Growth Factor/Insulin-like Growth Factor (GH/IGF)-1 Axis in Obese Subjects in Treatment With Orlistat
Condition: Obesity
MeSH terms: Obesity
Study type: Observational

Summary: 
      The beneficial effects on plasma lipids of Orlistat, a selective gastrointestinal lipase
      inhibitor, are largely independent of weight loss, and might include differential effects
      plasma non-esterified fatty acid (NEFA). Apart from their well-known effects on insulin
      resistance pathogenesis, elevated NEFA levels probably play also the most important role at
      peripheral levels in the pathogenesis of Growth Hormone (GH) insufficiency in obesity. Aim of
      this observational, mono-centre, randomized, simple-blind, cross-over study is to verify if
      the short-term treatment with Orlistat may results in decline in NEFA circulating levels when
      used in conjunction with low-fat diet and if this effect may restore the endogenous activity
      of GH/ Insulin-like growth factor (IGF)-1 axis, in the context of GH regulation of
      lipoprotein metabolism, thus adding a further benefit of Orlistat in obesity cross-linked
      neuroendocrine and metabolic dearrangement.
    

Detailed description: 
      Subjects:

      Twenty obese postmenopausal women (age: 53.6±6.2; BMI: 34.1±4.0. Subjects were recruited,
      evaluated, and monitored at the Endocrinology Unit of the Department of Molecular and
      Clinical Endocrinology and Oncology. Before starting the study, all subjects underwent an
      initial screening assessment including a medical history, physical examination, laboratory
      parameters, and body weight.

      Treatment protocol:

      At study entry plasma samples were obtained for fasting plasma glucose, insulin, lipaemia
      (total, HDL and LDL cholesterol, tryglycerides), GH, IGF-1, and IGFBP-3. The subjects were
      randomized in two groups of treatment: 10 subjects received normo-caloric diet plus +
      orlistat (Xenical, Roche, UK) at a dose of 120 mg tid; 10 subjects received normo-caloric
      diet without the additional treatment. The duration of follow-up was 10 days for each
      treatment period, without any wash-out between the two periods. Each patient has been
      assigned to each group. Dynamic testing performed at the end of each period were the
      following: glucose, and insulin after an OGTT; GH after GHRH + arginine (GHRH+ARG);
      post-prandial lipaemia after a standard fat-rich meal. During the study period, the subjects
      maintained their usual pattern of physical activity. Subjects and investigators remained
      unaware of laboratory results until the end of the study.

      Methods

      At baseline and at the end of each period of treatment, the following parameters were also
      measured:

        1. Anthropometric measurements, performed with the subjects wearing only underwear without
           shoes. Standing height was measured to the nearest cm using a wall-mounted stadiometer.
           Body weight was determined to the nearest 50 g using a calibrated balance beam scale.
           Body mass Index (BMI) was calculated as weight (kg) divided by height squared (m2) and
           used as an index for obesity. Measurements of the waist circumference, a measure of
           adipose tissue distribution and cardiovascular disease risk were taken at the mid-point
           between umbilicus and xiphoid.

        2. Body composition was determined by conventional Bioelectrical Impedance Analysis (BIA)
           and by Impedance Vector Analysis (BIVA). Resistance (R) and reactance (Xc) were measured
           by a single investigator with a single-frequency 50 kHz bioelectrical impedance analyzer
           (BIA 101 RJL, Akern Bioresearch, Firenze, Italy) according to the standard tetrapolar
           technique. All evaluations were performed by the same operator blind in respect to
           subjects treatment.

        3. Blood samples were obtained between 08:00 h and 09:00 h from antecubital vein after an
           overnight fast, with the patient in the resting position. Blood samples for hormonal
           determination were promptly centrifuged, and serum separated and stored at -20 C until
           assay. Blood glucose levels were determined by the glucose oxidase method immediately
           after the OGTT. The OGTT was performed using 75 g dextrose. Blood samples were obtained
           at 0, 30, 60, 90, 20, 150, and 180 minutes for plasma glucose and insulin measurements.
           The normal glycemic response to the OGTT was defined according to the criteria of the
           Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Total and
           HDL-cholesterol, and triglyceride concentrations were assayed in plasma by enzymatic
           colorimetric methods (Roche Molecular Biochemicals) on an autoanalyzer Cobas Mira (ABX
           Diagnostics). LDL-cholesterol was calculated using Friedewald formula. Changes in lipid
           profile was also analyzed by calculating the total/HDL cholesterol ratio. Plasma NEFA
           concentrations were analyzed by the enzymatic colorimetric method (Wako Chemicals).
           Serum insulin and c-peptide were measured by a solid-phase chemiluminescent enzyme
           immunoassay using commercially available kits (Immunolite Diagnostic Products Co, Los
           Angeles, CA, USA). The sensitivity of the assay were 0.1 and 0.3 ng/mL. The intra- and
           interassay coefficients of variations (CVs.) were 2.2 and 5.8%, respectively for insulin
           and 6.3 and 8.8%, respectively for c-peptide.

      The GHRH (1-29, Geref, Serono, Rome, Italy)+ ARG (arginine hydrochloride, Salf, Bergamo,
      Italy) was performed. The GH response after ARG+GHRH was classified as deficient (GHD) when
      the GH peak was <4.2 µg/L and sufficient (GHS) when the GH peak was >4.2 µg/L. Serum GH
      levels were measured by immunoradiometric assay (IRMA) using commercially available kits
      (HGH-CTK-IRMA, Sorin, Saluggia, Italy). The sensitivity of the assay was 0.02 µg/L. The
      intra- and interassay coefficients of variations (CVs.) were 4.5 and 7.9%, respectively.
      Circulating IGF-I levels measured by IRMA after ethanol extraction using Diagnostic System
      Laboratories Inc. (Webster, Texas, USA). The normal ranges in 31-40, 41-50 and 51-60 yr old
      women were 100-390, 96-288, 90-250 µg/l, respectively. The sensitivity of the assay was 0.8
      µg/l. The intra-assay CVs were 3.4, 3.0 and 1.5% for low, medium and high points of the
      standard curve, respectively. The inter-assay CVs were 8.2, 1.5 and 3.7% for low, medium and
      high points of the standard curve. For the purpose of this study, IGF-I levels were
      classified as normal when higher than -2 SD and deficient when it was lower than -2 SD. The
      IGFBP-3 assay had a sensitivity of 0•04 ng/l; the normal range for an adult female population
      of the same age range of our study population was 2.7-5.6 mg/L. The values for the molecular
      mass of IGF-I and IGFBP-3 used for the calculation were 7.649 kDa and 28.5 kDa,
      respectively.25 Post-prandial lipaemia was evaluated in the morning, after ≥ 12 h fasting,
      and over the 8 h following the standard meal (at 2, 4, 6 and 8) h. The standard meal
      consisted of a potato gateau (a pie made of mashed potato, whole milk, egg, cheese, ham and
      butter) which was consumed in 15-20 min. The meal, which provided 4090 kJ, was composed of
      34% carbohydrates, 51% fat (34% saturated fat) and 15% protein.
    

Intervention name(s): Orlistat; normo-caloric diet
Intervention type(s): Drug; Other
Intervention description(s): orlistat (Xenical, Roche, UK)120 mg tid; Food intake and dietary history were assessed by a skilled dietitian who used a computer-assisted interview (Winfood 1.5, Medimatica srl, Martinsicuro, Italy)
Other intervention name(s): gastrointestinal lipase inhibitor
Intervention MeSH terms: Orlistat
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        nondiabetic obese post-menopausal women
      
Keywords: obesity; GH/IGF-1 axis; postprandial NEFA