The Effects of Anti-Inflammatory Treatment on Insulin Resistance in Healthy Volunteers

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00339833
• Collaborator: (none)
• Enrollment: 54
• Location: 1
• Arms: 2
• Duration (Months): 64
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This study, conducted at the Phoenix Indian Medical Center, Phoenix, Arizona, will determine whether reducing subclinical inflammation lessens insulin resistance in healthy, obese volunteers. The study findings may lead to new strategies for preventing type 2 diabetes. In diabetes, blood sugar is higher than normal and can result in serious medical problems, such as blindness and kidney failure. People with subclinical inflammation-inflammation that does not produce symptoms, such as fever, pain, or skin redness-are at increased risk for diabetes. Although the reasons for this are not completely understood, it is known that subclinical inflammation exacerbates insulin resistance, which is a cause of diabetes. Insulin is a hormone that helps control blood sugar, and when it does not work properly, the condition is known as insulin resistance.

Normal, healthy volunteers between 18 and 45 years old with a body mass index of at least 30 kg/m2 and who have subclinical inflammation (determined by blood tests) may be eligible for this study. Candidates must be non-smokers and must not have an alcohol or drug problem. Candidates will be screened with a medical history and physical examination, electrocardiogram, and blood and urine tests. Participants will maintain a standard diet and undergo tests and procedures during a 14-day inpatient stay at the Phoenix Indian Medical Center.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Diabetes	Drug: Salsalate; Drug: Placebo	Phase 4

Detailed Description

In healthy subjects, low-grade inflammation, as measured by serum levels of cytokines or acute phase proteins, is positively associated with adiposity. Recent studies indicate that chronic low-grade inflammation in non-diabetic individuals may cause decline in insulin sensitivity and increases the risk of developing type 2 diabetes. It has been proposed that reduction of low-grade inflammation may reduce the risk of development of type 2 diabetes. In agreement with this hypothesis, the class of anti-inflammatory drugs called salicylates (such as aspirin) that influence a specific anti-inflammatory pathway have been found to decrease plasma glucose levels and increase insulin sensitivity in rodents as well as people with type 2 diabetes.

In the present study, we propose testing whether administration of the anti-inflammatory drug Salsalate improves insulin sensitivity in obese non-diabetic individuals and whether this improvement is related with a decrease in serum markers of inflammation. Subjects will be randomly assigned to two treatment groups: placebo or Salsalate (3g/d). An oral glucose tolerance test and a combined euglycemic/hyperglycemic clamp to assess insulin sensitivity and insulin secretion will be performed before and after seven days of treatment. Results of this study may help to identify novel strategies to prevent type 2 diabetes in high-risk groups.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Effect of Salsalate Treatment on Insulin Sensitivity and Insulin Secretion in Obese Non-Diabetic Individuals
• Study Start Date: Mar 1, 2003
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Salsalate Salsalate (3g/day) for 7 days	Drug: Salsalate; The intervention was salsalate (3g/day) for 7 days.
Placebo Comparator: Placebo Placebo	Drug: Placebo; Identical placebo for 7 days.

Outcome Measures

Primary Outcome Measures

1. Change in Fasting Plasma Glucose Concentration [7 days]

2. Change in the Average Serum Insulin Concentration During the Last 40 Min of Clamp [last 40 min of clamp]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Age: Greater than 18 and less than 45 years.

Number: 44 completed studies (22 placebo, 22 Salsalate).

Sex: 22 Males and 22 Females.

BMI: Greater than or equal to 30 kg.m(2)

EXCLUSION CRITERIA:

• Age below 18 or above 45 years to minimize the risk of glucose clamp.

• Diabetes mellitus (as per 75 g OGTT, WHO 1999 criteria)

• Cardiovascular disease including: abnormal EKG, personal history of coronary heart disease;symptomatic angina pectoris or cardiac insufficiency as defined by NYHA; classification as functional class III or IV.

• Systolic blood pressure greater than 160mmHG and/or diastolic blood pressure greater than 100 mmHg and/or on antihypertensive therapy or resting heart rate greater than 90 bpm.

• Hematological disorder, including prolonged prothrombin time (normal range 10.9-12.9 sec) and partial thromboplastin time (24-36 sec) and thrombocytopenia (less than 150,000 mm(3)).

• Respiratory disease (including influenza, asthma)

• Allergies (including hay fever)

• Gastrointestinal (including peptic ulcer), hepatic or renal disease (ALT and AST greater than 3-fold above upper limit of normal range, creatinine greater than 1.3 mg/dl).

• Alcoholism, alcohol-induced autonomic neuropathy.

• Any endocrinological disorder, including hypopituitarism/pituitary dysfunctions or lesions, hypo/hyperthyroidism, insulinoma.

• CNS disease

• Psychosis or personal history of any psychiatric disorder.

• Taking medications within one month prior to beginning the study, including medications known to have pharmacological interactions with salicylates or that may affect insulin sensitivity and secretion (including salicylates, COX 1 and COX 2 inhibitors, warfarin, Beta-Blockers, phenothiazines, antidepressants, antiarrhythmic drugs, antimuscarinic drugs).

