Mechanisms Underlying Metabolic Syndrome in Obesity
Condition: Metabolic Syndrome; Insulin Resistance; Prediabetes
MeSH terms: Obesity; Metabolic Syndrome; Insulin Resistance; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to better understand the link between obesity and diabetes or
      pre-diabetes.
    

Detailed description: 
      Obesity is the most common and powerful force for creating insulin resistance and metabolic
      syndrome, however, the molecular basis of this association is not well understood. In this
      proposal, three independently funded researchers-Philip Kern, MD a clinical investigator, and
      Charlotte Peterson, PhD and Robert McGehee, PhD, with significant experience in muscle and
      adipocyte biology, respectively-will formalize a collaborative effort as a natural extension
      of previous work and shared interests in the fields of obesity, insulin resistance, and
      tissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems
      largely from ectopic accumulation of intramyocellular lipid (IMCL) during the development of
      obesity. Further, we hypothesize that excess IMCL accumulation is dependent on secretory
      proteins derived from a complex interplay between adipocytes and macrophages in adipose
      tissue. To test these hypotheses, we will examine the interactions among adipocytes,
      macrophages, and muscle cells isolated and cultured from subjects that are obese with insulin
      resistance and impaired glucose tolerance (IGT), and from some with Type 2 Diabetes. This
      study population has elevated IMCL and is at high risk for obesity complications, but avoids
      the pathophysiologic complications of glucotoxicity. These subjects will be compared to obese
      subjects with normal glucose tolerance (NGT).

      Aim 1 will explore mechanisms that contribute to IMCL and elucidate its role in the
      development of IGT. Cultured muscle cells will be used to determine whether obese subjects
      with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic
      activity under differing extracellular fatty acid concentrations. Lipid accumulation and
      oxidation, and insulin-mediated glycogen synthesis and signaling will be assessed.

      Aim 2 will determine if the IMCL accumulation is dependent on adipose tissue secretory
      proteins. We will use co-cultures of adipocytes, myoblasts, and adipose stromal vascular
      cells to examine IMCL and the development of insulin resistance.

      Aim 3 will determine whether the stromal fraction from IGT subjects promotes IMCL more
      effectively than that from NGT subjects in co-cultures with muscle cells. We will compare the
      stromal vascular fractions with regard to monocyte/macrophage accumulation and cytokine
      expression.

      Aim 4 will determine if improved glucose tolerance in response to a 10-week treatment with
      pioglitazone results in decreased IMCL and identify cellular mechanisms involved. Co-culture
      studies will also be used with muscle and stromal cells, before and after pioglitazone
      treatment. These experiments will provide mechanistic insight into the link between obesity
      and muscle function leading to metabolic syndrome.
    

Intervention name(s): Pioglitazone
Intervention type(s): Drug
Intervention description(s): Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.
Other intervention name(s): Actos
Intervention MeSH terms: Pioglitazone
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: obesity; inflammation; diabetes