Decreased IKK Signaling in Skeletal Muscle of Patients with Hyperglycemic Crisis.

Gosmanov, Aidar; Smiley, Dawn; Robalino, G.; Umpierrez, Guillermo; Thomason, Donald

The majority of newly diagnosed obese patients that present with severe hyperglycemia and/or diabetic ketoacidosis have type 2 diabetes mellitus and are able to discontinue insulin during follow up. Shortly after presentation, these subjects have been shown to have impaired insulin action (Umpierrez et al, 1995; Mauvais-Javis 2005) associated with decreased AKT expression in skeletal muscle (Gosmanov et al, 2004). In this study, we examined the expression of proteins implicated in the pathogenesis of insulin resistance OR) via promotion of apoptosis, inflammation, and muscle remodeling. Six control subjects (BG of 84mg/dL) and seven newly-diagnosed subjects with hyperglycemic crisis (age: 37 yr, BMI: 39.6 kg/m2, BG 564 mg/dL, A1C 11.4%) underwent percutaneous needle biopsy of the vastus lateralis muscle within 48 hours of resolution of hyperglycemia. Muscle tissue was homogenized in protein lysis buffer and samples from each group were analyzed in duplicate using a commercial antibody microarmy and, to confirm expression of selected proteins, commercial pathway screening immunoblot analysis. Changes in expression of proteins by 70% or more were considered significant. Analysis of expression of nuclear factor κB (NF-κB), inhibitor of NF-κB (IκB), and kinases IκB (IKK) in skeletal muscle of patients with KPDM showed consistent and marked decrease in the abundance of both IKKα and IKKβ, compared with the control group. Analysis of key proteins of mitogen-activated protein kinase (MAPK) pathway revealed no changes in expression of ERK1,2, p38, and JNK1,2,3. In addition, we observed a significant decrease in expression of protein kinases C (PKC) α and β1 in diabetic muscle. Using focused proteomics of skeletal muscle, our study indicates that hyperglycemia in newly diagnosed patients with ketosis-prone diabetes mellitus (KPDM) is associated with decreased signaling in the NF-κB pathway and decreased expression of conventional PKC without concomitant changes in MAPK signal transduction pathway. The lack of activation of known pro-inflammatory or pro-apoptotic mechanisms suggests different underlying mechanisms for peripheral IR in patients with KPDM. ADA-Funded Research

PROTEINS; MUSCLES; MUSCULOSKELETAL system; PEOPLE with diabetes; HYPERGLYCEMIA; TYPE 2 diabetes

Diabetes, 2007, Vol 56, pA399

0012-1797

Academic Journal