Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus
Brief summary
The purpose of this study is to investigate the acute effects of the thiazolidinedione agent pioglitazone (which has combined PPAR alpha and gamma stimulation) on insulin's ability to suppress glucose production, stimulated glucose uptake, and impact a number of other metabolically important endpoints, including production of adiponectin (a protein hormone which regulates sugar levels and fatty acid breakdown) in subjects with type 2 diabetes.
Detailed description
Participants in this study were given a supply of either pioglitazone (a medication used to treat diabetes) or matched placebo for a duration of 10 days or 21 days. Changes to the body's response to insulin in the liver and in peripheral tissues (eg, muscle and fat) will be measured using a procedure called a pancreatic clamp. During the clamp procedure, glucose (a sugar) and insulin were infused with an intravenous catheter, and blood samples were collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body and are related to glucose metabolism. Small amounts of muscle and fat tissue were also taken during this study to measure changes in gene expression after taking the medication/placebo.
Interventions
DRUGPioglitazone
This was a randomized placebo-controlled crossover study in which subjects received both agents in random order, separated by a wash-out period. Following 10 or 21 days' intervention, subjects underwent a pancreatic clamp study.
DRUGPlacebo
This was a randomized placebo-controlled crossover study in which subjects received both agents in random order, separated by a wash-out period. Following 10 or 21 days' intervention, subjects underwent a pancreatic clamp study.
PROCEDUREPancreatic Clamp Study
During the clamp procedure, glucose (a sugar) and insulin were infused with an IV catheter, and blood samples were collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body and are related to glucose metabolism.
Sponsors
Takeda
Albert Einstein College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
• Individuals with Type 2 Diabetes
Exclusion criteria
* Individuals with bleeding disorders including gastrointestinal reflux disease (GERD), peptic ulcer disease (PUD), any gastrointestinal (GI) bleeding * High blood pressure * History of Coronary Artery Disease or chest pain on exertion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous Glucose Production (EGP) | Up to 6 hours | EGP (a measure of the body's production of sugar) was measured by using a 6-hour stepped pancreatic clamp procedure under various treatment conditions (e.g., Pioglitazone or placebo at 10-days and/or 21-days), by monitoring the level of a non-radioactive, naturally occurring form of glucose (sugar). The relevant data at the end of each last 60 minute bin of each run was reported for each of the four groups up to 6 hours. Results are summarized by study arm/group and reported in milligrams/kilograms/minute (mg/kg/min). |
| Glucose Rates of Disappearance (Rd) | Up to 6 hours | Glucose rates of disappearance were measured using a stepped pancreatic clamp study procedure under various treatment conditions (e.g., Pioglitazone or placebo at 10-days and/or 21-days) by monitoring the level of a non-radioactive, naturally occurring form of glucose (sugar). For purposes of this study, the most relevant data for the final hour is summarized within each study Pioglitazone and Placebo study arm/group, respectively. Results are summarized by study arm/group and reported in milligrams/kilograms/minute (mg/kg/min). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Outcome was compared prior to and post 10-day or 21-day administration of either placebo or Pioglitazone | Gene expression of inflammatory markers in both whole fat tissue and isolated macrophages were studied by quantitative, real-time reverse transcriptase polymerase chain reaction (RT-PCR) in placebo and Pioglitazone groups of either 10- or 21-day study. The reporting data was calculated as the ratio between the target genes and housekeeping genes in either the 10- or 21-day study. |
| Effects of Pioglitazone on Adipose Tissue Percentage of Macrophage Content | Assessed at day 1 prior to the intervention and on day 10 or 21 following the intervention, day 10 or 21 following the intervention reported | Adipose tissue biopsy was performed on day one or on the last day (10th or 21st day) for the corresponding Pioglitazone and placebo interventions. Macrophages were stained with immunofluorescence antibody after isolation from adipose tissue and processed. The percentage of macrophage content in stromal vascular fraction cells (SVF) analyzed by Fluorescence-activated cell sorter analysis (FACS) was determined. Results are summarized by study arm/group and reported in milligrams/kilograms/minute (mg/kg/min). |
| Adipose Tissue Percentage of Macrophage Content | Outcome was compared between Pioglitazone and placebo group prior to and after 21-day administration | Adipose tissue percentage of macrophage content was analyzed by Immuno-fluorescence staining (iNOS+ and CD68+). Both the immuno-fluorescence stained macrophages and all other stained cells will be counted after staining. The percentage of macrophage content will be calculated as the the ratio between the number of macrophage and all other cells. |
| Adipose Tissue Regulatory T Lymphocyte Content | Outcome was compared between Pioglitazone and placebo group prior to and after 21-day administration | Adipose tissue T lymphocyte content (%) was analyzed by Immunohistochemistry (IHC) staining with Treg-specific marker FOXP3 Both the IHC FOXP3 stained T lymphocyte and all other stained cells will be counted after staining. The percentage of T lymphocyte content will be calculated as the the ratio between the number of T lymphocyte and all other cells. |
Countries
United States
Participant flow
Pre-assignment details
A total of 26 adult volunteers with type 2 diabetes completed the 10-day and/or the 21-day protocols. 13 participants completed the 10-day studies, and 13 completed the 21-day studies. Three subjects participated in both the 10-day and 21-day studies, more than six months apart.
