The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index; none of the 21 sources its claims cite is checked for support yet.
Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease
Open accessAbstract
Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance and type 2 diabetes mellitus, but the molecular signals linking hepatic fat accumulation to hepatic insulin resistance are unknown. Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance. In this setting, PKCepsilon, but not other isoforms of PKC, is activated. To determine whether PKCepsilon plays a causal role in the pathogenesis of hepatic insulin resistance, we treated rats with an antisense oligonucleotide against PKCepsilon and subjected them to 3 days of high-fat feeding. Knocking down PKCepsilon expression protects rats from fat-induced hepatic insulin resistance and reverses fat-induced defects in hepatic insulin signaling. Furthermore, we show that PKCepsilon associates with the insulin receptor in vivo and impairs insulin receptor kinase activity both in vivo and in vitro. These data support the hypothesis that PKCepsilon plays a critical role in mediating fat-induced hepatic insulin resistance and represents a novel therapeutic target for type 2 diabetes.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In rats, 3 days of high-fat feeding causes hepatic steatosis and hepatic insulin resistance with specific activation of PKCε. Knocking down PKCε with an antisense oligonucleotide prevents fat-induced hepatic insulin resistance and improves hepatic insulin signaling, apparently by preventing PKCε from directly inhibiting insulin receptor kinase activity.
Key findings
- PKCε ASO specifically reduced PKCε expression in liver and white adipose tissue, but not muscle, without changing PKCδ; it caused no hepatotoxicity (AST: saline 57 ± 0.3 vs. PKCε 68 ± 3; ALT: saline 76 ± 3 vs. PKCε 87 ± 5), similar weight gain, and no differences in IL-6, leptin, adiponectin, or resistin.
- Despite unchanged liver triglyceride and DAG content and identical fasting plasma glucose, PKCε ASO lowered fasting plasma insulin by approximately 50% versus saline- and control ASO-treated rats, and improved hepatic insulin action: greater suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamping, modestly increased whole-body glucose disposal, nearly 2-fold higher epididymal white adipose tissue glucose uptake, and greater suppression of plasma fatty acids.
- In PKCε ASO-treated rats, insulin increased IRS2 tyrosine phosphorylation approximately 300% above basal, whereas saline and control ASO rats failed to increase IRS2 phosphorylation; insulin-stimulated AKT2 activity increased approximately 400% versus approximately 50% in controls. Adipose insulin-stimulated AKT2 activity was 221% ± 16% in PKCε ASO rats versus 32% ± 11% and 23% ± 20% in saline- and control ASO-treated rats.
- PKCε coimmunoprecipitated with the insulin receptor in vivo, and increasing molar ratios of PKCε to insulin receptor-β dose-dependently decreased insulin receptor-β tyrosine kinase activity in vitro. Liver insulin receptor kinase activation by insulin was diminished in saline- and control ASO-treated high-fat-fed rats but preserved in PKCε ASO-treated rats.
Methods
- Male Sprague-Dawley rats weighing approximately 250 g were treated for 4 weeks with saline, control ASO, or PKCε ASO at 75 mg/kg per week by intraperitoneal injection, then fed a high-fat diet (26% carbohydrate, 59% fat, 15% protein calories; safflower oil major constituent) for 3 days.
- Hyperinsulinemic-euglycemic clamp studies used [6,6-2H]glucose and 2-deoxy-d-[1-14C]glucose to assess basal and insulin-stimulated glucose turnover and tissue glucose uptake; liver triglyceride and DAG, plasma hormones and fatty acids, insulin signaling, PKC expression, and insulin receptor kinase activity were measured.
- PKCε ASO was ISIS-232697; control ASO was ISIS-141923. A separate group of similarly treated rats underwent 20 minutes of hyperinsulinemic-euglycemic clamping for insulin signaling assays. Statistics used 1-way ANOVA followed by Tukey’s HSD test, with P < 0.05 considered significant.
Limitations
- The paper does not include a dedicated limitations section. It states that the role of PKCε in the adipocyte is uncertain and that a similar mechanism in patients with diabetes is hypothesized based on prior human data, not directly tested here.
- Evident from the text: the findings are in male Sprague-Dawley rats after only 3 days of high-fat feeding and 4 weeks of ASO treatment, so they cannot establish long-term causality, safety, or efficacy in human NAFLD or type 2 diabetes.
