Defective Atypical Protein Kinase C (PKC) Activation in Diabetes and Metabolic Syndrome

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00690755
• Other study ID #: ENDA-037-04F
• Status: Completed
• Phase: N/A
• First received: June 2, 2008
• Last updated: December 3, 2014
• Start date: October 2005
• Est. completion date: September 2008

Study information

• Verified date: December 2014
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Observational

Clinical Trial Summary

The investigators are examining the activation of insulin signaling factors in skeletal muscles of human diabetics. The investigators are characterizing the defects in signaling, and are examining the effects of anti-diabetic agents and exercise on signaling to glucose transport biochemical machinery and whole body glucose disposal.

Description:

We have provided clear evidence that insulin activation of all three signaling components, Viz., IRS-1-dependent PI 3-Kinase, atypical protein kinase C (aPKC) and PKB/Akt is defective in diabetic muscle. These defects are best seen when insulin activation is conducted at both half-maximal and maximal stimulation. Moreover, whereas previous studies had shown that treatment with metformin (Met) alone improves aPKC activation, or that treatment with thiazolidinedione (TZD) alone produces increases in activation of IRS-1/PI3K and aPKC when evaluated at maximal insulin stimulation, we have recently found that combined treatment with Met plus TZD for 6 weeks provokes marked increases in insulin effects on all three signaling factors at both half-maximal and maximal insulin stimulation. This work is being prepared for submission for publication.

We have also evaluated the improvement in insulin signaling in diabetic muscle 4 hours after acute endurance (one-legged) exercise and found that the responsiveness of aPKC to the lipid PI3K-derived activator, PIP3, was improved. Also increased was the activation by insulin of IRS-2-dependent PI3K, ERK1/2, and downstream protein synthesis machinery, viz., p70S6 kinase and eukaryotic elongation factor eEF2. These effects of exercise would be expected to enhance glucose transport and utilization by muscle, and promote protein synthesis, i.e., an anabolic response.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: September 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 20 Years to 80 Years

Eligibility

Inclusion Criteria:

• Stable uncomplicated type 2 diabetes

• Able to be off oral treatments for 2 months

Exclusion Criteria:

• Type 1 diabetes

• Renal impairment

• Cardiovascular disease

• Hepatic disease

• Insulin therapy needed

Study Design

Observational Model: Cohort, Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Metabolic Syndrome X

Locations

Country	Name	City	State
United States	VA Medical Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improved insulin signaling with combined metformin-thiazolidinedione treatment.		Insulin signaling in muscle evaluated 6 weeks after combined Met-TZD treatmentall muscle samples obtained by 9/30/07final date for examination of samples 9/30/08	No