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Protein Kinase C Function in Muscle, Liver, and β-Cells and Its Therapeutic Implications for Type 2 Diabetes

From the Garvan Institute of Medical Research, Darlinghurst, Australia

Corresponding author: Trevor J. Biden, t.biden@garvan.org.au

The first 300 words of the full text of this article appear below.

Increased lipid availability is strongly associated with both β-cell dysfunction and insulin resistance, two key facets of type 2 diabetes. Isoforms of the protein kinase C (PKC) family have been viewed as candidates for mediating the effects of fat oversupply because they are lipid-dependent kinases with wide-ranging roles in signal transduction, including the positive and negative modulation of insulin action. Until recently, their involvement was based on correlative studies, but now causative roles for distinct PKC isoforms have also been addressed, in both pancreatic β-cells and insulin-sensitive tissues. Our goal here, therefore, is to review the hitherto disparate fields of PKC function in insulin signaling/resistance on the one hand and in regulating β-cell biology on the other hand. By integrating these two areas, we provide a reappraisal of the current paradigm regarding PKC and type 2 diabetes. In particular, we propose that PKC warrants further investigation, not merely as a treatment for insulin resistance as previously supposed, but also as a positive regulator of insulin availability.

	DIACYLGLYCEROL-MEDIATED ACTIVATION OF PROTEIN KINASE C

 
The protein kinase C (PKC) family comprises 10 isoforms that have been subdivided into three groups (Fig. 1) based on sequence homology and mechanisms of activation (rev. in 1). While differentiated by their sensitivity to Ca²⁺, both the conventional PKCs (cPKC, -β, and -) and novel PKCs (nPKC, -, -, and -) are dependent on diacylglycerol (DAG) for full activation. These isoforms are therefore responsive to the stimulation of G protein–coupled receptors or receptor tyrosine kinases, which activate phospholipase C, inducing the hydrolysis of phosphatidylinositol 4,5-bisphosphate at the plasma membrane and the resultant generation of DAG and Ca²⁺. Evidence for the acute elevation of DAG in this fashion by insulin was reported in early studies (2), although the identities of the . . . [Full Text of this Article]

	PKCs AS INSULIN SIGNAL TRANSDUCERS

 

	PKC AND INSULIN RESISTANCE

 

	MECHANISMS OF PKC-INDUCED INSULIN RESISTANCE

 

	THE RELATIONSHIP BETWEEN DAG ACCUMULATION, PKC ACTIVATION, AND INSULIN RESISTANCE

 

	RECENT FINDINGS FROM PKC TRANSGENIC AND KNOCKOUT MICE

 

	PKC IN β-CELLS

 

	PKC ISOFORMS AND GLUCOSE-STIMULATED INSULIN SECRETION

 

	PKC AND INSULIN SECRETION DUE TO FATTY ACIDS

 

	REGULATION OF β-CELL MASS OR DIFFERENTIATION BY PKC

 

	PKC IN SECRETORY DYSFUNCTION OF β-CELLS

 

	PKC AS A THERAPEUTIC TARGET FOR TYPE 2 DIABETES

 

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