Preventing Renal Functional Abnormalities With Calorie Restriction in Subjects With Abdominal Obesity and Type 2 Diabetes at Increased Renal and Cardiovascular Risk
Condition: Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Obesity; Diabetes Mellitus, Type 2; Obesity, Abdominal
Study type: Interventional
Phase: Phase 2

Summary: 
      The study investigates whether a caloric restricted dietary regime can prevent onset and/or
      progression of chronic kidney disease in type 2 diabetic patients with abdominal obesity,
      through the amelioration of concomitant metabolic abnormalities such as insulin resistance,
      dyslipidemia, hypertension and inflammation, possible risk factors for the onset of kidney
      disease.

      The main aim of the study is therefore to evaluate the renoprotective effect of caloric
      restriction (CR) on subjects at risk of nephropathy. Secondary aim is to better understand
      how dietary implementation can modulate renal disease and its associated metabolic
      abnormalities.
    

Detailed description: 
      Background:

      Obesity is the major risk factor for type 2 diabetes, which in turn is associated with
      nephropathy in about one third of patients. Obesity is also an independent risk factor for
      chronic renal disease, regardless of the association with diabetes. Furthermore, chronic
      renal disease is the strongest risk factor for cardiovascular morbidity and mortality in
      people with diabetes and without. However, the mechanisms responsible for the adverse
      nephrologic effects of obesity and type 2 diabetes are not clear, but likely involve insulin
      resistance, low-grade systemic inflammation, hyperlipidemia, and increased synthesis of
      vasoactive and fibrogenic substances, including angiotensin II, insulin, leptin and
      transforming growth factor β1. These substances may individually or interactively affect
      glomerular hyperfiltration, renal venous pressure, mesangial cell hypertrophy and matrix
      production, ultimately leading to renal scarring, impaired glomerular filtration rate, micro-
      and macro- albuminuria and end-stage renal disease (ESDR). Of interest, the risk for
      glomerular hyperfiltration and hyperperfusion is enhanced especially in subjects with
      abdominal obesity. Both conditions predispose to microalbuminuria, an early marker of renal
      disease and increased cardiovascular risk.

      A growing body of evidence is now showing that calorie restriction (CR) improves many of the
      metabolic abnormalities associated with obesity and type 2 diabetes. In particular, it was
      recently demonstrated that long-term CR results in profound and sustained beneficial effects
      on the major atherosclerosis risk factors, serum Total cholesterol, Low density lipoprotein
      (LDL)-C, High density lipoprotein (HDL)-C, triglycerides, and blood pressure. CR also
      provides a powerful protective effect against obesity, insulin resistance, inflammation, as
      reflected in extremely low C reactive protein (CRP) levels and tumor necrosis factor
      (TNF)-alpha, and cardiovascular aging itself (i.e. left ventricular stiffness). We also found
      that long-term CR reduces serum concentrations of proinflammatory cytokines, triiodothyronine
      and growth factors such as platelet-derived growth factor (PDGF), and transforming growth
      factor (TGF)-beta-1, also factors actively involved in the progression of chronic kidney
      diseases. Taken together, these preliminary evidences suggest that CR might prevent renal
      function deterioration in diabetic, obese patients. However, this hypothesis has not been
      tested so far.

      Objectives:

        -  The major goal of this pilot, explorative study is to provide a comprehensive evaluation
           of the effects of CR on the pathophysiological mechanisms that may affect the onset and
           the progression of chronic kidney disease in subjects with abdominal obesity and type 2
           diabetes.

        -  Evaluate whether CR reduces the glomerular filtration rate (GFR) in subjects with
           abdominal obesity and type 2 diabetes, but still no evidence of renal disease [serum
           creatinine <1.2 mg/dL and albuminuria <20 μg/min (median of the 3 consecutive
           measurements in overnight urine collections)], and to assess whether CR reduces also
           kidney perfusion and/or filtration fraction, and whether these hemodynamic changes
           correlate with a concomitant reduction in urinary albumin excretion rate.

        -  Investigate the relationships between the changes in renal hemodynamics and/or
           albuminuria and the concomitant changes in abdominal circumference, body weight, body
           mass index, blood pressure, insulin sensitivity (as assessed by
           euglycemic-hyperinsulinemic clamp), serum lipids, adipokines levels (namely adiponectin,
           leptin), angiotensin II, and markers of chronic inflammation.

        -  Assess whether CR may reduce risk factors for cardiovascular disease (CVD) in diabetic,
           obese patients (insulin resistance, visceral obesity, hypertension).

      Design:

      After a baseline evaluation of clinical (blood pressure, body weight, abdominal
      circumference) and routine laboratory parameters, renal hemodynamics [glomerular filtration
      rate (GFR) and renal plasma flow (RPF) assessed by iohexol and PAH plasma clearances,
      respectively, and filtration fraction (FF) and renal vascular resistance (RVR) calculated by
      standard formulas], insulin sensitivity (estimated by euglycemic-hyperinsulinemic clamp),
      full lipid profile assessments, and urinary albumin excretion rate (mean of three
      measurements in three consecutive overnight urine collections), patients satisfying the
      selection criteria will be randomly allocated to either the CR intervention (25% CR) or an
      "ad libitum" diet (AL) for 6 months. The dietary guidelines for the calorie restricted diet
      will be based on the measurement of the individual food-intake diary and "resting metabolic
      rate" (RMR) (measured using indirect calorimetry) at baseline. CR will correspond to a
      calorie decrease by 25% as calculated from the baseline calorie intake measured with a 7-days
      food-intake diary and "RMR x activity levels" (activity levels will be calculated using the
      physical activity questionnaire). A food-intake diary will be provided with specific
      instruction by the Investigator (in written form). Baseline evaluations will be repeated
      every three months until the end of the study (except the renal hemodynamics studies and the
      euglycemic-hyperinsulinemic clamp that will be repeated only at month 6).
    

Intervention name(s): Caloric restriction; No intervention
Intervention type(s): Other; Other
Intervention description(s): Caloric restriction.; Diet "ad libitum"
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Caloric restriction; type 2 diabetes; abdominal obesity; renal disease