Participants by arm
| Arm | Count |
|---|---|
| 2000-200 10-day Study Participants received either 45mg of Pioglitazone (pio) or Placebo (matched to Pioglitazone) via oral capsule daily for 10 days, in randomized, placebo-controlled, cross-over fashion. Following a 4 week wash-out period, participants were crossed over to the corresponding intervention (45mg of Pioglitazone or Placebo) via oral capsule daily for 10 days.
The investigators used a research procedure called a pancreatic clamp study to investigate the effects of pioglitazone. During the clamp procedure, glucose (a sugar) and insulin (a hormone that regulates the amount of glucose in the blood) are infused with an intravenous catheter, and blood samples are collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body and are related to glucose metabolism. | 13 |
| 2000-200 21-day Study Participants received either 45mg of Pioglitazone (pio) or Placebo (matched to Pioglitazone) via oral capsule daily for 21 days, in randomized, placebo-controlled, cross-over fashion. Following a 4 week wash-out period, participants were crossed over to the corresponding intervention (45mg of Pioglitazone or Placebo) via oral capsule daily for 21 days.
The investigators used a research procedure called a pancreatic clamp study to investigate the effects of pioglitazone. During the clamp procedure, glucose (a sugar) and insulin (a hormone that regulates the amount of glucose in the blood) are infused with an intravenous catheter, and blood samples are collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body and are related to glucose metabolism. | 13 |
| Total | 26 |
Baseline characteristics
| Characteristic | 2000-200 21-day Study | Total | 2000-200 10-day Study |
|---|---|---|---|
| Age, Continuous | 47.88 years | 46.86 years | 45.85 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 13 number of participants | 26 number of participants | 13 number of participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 16 | 1 / 16 |
| other Total, other adverse events | 0 / 13 | 0 / 13 | 0 / 16 | 1 / 16 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Endogenous Glucose Production (EGP)
EGP (a measure of the body's production of sugar) was measured by using a 6-hour stepped pancreatic clamp procedure under various treatment conditions (e.g., Pioglitazone or placebo at 10-days and/or 21-days), by monitoring the level of a non-radioactive, naturally occurring form of glucose (sugar). The relevant data at the end of each last 60 minute bin of each run was reported for each of the four groups up to 6 hours. Results are summarized by study arm/group and reported in milligrams/kilograms/minute (mg/kg/min).
Time frame: Up to 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2000-200 Study 10-day Pioglitazone | Endogenous Glucose Production (EGP) | 1.26 mg/kg/min | Standard Error 0.19 |
| 2000-200 Study 10-day Placebo | Endogenous Glucose Production (EGP) | 1.25 mg/kg/min | Standard Error 0.2 |
| 2000-200 Study 21-day Pioglitazone | Endogenous Glucose Production (EGP) | 0.90 mg/kg/min | Standard Error 0.13 |
| 2000-200 Study 21-day Placebo | Endogenous Glucose Production (EGP) | 1.48 mg/kg/min | Standard Error 0.18 |
Primary
Glucose Rates of Disappearance (Rd)
Glucose rates of disappearance were measured using a stepped pancreatic clamp study procedure under various treatment conditions (e.g., Pioglitazone or placebo at 10-days and/or 21-days) by monitoring the level of a non-radioactive, naturally occurring form of glucose (sugar). For purposes of this study, the most relevant data for the final hour is summarized within each study Pioglitazone and Placebo study arm/group, respectively. Results are summarized by study arm/group and reported in milligrams/kilograms/minute (mg/kg/min).