- Evident from the text: PKCε ASO reduced PKCε in liver and white adipose tissue but not muscle, and muscle glucose uptake was unchanged, limiting conclusions about skeletal muscle insulin action.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 of 21 cited sources checked · 0 supported · 0 flagged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, we show that PKCε associates with the insulin receptor in vivo and impairs insulin receptor kinase activity both in vivo and in vitro.”
- Also stated in: § PKCε interferes with insulin receptor activation. · plain
“Immunoprecipitation of insulin receptor from liver protein extracts pulled down PKCε, and immunoprecipitation of PKCε also pulled down insulin receptor (Figure 4D).”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · boosted
“First, we show here that PKCε and insulin receptor directly associate in vivo, as they each coimmunoprecipitate the other.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § PKCε interferes with insulin receptor activation. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The reduction in mRNA translated into a similar reduction in PKCε protein content relative to that in saline-treated animals (Figure 1B).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO is specific and effective.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Knocking down PKCε expression protects rats from fat-induced hepatic insulin resistance and reverses fat-induced defects in hepatic insulin signaling.”
- Also stated in: § PKCε ASO treatment does not alter liver lipids but lowers plasma insulin. · plain
“Under hyperinsulinemic conditions, suppression of hepatic glucose production was markedly greater in the PKCε group compared with the saline and control ASO groups (Figure 3B).”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · boosted
“Here we establish that decreasing PKCε expression protects against the development of hepatic insulin resistance and improves adipose insulin action by augmenting the activity of the insulin signaling pathway.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § PKCε ASO treatment does not alter liver lipids but lowers plasma insulin. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, PKCε ASO treatment did not alter muscle PKCε expression.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO is specific and effective.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Knocking down PKCε expression protects rats from fat-induced hepatic insulin resistance and reverses fat-induced defects in hepatic insulin signaling.”
- Also stated in: § PKCε ASO treatment improves insulin signaling. · plain
“In contrast, in rats treated with PKCε ASO, insulin increased IRS2 tyrosine phosphorylation approximately 300% above basal (Figure 4B).”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · plain
“Thus, PKCε ASO treatment prevents the defects in insulin signaling that lead to the development of hepatic insulin resistance.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § PKCε ASO treatment improves insulin signaling. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The amount of PKCδ was unchanged by PKCε ASO treatment.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO is specific and effective.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Insulin receptor tyrosine phosphorylation was similarly increased above basal by approximately 50% in all 3 groups.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO treatment improves insulin signaling.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition to the changes in hepatic insulin action, there was a modest but significant increase in insulin-stimulated whole-body glucose disposal in the PKCε ASO-treated animals (Figure 3C).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO treatment does not alter liver lipids but lowers plasma insulin.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, analysis of the insulin signaling pathway demonstrated that insulin signaling was improved in PKCε-treated rats.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The lower insulin concentration approaches values seen in rats on regular (low-fat) chow and suggests improved hepatic insulin sensitivity.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO treatment does not alter liver lipids but lowers plasma insulin.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 10
- Probably not a substantial claim. 4
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PKCε ASO treatment specifically reduced PKCε expression in liver and white adipose tissue after 4 weeks of treatment at 75 mg/kg per week (Figure 1A).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO is specific and effective.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, we show that PKCε associates with the insulin receptor in vivo and impairs insulin receptor kinase activity both in vivo and in vitro.”
- Also stated in: § PKCε interferes with insulin receptor activation. · hedged
“Increasing molar ratios of PKCε to insulin receptor-β resulted in a dose-dependent decrease in insulin receptor-β tyrosine kinase activity, suggesting that PKCε could directly inhibit insulin receptor kinase activity (Figure 4E).”
