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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00690755
Recruitment Status : Completed
First Posted : June 5, 2008
Results First Posted : May 19, 2016
Last Update Posted : May 19, 2016
Information provided by (Responsible Party):
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.

Condition or disease
Diabetes Mellitus, Type 2

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.

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Study Type : Observational
Actual Enrollment : 157 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome
Study Start Date : May 2000
Actual Primary Completion Date : September 2012
Actual Study Completion Date : September 2012

Resource links provided by the National Library of Medicine

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

Primary Outcome Measures :
  1. 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 ]
    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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00690755

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

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Responsible Party: VA Office of Research and Development Identifier: NCT00690755    
Other Study ID Numbers: ENDA-037-04F
First Posted: June 5, 2008    Key Record Dates
Results First Posted: May 19, 2016
Last Update Posted: May 19, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
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:
Additional relevant MeSH terms:
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Diabetes Mellitus
Metabolic Syndrome
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin Resistance