Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes
Brief summary
The purpose of this study is to examine the effect of exenatide, an anti-diabetes medication, on liver fat and blood levels of proteins that influence liver fat.
Detailed description
Obesity is characterized as generalized expansion of all adipose tissue depots, an increase in tissue lipid content, and dyslipidemia, insulin resistance, and type 2 diabetes. The adipocyte functions not only as a storage depot for fat but as an endocrine organ that releases hormones in response to specific extracellular stimuli or changes in metabolic status. These secreted proteins, carry out a variety of diverse functions, and they have been referred to collectively as adipokines. The adipokines have been postulated to play important roles in the pathogenesis of insulin resistance, hypertension, disorders of coagulation, dyslipidemia, and glucose intolerance, abnormalities associated with insulin resistance syndrome. These observations are of considerable interest because recent studies have provided evidence that increased hepatic fat content is an important determinant of hepatic insulin resistance in type 2 diabetic patients. Fatty liver is common in type 2 diabetic patients. The mechanisms responsible for the increase in hepatic fat content are unclear. It has been suggested that fatty liver results from accelerated fatty acid mobilization from expanded visceral fat stores and their deposition in the liver as well as decreased hepatic fatty acid oxidation. Weight loss in humans with Non Alcoholic Fatty Liver Disease (NAFLD) is associated with a decrease in hepatic fat content. In addition, thiazolidinediones have been shown to reduce hepatic fat content and improve hepatic insulin sensitivity in patients with type 2 diabetes as well as in non-diabetic patients with NAFLD. The thiazolidinediones initiate their action by binding the peroxisome proliferator activator receptors (PPAR) , which primarily are located on adipocytes. Treatment of insulin-resistant mice as well as type 2 diabetic patients with insulin sensitizing PPAR activators, such as thiazolidinediones, and increases plasma adiponectin levels. Indirect evidence suggests that adiponectin might mediate some of the insulin-sensitizing effects of PPAR agonists. Exenatide, a Glucagon Like Peptide-1 (GLP-1) receptor agonist approved for treatment of type 2 diabetes, elicited dose-dependent reductions in body weight in association with improved glycemic control in type 2 diabetic patients. In animal models of obesity, exenatide reduces hepatic fat. However, the effect of exenatide treatment in combination with a thiazolidinedione on liver fat content and plasma adipocytokines levels in patients with type 2 diabetes remains to be investigated.
Interventions
DRUGExenatide
Type 2 diabetic subjects will be randomized to receive exenatide 10 micrograms injected subcutaneously twice daily for 12 months. Prior to randomization, all subjects will receive baseline measurements of fasting plasma glucose, plasma adipocytokines, Free Fatty Acids, insulin, plasma lipids, and HbA1c as well as measurement of liver fat content with magnetic resonance spectroscopy. All subjects will undergo repeat measurements of fasting plasma glucose, Free Fatty Acids, insulin and adipocytokines as well as hepatic fat content determination at the end of the 12 month treatment period.
DRUGPioglitazone
Type 2 diabetic subjects will be randomized to receive pioglitazone 45 mg daily orally for 12 months. Prior to randomization, all subjects will receive baseline measurements of fasting plasma glucose, plasma adipocytokines, Free Fatty Acids, insulin, plasma lipids, and HbA1c as well as measurement of liver fat content with magnetic resonance spectroscopy. All subjects will undergo repeat measurements of fasting plasma glucose, Free Fatty Acids, insulin and adipocytokines as well as hepatic fat content determination at the end of the 12 month treatment period.
Sponsors
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must range in age from 30 to 70 years. 2. Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent. 3. Patients may be of either sex. Female patients must be non-lactating and must either be at least two years post-menopausal, or be using adequate contraceptive precautions or be surgically sterilized. 4. Patients must meet the American Diabetes Association Criteria for diagnosis of type 2 diabetes mellitus. 5. Patients must be on diet therapy alone and/or metformin treatment (stable dose) and have a fasting plasma glucose concentration between 126 and 260 mg/dl. 6. Patients must have Hematocrit greater than 34%. 7. Subjects whose body weight has been stable (±1 Kg) over the three months prior to study will be included.
Exclusion criteria
1, Type 1 diabetes. 2\. Fasting plasma glucose greater than 260 mg/dl. 3\. Patients must not have received a thiazolidinedione for at least 3 months prior to randomization. 4\. Patients must not be on insulin treatment or have received insulin for more than one week within the previous year prior to entry. Patients should not be on sulfonylureas, sitagliptin, or exenatide treatment. 5\. Patients taking systemic glucocorticoids or other medications known to affect glucose tolerance are excluded. 6\. Patients taking medications that affect gastrointestinal motility will be excluded 7\. Patients with a history of Congestive Heart failure (CHF), or clinically significant cardiac, liver or kidney disease (creatinine greater than 1.8 mg/dl).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Fat | one year | The effect of exenatide and pioglitazone on liver fat content after one year of treatment in patients with type 2 diabetes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Adipocytokines | one year | the effect of the intervention on plasma adiponectin levels. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone and Exenatide Exenatide 10 micrograms injected subcutaneously twice daily plus pioglitazone 45 mg daily orally for 12 months.
Pioglitazone and exenatide: Type 2 diabetic subjects will be randomized to receive either pioglitazone 45 mg daily orally or exenatide 10 micrograms injected subcutaneously twice daily plus pioglitazone 45 mg daily orally for 12 months. Prior to randomization, all subjects will receive baseline measurements of fasting plasma glucose, plasma adipocytokines, Free Fatty Acids, insulin, plasma lipids, and HbA1c as well as measurement of liver fat content with magnetic resonance spectroscopy. All subjects will undergo repeat measurements of fasting plasma glucose, Free Fatty Acids, insulin and adipocytokines as well as hepatic fat content determination at the end of the 12 month treatment period. | 11 |
| Pioglitazone Pioglitazone 45 mg daily orally for 12 months
Pioglitazone: Type 2 diabetic subjects will be randomized to receive either pioglitazone 45 mg daily orally or exenatide 10 micrograms injected subcutaneously twice daily plus pioglitazone 45 mg daily orally for 12 months. Prior to randomization, all subjects will receive baseline measurements of fasting plasma glucose, plasma adipocytokines, Free Fatty Acids, insulin, plasma lipids, and HbA1c as well as measurement of liver fat content with magnetic resonance spectroscopy. All subjects will undergo repeat measurements of fasting plasma glucose, Free Fatty Acids, insulin and adipocytokines as well as hepatic fat content determination at the end of the 12 month treatment period. | 10 |
| Total | 21 |
Baseline characteristics
| Characteristic | Pioglitazone | Pioglitazone and Exenatide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 11 Participants | 21 Participants |
| Age, Continuous | 55 years STANDARD_DEVIATION 3 | 49 years STANDARD_DEVIATION 3 | 52 years STANDARD_DEVIATION 3 |
| Region of Enrollment United States | 10 participants | 11 participants | 21 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Hepatic Fat
The effect of exenatide and pioglitazone on liver fat content after one year of treatment in patients with type 2 diabetes.
Time frame: one year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone and Exenatide | Hepatic Fat | 4.7 percent of liver fat | Standard Error 1.3 |
| Pioglitazone | Hepatic Fat | 6.5 percent of liver fat | Standard Error 1.9 |
Secondary
Plasma Adipocytokines
the effect of the intervention on plasma adiponectin levels.
Time frame: one year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone and Exenatide | Plasma Adipocytokines | 23.2 microgram per ml | Standard Error 2.7 |
| Pioglitazone | Plasma Adipocytokines | 15.8 microgram per ml | Standard Error 1.4 |