- Also stated in: § PKCε interferes with insulin receptor activation. · plain
“In contrast, insulin receptor obtained from PKCε ASO-treated rats had preserved activation of the insulin receptor kinase.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § PKCε interferes with insulin receptor activation. · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither fasting plasma glucose concentrations nor basal hepatic glucose production rates were affected by PKCε ASO therapy.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Immunoprecipitation of insulin receptor from liver protein extracts pulled down PKCε, and immunoprecipitation of PKCε also pulled down insulin receptor (Figure 4D).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε interferes with insulin receptor activation.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PKCε ASO specifically inhibits PKCε, without altering the levels of other PKC isoforms.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, rats remained free of hepatotoxicity, as reflected by the absence of transaminase elevation (aspartate aminotransferase [AST]: saline, 57 ± 0.3; PKCε, 68 ± 3; alanine aminotransferase [ALT]: saline, 76 ± 3; PKCε, 87 ± 5), and exhibited similar weight gain (Figure 1C) across all 3 groups.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO is specific and effective.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Amelioration of nonalcoholic fatty liver disease (NAFLD) in patients with T2DM by weight reduction is associated with reversal of hepatic insulin resistance and a return to normoglycemia (9).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Introduction
What the sources say
- Not checked yetcites [9] Petersen, 2005, Diabetes. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“An alternate hypothesis is that the development of hepatic steatosis per se causes hepatic insulin resistance.”
- Also stated in: § Introduction · boosted
“multiple lines of evidence support the role of intrahepatic fat in causing hepatic insulin resistance (7)(8)(9)(10)(11)(12).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Introduction
What the sources say
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true.
- Also stated in: § Introduction · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“Preventing fat accumulation by inhibiting lipid synthesis via disruption of the mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase (7) or promoting fat oxidation using either the mitochondrial uncoupler 2,4-dinitrophenol (10) or inhibition of acetyl-CoA carboxylase-1 and -2 (12) prevents PKCε activation and hepatic insulin resistance.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In this setting, PKCε, but not other isoforms of PKC, is activated.”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · plain
“we observed that the development of diet-induced hepatic steatosis was associated with the activation of PKCε (7,10,12).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · plain
None of the sources cited for this claim have been checked yet.
In the paper
“This is important since DAG is a known activator of classic and novel isoforms of PKC and DAG concentrations have closely paralleled insulin resistance in other models (7,12).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This is important since DAG is a known activator of classic and novel isoforms of PKC and DAG concentrations have closely paralleled insulin resistance in other models (7,12).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, in this model system, we specifically inhibit PKCε without altering other PKC isoforms or the concentration of PKC activators.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
ASOs are avidly taken up by the liver, where they inhibit specific genes of interest.
“ASOs are avidly taken up by the liver, where they inhibit specific genes of interest.”
The paper relies on this without support.
The control ASO does not have perfect complementarity to any known gene in public databases.
“The control ASO, ISIS-141923, has the sequence 5′-CCTTCCCT-GAAGGTTCCTCC-3′ and does not have perfect complementarity to any known gene in public databases.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [24]
In the citing paper
“Recent studies have shown that increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of the protein kinase C epsilon isoform, resulting in reduced insulin signaling and hepatic insulin resistance.23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Glucose tracer enrichment is identified as both M+6 and M+2
MinorThe methods describe the measured glucose enrichment as M+6, but then identify it as M+2 when specifying the mass ratio used. Both statements refer to the enrichment measurement for the same tracer.
“The atom percentage enrichment of glucoseM+6 was then measured by gas chromatographic/mass spectrometric analysis using a Hewlett-Packard 5890 gas chromatograph interfaced to a Hewlett-Packard 5971A mass-selective detector operating in the electron ionization mode (29).”
“GlucoseM+2 enrichment was determined from the m/z ratio 202:200.”
Citations
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751
A new mathematical model for relative quantification in real-time RT-PCR
Pfaffl, M. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.e45 · Cited by 34,610
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) · Diabetes Care · doi:10.2337/diacare.27.5.1047 · Cited by 15,297
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769
Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome
Kadowaki, T. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29126 · Cited by 2,824
Özcan, U., Yilmaz, E., Özcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O., Görgün, C. Z., & Hotamisligil, G. S. (2006) · Science · doi:10.1126/science.1128294 · Cited by 2,413
Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561
Self-citationGlobal Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030
Wild, S. H., Roglić, G., Green, A., Sicree, R. A., & King, H. O. M. (2004) · Diabetes Care · doi:10.2337/diacare.27.10.2569-a · Cited by 1,477
Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322
Self-citationPetersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005) · Diabetes · doi:10.2337/diabetes.54.3.603 · Cited by 911
Self-citation
Flagged first, then by citations
1 of the 39 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Self-citationDeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Self-citationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002
“Lowering PKCε expression in the liver protects rats from lipid-induced hepatic insulin resistance and preserves IRTK activity despite increases in liver lipid content (Samuel et al., 2007).”
