Study of Keto Acid (KA) on Insulin Resistance in Peritoneal Dialysis (PD) Patients

• Insulin resistance [ Time Frame: at 0, 12, 24 week after patients start their study prescription ] [ Designated as safety issue: Yes ]
  Insulin sensitivity will be measured at basal and stimulated states using HOMA-IR in all subjects and hyperinsulinemic euglycemic clamp in a select group of patients.
  
  

• Oxidative stress [ Time Frame: at 0, 12, 24 week after patients start their study prescription ] [ Designated as safety issue: Yes ]
  Oxidative stress will be assessed by Plasma F2-isoprostanes which will be measured by GC-MS.
  
  
• Inflammatory state [ Time Frame: at 0, 12, 24 week after patients start their study prescription ] [ Designated as safety issue: Yes ]
  Inflammatory state will be assessed by C-reactive protein and pro-inflammatory cytokine levels (IL-6, IL-1 and IL-10) using the automated Abbott FLX.
  
  

Specific Aims and Significance:

To evaluate the effects of KA plus regular protein diet on basal and stimulated insulin sensitivity in PD patients.

Hypothesis: Administration of KA plus regular protein diet will improve insulin resistance in peritoneal dialysis patients.

To evaluate the influence of KA plus regular protein diet on non-traditional cardiovascular disease (CVD) markers (markers of inflammation and oxidative stress) in PD patients.

Hypothesis: Administration of KA plus regular 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 regular protein intake in PD patients on insulin sensitivity is intriguing.