Effect of Pioglitazone and Exenatide on Body Weight and Beta Cell Function
Condition: Type 2 Diabetes; Healthy; Impaired Glucose Tolerance
MeSH terms: Diabetes Mellitus, Type 2; Glucose Intolerance; Body Weight
Study type: Interventional
Phase: Phase 4

Summary: 
      Pioglitazone, a drug used in treatment of type 2 diabetes has been shown to improve insulin
      sensitivity in skeletal muscle, liver, and fat cells. Despite the beneficial effects of
      pioglitazone to improve insulin sensitivity and reduce cardiovascular disease in high risk
      type 2 diabetic patients, weight gain has been a limiting factor. Exenatide, another agent
      used for treatment of T2DM, improves glycemic control and promotes moderate weight loss. In
      this proposal we will examine the effect of combination therapy with pioglitazone plus
      exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma
      lipid levels in subjects with type 2 diabetes mellitus compared to treatment with each drug
      separately. Assessment of beta cell function will be performed by measuring the maximal
      insulin secretory capacity using a maximal hyperglycemic stimulus combined with an
      intravenous arginine stimulus.
    

Detailed description: 
      The thiazolidinedione (TZD) class of drugs has been shown to improve insulin sensitivity in
      skeletal muscle, liver, and adipocytes and to have anti-inflammatory and cardioprotective
      effects. The beta cell function, measured by the insulin secretion/insulin resistance index
      during the OGTT, improves significantly. In the present study, we will perform a more
      definitive assessment of beta cell function in TZD-treated diabetic patients by measuring the
      maximal insulin secretory capacity using a maximal hyperglycemic stimulus combined with an
      intravenous arginine stimulus.

      Despite the beneficial effects of pioglitazone to improve insulin sensitivity and reduce
      cardiovascular events in high risk type 2 diabetic patients, weight gain has been a limiting
      factor for primary care physicians even though pioglitazone treatment leads to a
      redistribution of fat out of muscle/liver/visceral area to subcutaneous fat.

      Exenatide (Byetta) is 39 amino acid peptide which exhibits biological actions similar to
      GLP-1. In clinical trials exenatide reduces HbA1c by 1-1.2% in subjects with type 2 diabetes
      and promotes moderate weight loss which is sustained for up to 2 years.

      In this proposal we will examine the effect of combination therapy with pioglitazone plus
      exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma
      lipid levels in subjects with type 2 diabetes mellitus compared to monotherapy with each
      agent separately. We postulate that combination therapy will result in significant weight
      loss (in contrast to the weight gain which accompanies pioglitazone treatment) and have an
      additive, or even synergistic, effect to improve beta cell function and glycemic control in
      type 2 diabetic patients who are inadequately controlled on oral agent therapy with metformin
      alone, a sulfonylurea alone, or combination of metformin plus a sulfonylurea. We will also
      compare the insulin secretion in healthy control subjects (NGT, n=15) and subjects with
      impaired glucose tolerance (IGT, n=15) to evaluate the relative decline in beta cell function
      in T2DM compared to NGT and IGT subjects. NGT and IGT subjects will participate only in a
      OGTT and a Hyperglycemic clamp- they will not receive any medication.
    

Intervention name(s): Pioglitazone; Exenatide; Pioglitazone and Exenatide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Pioglitazone 15 mg/day for 1 month and then 45 mg/day for 5 months; Exenatide 5mcg twice daily for 1 month, then 10mcg twice daily for 5 months; Pioglitazone 30mg daily for 1 month and then 45mg daily for 5 months and Exenatide 5mcg twice daily for one month then 10mcg twice daily for 5 months
Other intervention name(s): ACTOS; BYETTA; ACTOS; BYETTA
Intervention MeSH terms: Pioglitazone; Exenatide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Type 2 diabetes pathogenesis, thiazolidinediones; impaired glucose tolerance; Incretins; Insulin secretion