BackgroundSelf-citationStanhope, K. L., Schwarz, J. M., Keim, N. L., Griffen, S. C., Bremer, A. A., Graham, J. L., Hatcher, B., Cox, C. L., Dyachenko, A., Zhang, W., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37385 · Cited by 1,765
Adipose tissue dysfunction as determinant of obesity-associated metabolic complications
Longo, M., Zatterale, F., Naderi, J., Parrillo, L., Formisano, P., Raciti, G. A., Beguinot, F., & Miele, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092358 · Cited by 1,575
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484
Self-citationInsulin Receptor Signaling in Normal and Insulin-Resistant StatesPreprint
Boucher, J., Kleinridders, A., & Kahn, C. R. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009191 · Cited by 1,550
Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease
Ipsen, D. H., Lykkesfeldt, J., & Tveden-Nyborg, P. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2860-6 · Cited by 1,471
Postic, C., & Girard, J. R. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34275 · Cited by 1,243
The integrative biology of type 2 diabetes
Roden, M., & Shulman, G. I. (2019) · Nature · doi:10.1038/s41586-019-1797-8 · Cited by 1,167
Self-citationMolecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes
Muoio, D. M., & Newgard, C. B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2327 · Cited by 1,177
Regulation of hepatic glucose metabolism in health and disease
Petersen, M. C., Vatner, D. F., & Shulman, G. I. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.80 · Cited by 1,159
Self-citationThe role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry, R. J., Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2014) · Nature · doi:10.1038/nature13478 · Cited by 1,170
Self-citationDisordered lipid metabolism and the pathogenesis of insulin resistance.
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2007) · Physiological Reviews · doi:10.1152/physrev.00024.2006 · Cited by 1,107
Self-citationInsulin Resistance: From Mechanisms to Therapeutic Strategies
Lee, S.-H., Park, S., & Choi, C. S. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0280 · Cited by 1,248
Copps, K. D., & White, M. F. (2012) · Diabetologia · doi:10.1007/s00125-012-2644-8 · Cited by 1,017
“Rodent and human studies validate the contribution of dyslipidaemia to skeletal muscle and liver insulin resistance via diacylglycerol-mediated activation of nPKCs, including PKCθ [65, 146, 147], PKCδ [148] and PKCε [149, 150] (reviewed in [74, 94]).”
BackgroundTrends in insulin resistance: insights into mechanisms and therapeutic strategy
Li, M., Chi, X., Wang, Y., Setrerrahmane, S., Xie, W., & Xu, H. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01073-0 · Cited by 939
“SREBP-1c is a major regulator of fatty acid synthesis and hepatic SREBP-1c overexpression increases DAG content and PKCε translocation that in turn impairs INSR tyrosine kinase activity, thereby inducing hepatic IR.(326,327) While ChREBP deficiency improves IR and hepatic steatosis by inhibiting the entire lipogenic a…”
BackgroundFullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3372 · Cited by 893
Nonalcoholic fatty liver disease
Brunt, E. M., Wong, V. W., Nobili, V., Day, C. P., Sookoian, S. C., Maher, J. J., Bugianesi, E., Sirlin, C. B., Neuschwander‐Tetri, B. A., & Rinella, M. E. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.80 · Cited by 889
Adiels, M., Olofsson, S.-O., Taskinen, M.-R., & Borén, J. (2008) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.107.160192 · Cited by 820
Inflammatory mechanisms in the regulation of insulin resistance
Tilg, H., & Moschen, A. R. (2008) · Molecular Medicine · doi:10.2119/2007-00119.tilg · Cited by 779
Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745
“Following a meal, the relatively high concentrations of insulin within the portal vein ( 33 peripheral vein) directly activate hepatic insulin receptor tyrosine kinase (IRTK) activity, initiating a coordinated relay of intracellular signals (Figure 1) (Samuel and Shulman, 2012).”
