Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetic
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.
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.
Interventions
None listed
Sponsors
VA Office of Research and Development
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Type 2 diabetic | 28 |
| Group 2 Type 1 Diabetic | 0 |
| Group 3 Control (non-diabetic) | 51 |
| Group 4 Non-Diabetic Overweight | 15 |
| Group 5 Non-Diabetic and Type 2 Diabetic subjected to exercise study | 0 |
| Group 6 Impaired glucose tolerance (IGT) | 6 |
| Group 7 Non-Diabetic treated with Metformin | 0 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 | 46 | 5 | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | Group 1 | Group 3 | Group 4 | Group 6 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 1 | 47 years STANDARD_DEVIATION 3 | 51 years STANDARD_DEVIATION 3 | 43 years STANDARD_DEVIATION 3 | 47 years STANDARD_DEVIATION 4 |
| Gender Female | 6 participants | 18 participants | 10 participants | 3 participants | 37 participants |
| Gender Male | 22 participants | 33 participants | 5 participants | 3 participants | 63 participants |
| Region of Enrollment United States | 28 participants | 51 participants | 15 participants | 6 participants | 100 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 30 | 0 / 0 | 0 / 51 | 0 / 15 | 0 / 0 | 0 / 6 | 0 / 0 |
| serious Total, serious adverse events | 0 / 30 | 0 / 0 | 0 / 97 | 0 / 20 | 0 / 0 | 0 / 10 | 0 / 0 |
Outcome results
Primary
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.
Time frame: PKC-zeta mRNA levels and aPKC activity in muscle evaluated 40 minutes post-insulin treatment
Population: PKC-zeta mRNA and aPKC activity in vastus lateralis skeletal muscle was measured by analysis of gene expression levels of PKC and measuring them in relative amounts in comparison to control subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles | 1.76 arbitrary units/ng rRNA | Standard Error 0.088 |
| Group 3 | Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles | 3.58 arbitrary units/ng rRNA | Standard Error 0.179 |
| Group 4 | Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles | 2.14 arbitrary units/ng rRNA | Standard Error 0.107 |
| Group 6 | Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles | 2.22 arbitrary units/ng rRNA | Standard Error 0.11 |
p-value: 0.001ANOVA