Impaired Adipogenesis in Insulin Resistance: Pilot Clinical and In Vitro Studies
Condition: Adipocyte Differentiation; Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Observational

Summary: 
      Obesity is a strong risk factor for developing type 2 diabetes (T2DM), but the reasons for
      this are not fully understood. In particular, it is not known why some obese people develop
      T2DM while other obese individuals do not. This study tests whether differences in fat cells
      (adipocytes) are to blame. Even in adults, fat cells are constantly being formed to replace
      old fat cells and to respond to the body's need to store excess energy. The ability to form
      new fat cells may be diminished in some individuals, leading to larger fat cells. These large
      fat cells secrete hormones that may increase risk for T2DM. This study tests whether fat
      cells from obese insulin resistant subjects (who are at risk for developing T2DM) form at a
      slower rate than those from insulin sensitive subjects (who are at lower risk for developing
      T2DM).

      To address this question we will recruit and study two groups of obese subjects, selected to
      be similar in age, gender and degree of obesity. One group of subjects will be obese and
      insulin resistant (the OIR group), while the other will be comparably obese, but insulin
      sensitive (OIS). Subjects will undergo a series of studies to characterize their metabolism
      including measurement of body fat by DEXA scanning, oral glucose tolerance (a test used to
      diagnose diabetes) and measurement of insulin sensitivity in response to an infusion of
      insulin (a research study used to classify patients into the OIR and OIS groups). Small
      samples of fat (from just under the skin of the belly and the buttocks) will obtained using a
      needle on two occasions over 12 weeks. During these 12 weeks, subjects will drink a small
      amount of water that contains a non-radioactive label. This labeled water will allow us to
      measure the rate of growth of new fat cells in the body. We will also look at the rate of
      growth of fat cells obtained from these biopsies in the laboratory.

      The results of this study may tell us more about why certain obese people develop diabetes
      and why others do not. This might lead to new ways to prevent or treat T2DM.
    

Detailed description: 
      Overview of design: To address the specific aims of this study we will recruit and study two
      groups of obese subjects, selected to be similar in age, gender and BMI. Based on the results
      of an oral glucose tolerance test (OGTT) and hyperinsulinemic-glucose clamp, one group will
      be obese and insulin resistant (OIR) and one will be obese and insulin sensitive (OIS).
      Subjects will undergo measurement of body fat and fat distribution, oral glucose tolerance,
      in vivo insulin sensitivity, percutaneous needle biopsies of subcutaneous abdominal and
      gluteal fat and in vivo measurement of SVC and adipocyte turnover using the D2O DNA labeling
      technique. Adipocyte size and the expression of pro-inflammatory cytokines and adipokines
      will be compared in the two groups. Primary cultures of preadipocytes will be derived from
      subjects and proliferation and differentiation measured in vitro and compared to in vivo
      measures.

      Measurement of adipocyte proliferation and differentiation in vivo: The stable isotope
      technique of Hellerstein et al. for the measurement of slowly dividing cells is based on the
      incorporation of deuterium oxide (D2O) into DNA. This method has been used to estimate rates
      of turnover of adipocytes and stromal vascular cells in healthy normal volunteers. It has
      not, to date, been employed to compare groups of subjects who may differ in their adipogenic
      propensity. A major objective of the study, therefore, is to evaluate the utility of this
      approach for quantifying in vivo differences in adipocyte and SVC turnover between groups
      that vary by insulin sensitivity and to compare the in vivo measures obtained using this
      technique with in vitro measures of adipogenesis.
    

Intervention name(s): Administration of 70% deuterated water
Intervention type(s): Other
Intervention description(s): Subjects will drink 70% deuterated water daily for 8 weeks.
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Community sample
      
Biospecimen description: 
      Adipose tissue, plasma
    
Keywords: Adipokines; Inflammation; Metabolic syndrome