Mechanisms of Insulin Resistance in Humans

• Sponsor: US Department of Veterans Affairs (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00330967
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Duration (Months): 100
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The Objectives of the study are to: (1)compare the inflammatory response and insulin resistance in skeletal muscles during a systemic infusion of lipid with that during a local infusion of lipid into the femoral artery. which would cause minimal or no systemic hyperlipidemia but local plasma free fatty acid (FFA) concentrations similar to those during the systemic lipid infusion, and (2) determine the inflammatory response and insulin resistance in skeletal muscle during an infusion of lipid into the femoral artery as described above after NF-KB inhibition by high dose salicylate treatment in humans.

Condition or Disease	Intervention/Treatment	Phase
Inflammation; Insulin Resistance	Drug: 20% Intralipid

Detailed Description

Insulin resistance in skeletal muscle is a characteristic abnormality in obesity and the metabolic syndrome and a major factor responsible for the development of type 2 diabetes. Although the mechanisms responsible for muscle insulin resistance are largely unclear, lipid oversupply is an important factor. Among numerous potential mechanisms whereby lipid oversupply may cause muscle insulin resistance, current evidence points towards inflammation as being critical. Recent studies in animals, however, indicate that the inflammatory response in skeletal muscles may require the presence of circulating pro-inflammatory factors suggesting that the inflammation induced insulin resistance in skeletal muscles may be a secondary event. More specifically, activation of Nuclear Factor-Kappa B(NF-kB), and inflammatory master switch that drives the production of numerous pro-inflammatory cytokines in fat and liver, has been implicated in causing insulin resistance in skeletal muscles by increasing circulating pro-inflammatory cytokines. In contrast, animal studies have found that activation of NF-KB directly in skeletal muscles has no or little effect on its insulin sensitivity but does produce other abnormalities such as increased proteasome activity. The study shall therefore be undertaken to determine to what extent lipid-induced inflammation and insulin resistance in skeletal muscles requires the presence of circulating proinflammatory factors in humans.

Study Design

• Study Type: Observational
• Actual Enrollment: 25 participants
• Time Perspective: Prospective
• Official Title: Mechanisms of Insulin Resistance in Humans
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Group 1 healthy subjects	Drug: 20% Intralipid; lipid infusion
Group 2 healthy subjects different from group 1	Drug: 20% Intralipid; lipid infusion

Outcome Measures

Primary Outcome Measures

1. Insulin Signaling With Lipid Infusion [4 h]

   IRS-1 expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blot bands, normalized to a housekeeping protein, GAPDH, in control and treated groups.

2. Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions [4 h]

   Phosphorylation of p38 MAPK in response to femoral lipid and insulin infusions. phospho-p38 MAPK expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.

3. p38 MAPK Expression With Femoral Lipid and Insulin Infusions [4 h]

   p38 MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.

4. Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions [4 h]

   Phosphorylation of ERK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.

5. ERK MAPK Expression With Femoral Lipid and Insulin Infusions [4 h]

   ERK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.

6. Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions [4 h]

   Phosphorylation of JNK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.

7. JNK MAPK Expression With Femoral Lipid and Insulin Infusions [4 h]

   JNK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• two groups of 16 healthy subjects

Exclusion Criteria:

• diabetes or impaired glucose tolerance

• peripheral vascular disease

• pulmonary disease

• clinically significant hepatic or renal disease

• triglycerides >200mg/dl

• anemia

• abnormal PT, PTT or INR

• pregnancy or lactation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ	Phoenix	Arizona	United States	85012

Sponsors and Collaborators

• US Department of Veterans Affairs

Investigators

• Principal Investigator: Charles C Oh, MD, Phoenix VA Health Care System Carl T. Hayden VA Medical Center, Phoenix, AZ

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: US Department of Veterans Affairs
• ClinicalTrials.gov Identifier: NCT00330967
• Other Study ID Numbers: ENDA-029-05F
• First Posted: May 29, 2006
• Last Update Posted: Apr 3, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by US Department of Veterans Affairs: Fat Emulsions, Intravenous; Free Fatty Acids; Glucose Clamp Technique; Inflammation; Insulin Resistance; Muscle, Skeletal; NF-Kappa B
• Additional relevant MeSH terms: Insulin Resistance; Inflammation; Soybean oil, phospholipid emulsion

Study Results

Participant Flow

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Systemic Intralipid infusion subjects 20% Intralipid: lipid infusion	Femoral arterial Intralipid infusion subjects 20% Intralipid: lipid infusion
Period Title: Overall Study
STARTED	0	25
COMPLETED	0	11
NOT COMPLETED	0	14