• Acute inflammation as assessed by history, physical and laboratory examination (subjects with C-reactive protein 2 standard deviations above the population mean will not be admitted). The population mean was calculated from subjects admitted at our research unit.

• Pregnant or lactating females or females on hormonal contraceptives.

• History of metabolic acidosis.

• Allergy to aspirin, other salicylates, or bleeding diathesis or currently on oral anticoagulants.

• Any current viral illness.

• Active cancer within 5 years prior to screening for the study.

• Positive urine drug screening test.

• Inability to provide informed consent.

• Smokers

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NIDDK, Phoenix	Phoenix	Arizona	United States	85014

Sponsors and Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Bogardus Clifton, MD, National Institues of Diabetes and Digestive and Kidney Disease

Study Documents (Full-Text)

None provided.

More Information

Publications

• Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998 Oct;41(10):1241-8. Review.
• Pratley RE, Wilson C, Bogardus C. Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes Res. 1995 Nov;3(6):563-71.
• Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001 Jul;9(7):414-7.

• Responsible Party: Clifton Bogardus, Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00339833
• Other Study ID Numbers: 999903121; 03-DK-N121; 03-DK-N121
• First Posted: Jun 21, 2006
• Last Update Posted: Mar 6, 2013
• Last Verified: Jan 1, 2013

• Keywords provided by Clifton Bogardus, Principal Investigator, National Institutes of Health Clinical Center (CC): Salsalate; Insulin Resistance; Diabetes Mellitus; Inflammation; Diabetes; HCV
• Additional relevant MeSH terms: Diabetes Mellitus; Insulin Resistance; Salicylsalicylic acid

Study Results

Participant Flow

Recruitment Details	Recruitment location: clinical research unit at the NIDKK (Phoenix, AZ, USA)
Pre-assignment Detail	Upon admission, all participants were placed on a weight maintaining diet (containing 50% of energy as carbohydrate, 30% as fat and 20% as protein). Body composition was measured by dual-energy x-ray absorptiometry. At least 3 days after admission and after a 12 h overnight fast a 2-h 75 g OGTT was performed to exclude diabetes.

Arm/Group Title	Salsalate	Placebo
Arm/Group Description	The intervention was salsalate (3g/day) for 7 days	Placebo for 7 days.
Period Title: Overall Study
STARTED	28	26
COMPLETED	22	18
NOT COMPLETED	6	8

Baseline Characteristics

Arm/Group Title	Salsalate	Placebo	Total
Arm/Group Description	Salsalate (3g/day) for 7 days	Identical placebo for 7 days	Total of all reporting groups
Overall Participants	22	18	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29 (7)	33 (8)	31 (7.5)
Sex: Female, Male (Count of Participants)
Female	12 54.5%	9 50%	21 52.5%
Male	10 45.5%	9 50%	19 47.5%
Race/Ethnicity, Customized (participants) [Number]
Hispanic	0 0%	1 5.6%	1 2.5%
White	3 13.6%	3 16.7%	6 15%
Native American	19 86.4%	14 77.8%	33 82.5%
Region of Enrollment (participants) [Number]
United States	22 100%	18 100%	40 100%
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	37 (5)	38 (6)	37.5 (5.5)
Body Fat (% body fat) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% body fat]	38 (6)	38 (7)	38 (6.5)
Fasting plasma glucose (mmol/l) [Median (Standard Deviation) ]
Median (Standard Deviation) [mmol/l]	5.11 (0.33)	5.06 (0.33)	5.09 (0.33)
2 hour plasma glucose (mmol/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/l]	6.67 (1.17)	6.61 (1.83)	6.64 (1.50)
Fasting plasma insulin (pmol/l) [Median (Full Range) ]
Median (Full Range) [pmol/l]	80	63	76
Basal EGP (micro-mol/(kg*min)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [micro-mol/(kg*min)]	10 (2)	11 (2)	10.5 (2)
Clamp R_d (micro-mol/(kg*min)) [Median (Full Range) ]
Median (Full Range) [micro-mol/(kg*min)]	13	16	14

Outcome Measures

1. Primary Outcome

Title	Change in Fasting Plasma Glucose Concentration
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Salsalate	Placebo
Arm/Group Description	Salsalate (3g/day) for 7 days	Identical placebo for 7 days
Measure Participants	22	18
Mean (Standard Deviation) [mmol/l]	4.7 (6.5)	0.0 (3.7)

2. Primary Outcome

Title	Change in the Average Serum Insulin Concentration During the Last 40 Min of Clamp
Time Frame	last 40 min of clamp

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Salsalate	Placebo
Arm/Group Description	Salsalate (3g/day) for 7 days	Identical placebo for 7 days
Measure Participants	22	18
Mean (Standard Deviation) [l/min]	0.15 (0.21)	-0.06 (0.23)

Adverse Events

Arm/Group Title	Salsalate		Placebo
Arm/Group Description	Salsalate (3g/day) for 7 days		Identical placebo for 7 days
All Cause Mortality
	Salsalate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Salsalate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Salsalate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/18 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.