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

This study has been completed.
Information provided by (Responsible Party):
VA Office of Research and Development Identifier:
First received: June 2, 2008
Last updated: December 3, 2014
Last verified: December 2014
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.

Diabetes Mellitus, Type 2

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome

Resource links provided by NLM:

Further study details as provided by VA Office of Research and Development:

Primary Outcome Measures:
  • Improved insulin signaling with combined metformin-thiazolidinedione treatment. [ Time Frame: 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 ] [ Designated as safety issue: No ]

Biospecimen Retention:   None Retained
Muscle biopsies taken before and after insulin stimulation in euglycemic clamp studies

Estimated Enrollment: 8
Study Start Date: October 2005
Study Completion Date: September 2008
Primary Completion Date: September 2008 (Final data collection date for primary outcome measure)
Group 1

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.


Ages Eligible for Study:   20 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
type 2 diabetes controlled by diet or oral agents and comparable non-diabetic control subjects

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00690755

United States, Florida
VA Medical Center
Tampa, Florida, United States, 33612
Sponsors and Collaborators
VA Office of Research and Development
Principal Investigator: Robert V Farese, MD VA Office of Research and Development
  More Information

No publications provided

Responsible Party: VA Office of Research and Development Identifier: NCT00690755     History of Changes
Other Study ID Numbers: ENDA-037-04F 
Study First Received: June 2, 2008
Last Updated: December 3, 2014
Health Authority: United States: Federal Government

Keywords provided by VA Office of Research and Development:

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Metabolic Syndrome X
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Insulin Resistance
Metabolic Diseases processed this record on February 04, 2016