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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome

Conditions
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Diabetes Mellitus, Type 2

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>type 2 diabetic individuals | |
| Group 2<br>type 1 diabetic individuals or those with diabetes secondary to pancreatic disease | |
| Group 3<br>non-diabetic individuals who are not considered to be overweight | |
| Group 4<br>non-diabetic individuals who are considered to be overweight | |
| Group 5<br>non-diabetic and type 2 diabetic individuals who will be subjected to an exercise study | |
| Group 6<br>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<br>healthy non-diabetic subjects who will receive one dose of metformin orally 1-2 hours before performing procedures | |

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic