Diabetes Mellitus, Type 2NCT00690755
Defective Atypical Protein Kinase C (PKC) Activation in Diabetes and Metabolic Syndrome
An observational study of Diabetes Mellitus, Type 2, run by VA Office of Research and Development at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Type 2
- Type of treatment
- Pill or oral medicine
- How many people
- 157 participants
- Where
- 1 siteUnited States
- Study dates
- May 2000to Sep 2012
- Phase
- Observational
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: type 2 diabetes controlled by diet or oral agents and comparable non-diabetic control subjects
Who may be able to join
- Stable uncomplicated type 2 diabetes
- Able to be off oral treatments for 2 months
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- Diabetic
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 being measured
The primary outcome is the main question the study is designed to answer.
Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles
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.
Measured: PKC-zeta mRNA levels and aPKC activity in muscle evaluated 40 minutes post-insulin treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jun 2008 (estimated)
- Study startMay 2000
- Primary completionSep 2012
- Study completionSep 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 157 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Robert V Farese, MD, Principal investigator, VA Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00690755
- Sponsor's protocol ID
- ENDA-037-04F
- Status last verified
- Apr 2016
- First submitted
- 2 Jun 2008
- Last updated
- 19 May 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: Individual participant data will not be shared, as data is presented in the published paper as a mean plus or minus SEM.
Publications
Temofonte N, Sajan MP, Nimal S, Pastoor T, Fumero C, Casaubon L, Powe JL, Standaert ML, Farese RV. Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle. Diabetologia. 2009 Jan;52(1):60-4. doi: 10.1007/s00125-008-1180-z. Epub 2008 Oct 30.
PubMed 18972094Beeson M, Sajan MP, Daspet JG, Luna V, Dizon M, Grebenev D, Powe JL, Lucidi S, Miura A, Kanoh Y, Bandyopadhyay G, Standaert ML, Yeko TR, Farese RV. Defective Activation of Protein Kinase C-z in Muscle by Insulin and Phosphatidylinositol-3,4,5,-(PO(4))(3) in Obesity and Polycystic Ovary Syndrome. Metab Syndr Relat Disord. 2004 Spring;2(1):49-56. doi: 10.1089/met.2004.2.49.
PubMed 18370676Casaubon L, Sajan MP, Rivas J, Powe JL, Standaert ML, Farese RV. Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans. Diabetologia. 2006 Dec;49(12):3000-8. doi: 10.1007/s00125-006-0471-5. Epub 2006 Oct 7.
PubMed 17028898Luna V, Casauban L, Sajan MP, Gomez-Daspet J, Powe JL, Miura A, Rivas J, Standaert ML, Farese RV. Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects. Diabetologia. 2006 Feb;49(2):375-82. doi: 10.1007/s00125-005-0112-4. Epub 2006 Jan 5.
PubMed 16395615Beeson M, Sajan MP, Dizon M, Grebenev D, Gomez-Daspet J, Miura A, Kanoh Y, Powe J, Bandyopadhyay G, Standaert ML, Farese RV. Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. Diabetes. 2003 Aug;52(8):1926-34. doi: 10.2337/diabetes.52.8.1926.
PubMed 12882907
Study at a glance
From the registry record, last updated by the sponsor on 19 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome
- ClinicalTrials.gov ID
- NCT00690755
- Acronym / sponsor ID
- ENDA-037-04F
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- Diabetic
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 157 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- May 2000
- Primary completion
- Sep 2012 (actual)
- Study completion
- Sep 2012 (actual)
- First posted
- 5 Jun 2008 (estimated)
- Results
- Posted 19 May 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- type 2 diabetes controlled by diet or oral agents and comparable non-diabetic control subjects
Key inclusion criteria (2 listed)
- Stable uncomplicated type 2 diabetes
- Able to be off oral treatments for 2 months
Key exclusion criteria (6 listed)
- Diabetic complications related to heart, eye, nerve problems
- Renal impairment
- Cardiovascular disease
- Hepatic disease
- Prior history of other disorders or complications caused by diseases
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 May 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 18972094Temofonte N, Sajan MP, Nimal S, Pastoor T, Fumero C, Casaubon L, Powe JL, Standaert ML, Farese RV. Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle. Diabetologia. 2009 Jan;52(1):60-4. doi: 10.1007/s00125-008-1180-z. Epub 2008 Oct 30.
- Results publication: PubMed 18370676Beeson M, Sajan MP, Daspet JG, Luna V, Dizon M, Grebenev D, Powe JL, Lucidi S, Miura A, Kanoh Y, Bandyopadhyay G, Standaert ML, Yeko TR, Farese RV. Defective Activation of Protein Kinase C-z in Muscle by Insulin and Phosphatidylinositol-3,4,5,-(PO(4))(3) in Obesity and Polycystic Ovary Syndrome. Metab Syndr Relat Disord. 2004 Spring;2(1):49-56. doi: 10.1089/met.2004.2.49.
- Results publication: PubMed 17028898Casaubon L, Sajan MP, Rivas J, Powe JL, Standaert ML, Farese RV. Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans. Diabetologia. 2006 Dec;49(12):3000-8. doi: 10.1007/s00125-006-0471-5. Epub 2006 Oct 7.
- Results publication: PubMed 16395615Luna V, Casauban L, Sajan MP, Gomez-Daspet J, Powe JL, Miura A, Rivas J, Standaert ML, Farese RV. Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects. Diabetologia. 2006 Feb;49(2):375-82. doi: 10.1007/s00125-005-0112-4. Epub 2006 Jan 5.
- Results publication: PubMed 12882907Beeson M, Sajan MP, Dizon M, Grebenev D, Gomez-Daspet J, Miura A, Kanoh Y, Powe J, Bandyopadhyay G, Standaert ML, Farese RV. Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. Diabetes. 2003 Aug;52(8):1926-34. doi: 10.2337/diabetes.52.8.1926.
- Individual participant dataSharing planned: No. Individual participant data will not be shared, as data is presented in the published paper as a mean plus or minus SEM.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert V Farese, MD principal investigator
VA Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Diabetes Mellitus, Type 2, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 May 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00690755, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 May 2016.