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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT00690755
First received: June 2, 2008
Last updated: April 12, 2016
Last verified: April 2016
  Purpose
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.

Condition
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:
  • Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles [ Time Frame: PKC-zeta mRNA levels and aPKC activity in muscle evaluated 40 minutes post-insulin treatment ] [ Designated as safety issue: No ]
    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.


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

Enrollment: 157
Study Start Date: May 2000
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts
Group 1
type 2 diabetic individuals
Group 2
type 1 diabetic individuals or those with diabetes secondary to pancreatic disease
Group 3
non-diabetic individuals who are not considered to be overweight
Group 4
non-diabetic individuals who are considered to be overweight
Group 5
non-diabetic and type 2 diabetic individuals who will be subjected to an exercise study
Group 6
individuals who have or are suspected of having glucose intolerance, including patients who have a history of gestational diabetes and patients who have polycystic ovary syndrome
Group 7
healthy non-diabetic subjects who will receive one dose of metformin orally 1-2 hours before performing procedures

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
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
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00690755

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

Publications:

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT00690755     History of Changes
Other Study ID Numbers: ENDA-037-04F 
Study First Received: June 2, 2008
Results First Received: May 22, 2015
Last Updated: April 12, 2016
Health Authority: United States: Federal Government
Individual Participant Data  
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared, as data is presented in the published paper as a mean plus or minus SEM.

Keywords provided by VA Office of Research and Development:
Diabetic

Additional relevant MeSH terms:
Diabetes Mellitus
Metabolic Syndrome X
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin Resistance
Hyperinsulinism

ClinicalTrials.gov processed this record on August 30, 2016