Clinical trial NCT00690755: Defective Atypical Protein Kinase C (PKC) Activation in Diabetes and Metabolic Syndrome
Official title: Defective Atypical PKC Activation in Diabetes and Metabolic Syndrome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetic
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2008-06-05
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: type 2 diabetes controlled by diet or oral agents and comparable non-diabetic control subjects

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.

Eligibility criteria: 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

Primary outcomes:
measure: Alterations in PKC-zeta mRNA in Vastus Lateralis Skeletal Muscles
timeFrame: PKC-zeta mRNA levels and aPKC activity in muscle evaluated 40 minutes post-insulin treatment
Secondary outcomes:
Other outcomes:
Locations:
city: Tampa
country: United States
facility: VA Medical Center
state: Florida
Study officials:
affiliation: VA Medical Center
name: Robert V Farese, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Beeson 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.
citation: Casaubon 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.
citation: Luna 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.
citation: Beeson 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.