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

April 12, 2016 updated by: VA Office of Research and Development

Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome

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.

Study Overview

Status

Completed

Conditions

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 Type

Observational

Enrollment (Actual)

157

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Tampa, Florida, United States, 33612
        • Va Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

type 2 diabetes controlled by diet or oral agents and comparable non-diabetic control subjects

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
PKC-zeta mRNA levels and aPKC activity in muscle evaluated 40 minutes post-insulin treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Principal Investigator: Robert V Farese, MD, Va Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2000

Primary Completion (Actual)

September 1, 2012

Study Completion (Actual)

September 1, 2012

Study Registration Dates

First Submitted

June 2, 2008

First Submitted That Met QC Criteria

June 4, 2008

First Posted (Estimate)

June 5, 2008

Study Record Updates

Last Update Posted (Estimate)

May 19, 2016

Last Update Submitted That Met QC Criteria

April 12, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ENDA-037-04F

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data will not be shared, as data is presented in the published paper as a mean plus or minus SEM.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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