Time frame: Up to 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2000-200 Study 10-day Pioglitazone | Glucose Rates of Disappearance (Rd) | 3.9 mg/kg/min | Standard Error 0.15 |
| 2000-200 Study 10-day Placebo | Glucose Rates of Disappearance (Rd) | 3.6 mg/kg/min | Standard Error 0.1 |
| 2000-200 Study 21-day Pioglitazone | Glucose Rates of Disappearance (Rd) | 3.90 mg/kg/min | Standard Error 0.15 |
| 2000-200 Study 21-day Placebo | Glucose Rates of Disappearance (Rd) | 3.60 mg/kg/min | Standard Error 0.1 |
Secondary
Adipose Tissue Percentage of Macrophage Content
Adipose tissue percentage of macrophage content was analyzed by Immuno-fluorescence staining (iNOS+ and CD68+). Both the immuno-fluorescence stained macrophages and all other stained cells will be counted after staining. The percentage of macrophage content will be calculated as the the ratio between the number of macrophage and all other cells.
Time frame: Outcome was compared between Pioglitazone and placebo group prior to and after 21-day administration
Population: Due to the unsuccessful IHF assay macrophage % content data was not collected for the 10-day study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2000-200 Study 10-day Pioglitazone | Adipose Tissue Percentage of Macrophage Content | 18 percentage of macrophage content | Standard Error 7 |
| 2000-200 Study 10-day Placebo | Adipose Tissue Percentage of Macrophage Content | 43 percentage of macrophage content | Standard Error 15 |
Secondary
Adipose Tissue Regulatory T Lymphocyte Content
Adipose tissue T lymphocyte content (%) was analyzed by Immunohistochemistry (IHC) staining with Treg-specific marker FOXP3 Both the IHC FOXP3 stained T lymphocyte and all other stained cells will be counted after staining. The percentage of T lymphocyte content will be calculated as the the ratio between the number of T lymphocyte and all other cells.
Time frame: Outcome was compared between Pioglitazone and placebo group prior to and after 21-day administration
Population: Due to the unsuccessful IHC assay, T lymphocyte % content was unable to be collected for the 10-day study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2000-200 Study 10-day Pioglitazone | Adipose Tissue Regulatory T Lymphocyte Content | 14 percentage of T lymphocyte content | Standard Error 3 |
| 2000-200 Study 10-day Placebo | Adipose Tissue Regulatory T Lymphocyte Content | 17 percentage of T lymphocyte content | Standard Error 5 |
Secondary
Effects of Pioglitazone on Adipose Tissue Percentage of Macrophage Content
Adipose tissue biopsy was performed on day one or on the last day (10th or 21st day) for the corresponding Pioglitazone and placebo interventions. Macrophages were stained with immunofluorescence antibody after isolation from adipose tissue and processed. The percentage of macrophage content in stromal vascular fraction cells (SVF) analyzed by Fluorescence-activated cell sorter analysis (FACS) was determined. Results are summarized by study arm/group and reported in milligrams/kilograms/minute (mg/kg/min).
Time frame: Assessed at day 1 prior to the intervention and on day 10 or 21 following the intervention, day 10 or 21 following the intervention reported
Population: Day 1 macrophage data was not collected and reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2000-200 Study 10-day Pioglitazone | Effects of Pioglitazone on Adipose Tissue Percentage of Macrophage Content | 10.20 percentage of macrophage content | Standard Error 1.6 |
| 2000-200 Study 10-day Placebo | Effects of Pioglitazone on Adipose Tissue Percentage of Macrophage Content | 12.00 percentage of macrophage content | Standard Error 1.9 |
| 2000-200 Study 21-day Pioglitazone | Effects of Pioglitazone on Adipose Tissue Percentage of Macrophage Content | 4.20 percentage of macrophage content | Standard Error 2.8 |
| 2000-200 Study 21-day Placebo | Effects of Pioglitazone on Adipose Tissue Percentage of Macrophage Content | 13.50 percentage of macrophage content | Standard Error 1.5 |
Secondary
Gene Expression in Both Whole Fat Tissue and Isolated Macrophages
Gene expression of inflammatory markers in both whole fat tissue and isolated macrophages were studied by quantitative, real-time reverse transcriptase polymerase chain reaction (RT-PCR) in placebo and Pioglitazone groups of either 10- or 21-day study. The reporting data was calculated as the ratio between the target genes and housekeeping genes in either the 10- or 21-day study.
