects in maintenance dialysis patients, especially in PD
      patients. One potential mechanism for the improvement in insulin resistance by KA is the
      reduction of circulating uremic toxins, although the specific elements are not well
      delineated. In addition, the supplementation of KA might be helpful since plasma total
      branched-chain amino acid concentrations correlate with glucose tolerance index in dialysis
      patients. Since the safety of LPD has not been entirely shown in previous studies for PD
      patients, and our data indicated that DPI < 0.74g/kg/d was harmful in the long-term PD, the
      investigators will not provide the LPD for improving the IR. However, the exploration of
      possible benefits of KA plus usual protein intake in PD patients on insulin sensitivity is
      intriguing.
    

Intervention name(s): Keto Acid
Intervention type(s): Drug
Intervention description(s): 12 tablets per day
Other intervention name(s): Compound α-Ketoacid Tablets
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Keto Acid; Peritoneal dialysis; Insulin resistance