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

Completed

• Conditions: Diabetes Mellitus, Type 2

• Registration Number: NCT00690755
• Lead Sponsor: VA Office of Research and Development

Brief 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.

Detailed 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.

Study Timeline

• Study Start: 2000-05
• Study First Submitted: 2008-06-02
• Study First Submitted QC: 2008-06-04
• Study First Posted: 2008-06-05
• Primary Completion: 2012-09
• Study Completion: 2012-09
• Results First Submitted: 2015-05-22
• Status Verified: 2016-04
• Results First Submitted QC: 2016-04-12
• Last Update Submitted: 2016-04-12
• Results First Posted: 2016-05-19
• Last Update Posted: 2016-05-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 157

Inclusion Criteria

• Stable uncomplicated type 2 diabetes
• Able to be off oral treatments for 2 months

Exclusion Criteria

• Diabetic complications related to heart, eye, nerve problems
• Renal impairment
• Cardiovascular disease
• Hepatic disease
• Prior history of other disorders or complications caused by diseases
• Insulin therapy needed

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles	PKC-zeta mRNA levels and aPKC activity in muscle evaluated 40 minutes post-insulin treatment	All muscle samples obtained by 9/30/07, final date for examination of samples 9/30/08 Muscle dependent ability to diminish blood glucose levels during insulin treatment.

Trial Locations

Locations (1)

VA Medical Center; 🇺🇸 Tampa, Florida, United States