Time frame: Outcome was compared prior to and post 10-day or 21-day administration of either placebo or Pioglitazone
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DEC205 | 0.0009 ratio | Standard Error 0.0002 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD68 expression | 0.23 ratio | Standard Error 0.07 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD14 expression | 0.79 ratio | Standard Error 0.01 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage CCR2 | 0.009 ratio | Standard Error 0.001 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DC SIGN | 0.0007 ratio | Standard Error 0.0002 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue FOXP3 | 0.0005 ratio | Standard Error 0.0001 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan synthase expression | 0.007 ratio | Standard Error 0.001 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue MPO-3 | 0.018 ratio | Standard Error 0.009 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue CD25 | 0.89 ratio | Standard Error 0.04 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage MCP-1 | 0.80 ratio | Standard Error 0.6 |
| 2000-200 Study 10-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan receptor CD44 expression | 0.150 ratio | Standard Error 0.075 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage MCP-1 | 1.90 ratio | Standard Error 0.5 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DC SIGN | 0.001 ratio | Standard Error 0.0001 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DEC205 | 0.0016 ratio | Standard Error 0.02 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD14 expression | 0.84 ratio | Standard Error 0.02 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan receptor CD44 expression | 0.225 ratio | Standard Error 0.025 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue CD25 | 0.90 ratio | Standard Error 0.05 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue FOXP3 | 0.0006 ratio | Standard Error 0.0001 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage CCR2 | 0.023 ratio | Standard Error 0.007 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan synthase expression | 0.015 ratio | Standard Error 0.002 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD68 expression | 0.26 ratio | Standard Error 0.02 |
| 2000-200 Study 10-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue MPO-3 | 0.031 ratio | Standard Error 0.012 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue FOXP3 | 0.0035 ratio | Standard Error 0.001 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan receptor CD44 expression | 0.050 ratio | Standard Error 0.01 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD14 expression | 0.07 ratio | Standard Error 0.01 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD68 expression | 0.20 ratio | Standard Error 0.05 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DC SIGN | 0.005 ratio | Standard Error 0.002 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage MCP-1 | 0.07 ratio | Standard Error 0.01 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan synthase expression | 0.013 ratio | Standard Error 0.007 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DEC205 | 0.0015 ratio | Standard Error 0.0004 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue MPO-3 | 0.009 ratio | Standard Error 0.002 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage CCR2 | 0.0020 ratio | Standard Error 0.0005 |
| 2000-200 Study 21-day Pioglitazone | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue CD25 | 0.0035 ratio | Standard Error 0.0008 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan synthase expression | 0.019 ratio | Standard Error 0.006 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue hyaluronan receptor CD44 expression | 0.10 ratio | Standard Error 0.01 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue MPO-3 | 0.02 ratio | Standard Error 0.004 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage CCR2 | 0.0040 ratio | Standard Error 0.0005 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Adipose tissue macrophage MCP-1 | 0.11 ratio | Standard Error 0.02 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue CD25 | 0.0045 ratio | Standard Error 0.0013 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue FOXP3 | 0.0045 ratio | Standard Error 0.0013 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DC SIGN | 0.0125 ratio | Standard Error 0.004 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Whole adipose tissue DEC205 | 0.0024 ratio | Standard Error 0.0003 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD68 expression | 0.40 ratio | Standard Error 0.1 |
| 2000-200 Study 21-day Placebo | Gene Expression in Both Whole Fat Tissue and Isolated Macrophages | Macrophage CD14 expression | 0.11 ratio | Standard Error 0.02 |