InfluentialSelf-citationThe role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome
Petersen, K. F., Dufour, S., Savage, D. B., Bilz, S., Solomon, G., Yonemitsu, S., Cline, G. W., Befroy, D., Zemany, L., Kahn, B. B., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705408104 · Cited by 759
Self-citationNonalcoholic Fatty Liver Disease, Hepatic Insulin Resistance, and Type 2 Diabetes
Birkenfeld, A. L., & Shulman, G. I. (2013) · Hepatology · doi:10.1002/hep.26672 · Cited by 752
Self-citationBiochemical and cellular properties of insulin receptor signalling
Haeusler, R. A., McGraw, T. E., & Accili, D. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.89 · Cited by 739
Kammoun, H. L., Chabanon, H., Hainault, I., Luquet, S., Magnan, C., Koike, T., Ferré, P., & Foufelle, F. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37007 · Cited by 732
Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome
Lonardo, A., Ballestri, S., Marchesini, G., Angulo, P., & Loria, P. (2014) · Digestive and Liver Disease · doi:10.1016/j.dld.2014.09.020 · Cited by 692
Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)
Musso, G., Gambino, R. J., & Cassader, M. (2008) · Progress in Lipid Research · doi:10.1016/j.plipres.2008.08.001 · Cited by 691
Metabolites as regulators of insulin sensitivity and metabolism
Yang, Q., Vijayakumar, A., & Kahn, B. B. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0044-8 · Cited by 698
Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum
Hardy, T., Oakley, F., Anstee, Q. M., & Day, C. P. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044224 · Cited by 641
“Accumulation of hepatic DAG within cytosolic lipid droplets is associated with increased translocation of the primary novel protein kinase C (PKC) isoform in the liver, PKCε, to the plasma membrane where it binds and inhibits the intracellular kinase domain of the insulin receptor (134, 135).”
BackgroundThe inflammation highway: metabolism accelerates inflammatory traffic in obesity
Johnson, A. R., Justin Milner, J., & Makowski, L. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01151.x · Cited by 603
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113359108 · Cited by 585
Self-citationCrucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
Matsuzaka, T., Shimano, H., Yahagi, N., Kato, T., Atsumi, A., Yamamoto, T., Inoue, N., Ishikawa, M., Okada, S., Ishigaki, N., et al. (2007) · Nature Medicine · doi:10.1038/nm1662 · Cited by 557
“Diacylglycerol accumulation has been reported to be linked to the increased protein kinase C (PKC) e activity and impaired phosphorylation of IRS-2 tyrosine induced by insuli”
BackgroundCauses and Metabolic Consequences of Fatty Liver
Stefan, N., Kantartzis, K., & Häring, H. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0009 · Cited by 536
“This observation is important because hepatic protein kinase C is involved in the development of hepatic insulin resistance (349).”
BackgroundPathophysiology of obesity and its associated diseases
Jin, X., Qiu, T., Li, L., Yu, R., Chen, X., Li, C., Proud, C. G., & Jiang, T. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.01.012 · Cited by 603
Diacylglycerol-mediated insulin resistance
Erion, D. M., & Shulman, G. I. (2010) · Nature Medicine · doi:10.1038/nm0410-400 · Cited by 502
Self-citationErtunc, M. E., & Hotamışlıgil, G. S. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r066514 · Cited by 500
Wilson, C. G., Tran, J. L., Erion, D. M., Vera, N. B., Febbraio, M., & Weiss, E. J. (2015) · Endocrinology · doi:10.1210/en.2015-1866 · Cited by 473
Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A., & Smith, U. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2017 · Cited by 462
Endoplasmic Reticulum Stress and Inflammation in Obesity and Diabetes
Hummasti, S., & Hotamışlıgil, G. S. (2010) · Circulation Research · doi:10.1161/circresaha.110.225698 · Cited by 445
Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease
Petersen, K. F., Dufour, S., Hariri, A., Nelson-Williams, C., Foo, J. N., Zhang, X.-M., Dziura, J., Lifton, R. P., & Shulman, G. I. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907295 · Cited by 428
Self-citationBenhamed, F., Denechaud, P.-D., Lemoine, M., Robichon, C., Moldes, M., Bertrand-Michel, J., Ratziu, V., Serfaty, L., Housset, C., Capeau, J., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci41636 · Cited by 408
Roles of diacylglycerols and ceramides in hepatic insulin resistance
Petersen, M. C., & Shulman, G. I. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.04.004 · Cited by 373
Self-citationMolecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis
Anderson, N., & Borlak, J. T. (2008) · Pharmacological Reviews · doi:10.1124/pr.108.00001 · Cited by 395
Choi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704213200 · Cited by 383
Self-citationFructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease
ter Horst, K. W., & Serlie, M. J. M. (2017) · Nutrients · doi:10.3390/nu9090981 · Cited by 379
Benoit, S. C., Kemp, C. J., Elias, C. F., Abplanalp, W., Herman, J. P., Migrenne, S., Lefevre, A.-L., Cruciani-Guglielmacci, C., Magnan, C., Yu, F., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36714 · Cited by 351
Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration
Sun, Z., Miller, R. A., Patel, R. T., Chen, J., Dhir, R., Wang, H., Zhang, D., Graham, M. J., Unterman, T. G., Shulman, G. I., et al. (2012) · Nature Medicine · doi:10.1038/nm.2744 · Cited by 335
Self-citationMetabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?
