Role of Caveolin-1 in Diabetes and Its Complications

Figures

• 

  Figure 1. Insulin secretion mechanism and the role of CAV1. At high glucose conditions, the increased ATP/ADP ratio results in the closure of the ATP-sensitive K+ channel Kv2.1, which in turn prompts the opening of the voltage-dependent Ca2+ channel Cav1.2. The increased cytoplasmic Ca2+ triggers the activation of exocytotic machinery. The process is initiated by the dissociation of the CAV1-cdc42-GDP complex through CAV1Tyr14 phosphorylation. The released inactive cdc42-GDP binds to βPIX resulting in an active cdc42-GTP, which interacts with VAMP2-bound insulin secretory granules. These vesicles are then targeted to fusion with the plasma membrane through the interaction between cdc42, VAMP2, F-actin, Syntaxin 1A, and SNAP-25 modulations. Abbreviations: β cell—pancreatic β cell line; GLUT—glucose transporter; TCA cycle—tricarboxylic acid cycle or Krebs cycle; cdc42—cell division cycle 42; βPIX—guanine nucleotide exchange factor 7; VAMP2—vesicle-associated membrane protein 2; F-actin—filamentous actin; SNAP-25—synaptosomal-associated protein 25.

• 

  Figure 2. During normal insulin sensitivity, IR binds and activates CAV1 and then undergoes a series of autophosphorylations and activates the IRS/PI3K/AKT signaling pathway, which eventually leads to GLUT4 translocation in CAV1-mediated vesicles to the surface. During insulin resistance, while CAV1 and IR expression is increased, IR dissociates from CAV1 and moves into GM3-rich lipid rafts leading to impaired insulin signaling and decreased GLUT4 translocation to the membrane and causing a reduction in glucose uptake by the cell. Abbreviations: IR—insulin receptor; AKT—RAC-alpha serine threonine protein kinase; PI3K—phosphatidylinositol-3-kinase; IRS1—insulin receptor substrate 1; GLUT4—glucose transporter 4.

• 

  Figure 3. Forest plot representing relative odds ratio of MetS and LHDLC and their association with CAV1 rs1997623. CA—heterozygous; CC—wild type; A—A-allele; C—C-allele. The width of the horizontal lines represents the 95% confidence intervals for each measurement. Abbreviations: MetS—metabolic syndrome; LHDLC—low HDL cholesterol.

• 

  Figure 4. (a) Variants CAV1-C and CAV1-A cloning into the pRMT-Luc reporter vector. (b) Relative luciferase activity for pRMT-CAV1-C-Luc and pRMT-CAV1-A-Luc in lean, obese, and diabetic adipocytes. (c) Predicted binding sites for transcription factors depending on the CAV1-C and the sequence presenting rs1997623 SNP (CAV1-A). Abbreviations: NKX2-1—NK2 Homeobox 1; MXD1—MAX Dimerization Protein 1; AP-2β1—Adaptor-Related Protein Complex 2 Subunit Beta 1; EBF1—EBF Transcription Factor 1.

• 

  Figure 5. Simplified presentation of the role of CAV1 under oxidative stress and diabetes. During normal CAV1 expression, Sirt1 and p-AKT block p21 activator FOXO3. PP2A dephosphorylates ATM, thus attenuating p53 activation. Active AKT induces MDM2 activation, thus leading to the induction of p53 proteasomal degradation and ultimately normal cellular growth. During diabetes, CAV1 expression increases and caveolae sequester Sirt1, PP2A, and MDM2 preventing their actions, hence leading to the release of FOXO3, phosphorylation of p53 by ATM, and cell cycle arrest. CAV1 decreases p-AKT possibly by interacting with PTEN. The decrease in p-AKT reduces MDM2 activation and attenuates the deactivation of FOXO3 and p21, which eventually leads to cellular senescence. Abbreviations: Sirt1—Sirtuin 1; FOXO3—forkhead box protein O3; ATM—ataxia telangiectasia-mutated; PP2A—protein phosphatase 2A; AKT—RAC-alpha serine threonine protein kinase; MDM2—E3 ubiquitin ligase mouse double minute 2 homolog; p53—tumor protein p53.