Mechanism of Fatty Acid-induced Impairment of Glucose-simulated Insulin Secretion - Effect of Buphenyl

NCT00533559 | Completed Phase 4

• 2 other identifiers: 07-0274-BCanadian Diabetes Association
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

An increase of plasma free fatty acids impairs insulin secretion and insulin sensitivity, thereby playing an important role in causing type 2 diabetes. Lipotoxicity plays an important role in the progression from normal glucose tolerance to fasting hyperglycemia and coversion to frank type 2 diabetes. A recent publication in the journal Science showed that buphenyl, when given to obese diabetic mice, resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease and inhancement of insulin action in liver, muscle and adipose tissue. the mechanism of action is believed to be due to reduction of endoplasmic reticulum (ER) stress. Buphenyl is currently approved for the treatment of rare inherited disorders of the urea cycle. We plan to administer Buphenyl orally to humans at a dose far lower than that used for the treatment of urea cycle disorders for 2 weeks prior to the testing of pancreatic function. One potential mechanism whereby chromically elevated plasma FFAs and glucose impairment beta cell function and insuln sensitivity is by ER stress and this can be prevented by administeration of buphenyl.

Conditions

Diabetes; Insulin Resistance

Keywords

type 2 diabetes; free fatty acids; insulin resistance; beta cell lipotoxic effect

Outcome Measures

Primary Outcomes (1)

• we will measure insulin secretion, calculate disposition index and insulin clearance during a hyperglycemic clamp. We will also measure insulin sensitivity during a euglycemic hyperinsulinemic clamp

  one year

Secondary Outcomes (1)

• During the hyperglycemic clamp we will also measure Free Fatty Acid, C-peptide and triyglycerides. During the euglycemic hyperinsulinemic clamp we will determine the insulin sensitivity index and the disposition index.

  1 year

Study Arms (2)

buphenyl

EXPERIMENTAL

Drug: sodium phenylbutyrate

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

sodium phenylbutyrate DRUG

buphenyl, 7.5 gm/day for two weeks for two studies, one with saline and one admission with intralipid and heparin

buphenyl

Placebo DRUG

Placebo comparator

Placebo

Eligibility Criteria

• Age: 35 Years - 60 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Body mass index (BMI) \> 27kg/m2. Fasting triglycerides \> 2 mmol/l and \< 5mmol/l Waist circumference \> 90 cm Fasting blood glucose \< 7 mmol/l Hemoglobin above 130g/L.

You may not qualify if:

• History of hepatitis/hepatic disease that has been active within the previous two years
• any significant aactive disease of the gastrointestinal, pulmonary, neurological, renal, genitourinary,hematological systems or has severe uncontrolled treated or untreated hypertension or proliferative retinopathy
• fasting blood glucose \> 7mmol/l or known diabetes
• History of MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or hkeart failure
• any laboratory values\>2x the upper limit of normal
• known or suspected allergy to the mediction or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions, History of hypersensitivity to heparin
• current addiction to alcohol or substances of abuse as determined by the investigator
• Metal incapacity, unwillingness or language barrier precdluding adequate understanding or cooperation
• any lipid lowering or hypoglycemic agents
• previous history of asthma
• will not donate blood thre months prior to and three months post study procedures thrombocytopenis

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (1)

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

MeSH Terms

Conditions

Diabetes Mellitus; Insulin Resistance; Diabetes Mellitus, Type 2

Interventions

4-phenylbutyric acid

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Study Officials

• Gary F. Lewis, MD

  University Health Network, Toronto General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 19, 2007
• First Posted: September 21, 2007
• Study Start: September 1, 2007
• Primary Completion: December 1, 2009
• Study Completion: March 1, 2010
• Last Updated: June 25, 2010

Record last verified: 2007-08

Locations

CA (1)