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Total
Arm/Group Description	Systemic Intralipid infusion subjects 20% Intralipid: lipid infusion	Femoral Intralipid infusion subjects 20% Intralipid: lipid infusion	Total of all reporting groups
Overall Participants	0	25	25
Age (participants) [Number]
<=18 years	0 NaN	0 0%
Between 18 and 65 years	25 Infinity	25 100%
>=65 years	0 NaN	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.65 (11.43)	47.65 (11.43)
Gender (participants) [Number]
Female	4 Infinity	4 16%
Male	21 Infinity	21 84%
Region of Enrollment (participants) [Number]
United States	25 Infinity	25 100%

Outcome Measures

1. Primary Outcome

Title	Insulin Signaling With Lipid Infusion
Description	IRS-1 expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blot bands, normalized to a housekeeping protein, GAPDH, in control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion subjects 20% Intralipid: lipid infusion
Measure Participants	2
IRS-1 Basal	0.4334 (0.2199)
IRS-1 Basal Lipid	0.7276 (0.0173)
IRS-1 Insulin	0.5264 (0.3810)
IRS-1 Insulin Lipid	0.3534 (0.1391)

2. Primary Outcome

Title	Phos-p38 MAPK Expression With Femoral Lipid and Insulin Infusions
Description	Phosphorylation of p38 MAPK in response to femoral lipid and insulin infusions. phospho-p38 MAPK expression in response to femoral lipid infusion in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion group
Measure Participants	2
Phos-p38 MAPK Basal	0.000394 (0.000164)
Phos-p38 MAPK Basal Lipid	0.001271 (0.001013)
Phos-p38 MAPK Insulin	0.000337 (0.000140)
Phos-p38 MAPK Insulin Lipid	0.000270 (0.000049)

3. Primary Outcome

Title	p38 MAPK Expression With Femoral Lipid and Insulin Infusions
Description	p38 MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion group
Measure Participants	2
p38 MAPK Basal	0.000455 (0.0000088)
p38 MAPK Basal Lipid	0.001291 (0.0008)
p38 MAPK Insulin	0.000502 (0.000337)
p38 MAPK Insulin Lipid	0.000377 (0.0000903)

4. Primary Outcome

Title	Phospho-ERK MAPK Expression With Femoral Lipid and Insulin Infusions
Description	Phosphorylation of ERK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion group
Measure Participants	2
Phos-ERK MAPK Basal	0.000091 (0.0000378)
Phos-ERK MAPK Basal Lipid	0.000108 (0.0000366)
Phos-ERK MAPK Insulin	0.000096 (0.0000103)
Phos-ERK MAPK Insulin Lipid	0.000092 (0.0000070)

5. Primary Outcome

Title	ERK MAPK Expression With Femoral Lipid and Insulin Infusions
Description	ERK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion group
Measure Participants	2
ERK MAPK Basal	0.000103 (0.0000722)
ERK MAPK Basal Lipid	0.000158 (0.0000826)
ERK MAPK Insulin	0.000124 (0.0000237)
ERK MAPK Insulin Lipid	0.000114 (0.0000017)

6. Primary Outcome

Title	Phospho-JNK MAPK Expression With Femoral Lipid and Insulin Infusions
Description	Phosphorylation of JNK MAPK in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion group
Measure Participants	2
Phos-JNK MAPK Basal	0.00401 (0.002967)
Phos-JNK MAPK Basal Lipid	0.005888 (0.004952)
Phos-JNK MAPK Insulin	0.003756 (0.002537)
Phos-JNK MAPK Insulin Lipid	0.00224 (0.001161)

7. Primary Outcome

Title	JNK MAPK Expression With Femoral Lipid and Insulin Infusions
Description	JNK MAPK expression in response to femoral lipid and insulin infusions in skeletal muscle. Relative protein expression was calculated by densitometry analysis of Western blots, normalized to a housekeeping protein, GAPDH, of control and treated groups.
Time Frame	4 h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 2
Arm/Group Description	Femoral Intralipid infusion group
Measure Participants	2
JNK MAPK Basal	0.001364 (0.00594)
JNK MAPK Basal Lipid	0.002996 (0.002837)
JNK MAPK Insulin	0.002151 (0.002032)
JNK MAPK Insulin Lipid	0.001783 (0.001883)

Adverse Events

Arm/Group Title	Group 1		Group 2
Arm/Group Description	Systemic Intralipid infusion group 20% Intralipid: lipid infusion		Femoral Intralipid infusion group 20% Intralipid: lipid infusion
All Cause Mortality
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/25 (4%)
Surgical and medical procedures
Edema	0/0 (NaN)	0	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/25 (0%)

Limitations/Caveats

The study's original Principal Investigator left the VA prior to the completion of data acquisition and no further subjects were enrolled. The data entered were analyzed based solely on study files in the system.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.