ArticleDiabetologia2012
Insulin signalling in hepatocytes of humans with type 2 diabetes: excessive production and activity of protein kinase C-ι (PKC-ι) and dependent processes and reversal by PKC-ι inhibitors.
Article in Diabetologia, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- The Impact of Exercise Training on the Brain and Cognition in Type 2 Diabetes, and its Physiological Mediators: A Systematic Review.Sports medicine - open · 2025Pooled it
- Inhibition of PKCγ phosphorylation protects against cerebral ischemia-reperfusion injury.Redox biology · 2026Article
- Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.iScience · 2026Article
- Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice.The Journal of clinical investigation · 2025Article
- Activating PKC-ε induces HIV expression with improved tolerability.PLoS pathogens · 2025Article
- Review
- A Novel Approach Based on Metabolomics Coupled With Intestinal Flora Analysis and Network Pharmacology to Explain the Mechanisms of Action of Bekhogainsam Decoction in the Improvement of Symptoms of Streptozotocin-Induced Diabetic Nephropathy in Mice.Frontiers in pharmacology · 2020Article
- Atypical PKC, PKCλ/ι, activates β-secretase and increases AβNeurobiology of aging · 2018Article
- Hepatoprotective potential of isoquercitrin against type 2 diabetes-induced hepatic injury in rats.Oncotarget · 2017Article
- A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance.Nature communications · 2017Article
- Article
- Protein kinase Cζ exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation.The Biochemical journal · 2016Article
- BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans.Metabolism: clinical and experimental · 2015Article
- Hepatic insulin resistance in ob/ob mice involves increases in ceramide, aPKC activity, and selective impairment of Akt-dependent FoxO1 phosphorylation.Journal of lipid research · 2015Article
- Higher protein kinase C ζ in fatty rat liver and its effect on insulin actions in primary hepatocytes.PloS one · 2015Article
- Requirements for pseudosubstrate arginine residues during autoinhibition and phosphatidylinositol 3,4,5-(PO₄)₃-dependent activation of atypical PKC.The Journal of biological chemistry · 2014Article
- Article
- Hepatic Atypical Protein Kinase C: An Inherited Survival-Longevity Gene that Now Fuels Insulin-Resistant Syndromes of Obesity, the Metabolic Syndrome and Type 2 Diabetes Mellitus.Journal of clinical medicine · 2014Review
- PKCλ haploinsufficiency prevents diabetes by a mechanism involving alterations in hepatic enzymes.Molecular endocrinology (Baltimore, Md.) · 2014Article
- Role of protein kinase C in podocytes and development of glomerular damage in diabetic nephropathy.Frontiers in endocrinology · 2014Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
aims/hypothesisWe examined the role of protein kinase C-ι (PKC-ι) in mediating alterations in the abundance of enzymes in hepatocytes of type 2 diabetic humans that contribute importantly to the development of lipid and carbohydrate abnormalities in type 2 diabetes.
methodsWe examined (1) insulin signalling in isolated hepatocytes of non-diabetic and type 2 diabetic humans and (2) the effects of two newly developed small molecule PKC-ι inhibitors on aberrant signalling and downstream processes.
resultsIn contrast with PKC-ι deficiency in diabetic muscle, which diminishes glucose transport, PKC-ι in diabetic hepatocytes was overproduced and overactive, basally and after insulin treatment, and, moreover, was accompanied by increased abundance of PKC-ι-dependent lipogenic, proinflammatory and gluconeogenic enzymes. Heightened PKC-ι activity most likely reflected heightened activity of IRS-2-dependent phosphatidylinositol 3-kinase (PI3K), as IRS-1 levels and IRS-1/PI3K activity were markedly diminished. Importantly, insulin-stimulated PKC-ι abundance and its overabundance in diabetic hepatocytes was reversed in vitro by both insulin deprivation and PKC-ι inhibitors; this suggested operation of an insulin-driven, feed-forward/positive-feedback mechanism. In contrast with PKC-ι, protein kinase B (Akt2) activity and activation by insulin was diminished, apparently reflecting IRS-1 deficiency. Treatment of diabetic hepatocytes with PKC-ι/λ inhibitors diminished abundance of lipogenic, proinflammatory and gluconeogenic enzymes. CONCLUSIONS/
interpretationOur findings suggest that a vicious cycle of PKC-ι overactivity and overproduction exists in hepatocytes of humans with type 2 diabetes and contributes importantly to maintaining overactivity of lipogenic, proinflammatory and gluconeogenic pathways, which underlies the lipid and carbohydrate abnormalities in type 2 diabetes.
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Registered trials
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