| First Author | Sajan MP | Year | 2014 |
| Journal | Mol Endocrinol | Volume | 28 |
| Issue | 7 | Pages | 1097-107 |
| PubMed ID | 24877563 | Mgi Jnum | J:216249 |
| Mgi Id | MGI:5608556 | Doi | 10.1210/me.2014-1025 |
| Citation | Sajan MP, et al. (2014) PKClambda haploinsufficiency prevents diabetes by a mechanism involving alterations in hepatic enzymes. Mol Endocrinol 28(7):1097-107 |
| abstractText | Tissue-specific knockout (KO) of atypical protein kinase C (aPKC), PKC-lambda, yields contrasting phenotypes, depending on the tissue. Thus, whereas muscle KO of PKC-lambda impairs glucose transport and causes glucose intolerance, insulin resistance, and liver-dependent lipid abnormalities, liver KO and adipocyte KO of PKC-lambda increase insulin sensitivity through salutary alterations in hepatic enzymes. Also note that, although total-body (TB) homozygous KO of PKC-lambda is embryonic lethal, TB heterozygous (Het) KO (TBHetlambdaKO) is well-tolerated. However, beneath their seemingly normal growth, appetite, and overall appearance, we found in TBHetlambdaKO mice that insulin receptor phosphorylation and signaling through insulin receptor substrates to phosphatidylinositol 3-kinase, Akt and residual aPKC were markedly diminished in liver, muscle, and adipose tissues, and glucose transport was impaired in muscle and adipose tissues. Furthermore, despite these global impairments in insulin signaling, other than mild hyperinsulinemia, glucose tolerance, serum lipids, and glucose disposal and hepatic glucose output in hyperinsulinemic clamp studies were normal. Moreover, TBHetlambdaKO mice were protected from developing glucose intolerance during high-fat feeding. This metabolic protection (in the face of impaired insulin signaling) in HetlambdaKO mice seemed to reflect a deficiency of PKC-lambda in liver with resultant 1) increases in FoxO1 phosphorylation and decreases in expression of hepatic gluconeogenic enzymes and 2) diminished expression of hepatic lipogenic enzymes and proinflammatory cytokines. In keeping with this postulate, adenoviral-mediated supplementation of hepatic PKC-lambda induced a diabetic state in HetlambdaKO mice. Our findings underscore the importance of hepatic PKC-lambda in provoking abnormalities in glucose and lipid metabolism. |