Asrih, M., & Jornayvaz, F. R. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.02.018 · Cited by 336
“Supporting these findings, inhibition of PKCε using an antisense oligonucleotide prevented hepatic insulin resistance despite hepatic lipid accumulation (Samuel et al., 2007).”
BackgroundChoi, C. S., Savage, D. B., Abu-Elheiga, L., Liu, Z.-X., Kim, S., Kulkarni, A., Distefano, A., Hwang, Y.-J., Reznick, R. M., Codella, R., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706794104 · Cited by 325
Self-citationDiacylglycerol Activation of Protein Kinase Cε and Hepatic Insulin Resistance
Jornayvaz, F. R., & Shulman, G. I. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.005 · Cited by 331
“were able to show that knocking down PKCε expression in liver protected rats from lipid-induced hepatic insulin resistance despite increases in hepatic lipid content (Samuel et al., 2007).”
BackgroundResultInfluentialSelf-citationDAG tales: the multiple faces of diacylglycerol—stereochemistry, metabolism, and signaling
Eichmann, T. O., & Lass, A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1982-3 · Cited by 332
Fructose: Metabolic, Hedonic, and Societal Parallels with Ethanol
Lustig, R. H. (2010) · Journal of the American Dietetic Association · doi:10.1016/j.jada.2010.06.008 · Cited by 317
Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases
Ruiz‐Ojeda, F. J., Méndez-Gutiérrez, A., Aguilera, C. M., & Plaza‐Díaz, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194888 · Cited by 334
Kantartzis, K., Peter, A., Machicao, F. E., Machann, J., Wagner, S., Königsrainer, I., Königsrainer, A., Schick, F., Fritsche, A., Häring, H., et al. (2009) · Diabetes · doi:10.2337/db09-0279 · Cited by 305
Zhang, D., Liu, Z.-X., Choi, C. S., Tian, L., Kibbey, R., Dong, J., Cline, G. W., Wood, P. A., & Shulman, G. I. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707060104 · Cited by 291
Self-citationDietary carbohydrates and fats in nonalcoholic fatty liver disease
Yki-Järvinen, H., Luukkonen, P. K., Hodson, L., & Moore, J. B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00472-y · Cited by 294
Molecular mechanisms involved in NAFLD progression
Malaguarnera, M., Rosa, M. D., Nicoletti, F., & Malaguarnera, L. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0464-1 · Cited by 288
Hepatic triacylglycerol accumulation and insulin resistance
Nagle, C. A., Klett, E. L., & Coleman, R. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800053-jlr200 · Cited by 272
Role of Insulin Resistance and Lipotoxicity in Non-Alcoholic Steatohepatitis
Cusi, K. J. (2009) · Clinics in Liver Disease · doi:10.1016/j.cld.2009.07.009 · Cited by 270
Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes
Yung, J. H. M., & Giacca, A. (2020) · Cells · doi:10.3390/cells9030706 · Cited by 284
Fructose induced lipogenesis: from sugar to fat to insulin resistance
Samuel, V. T. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.10.003 · Cited by 271
Self-citationThe Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis
Herman, M. A., & Samuel, V. T. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.06.005 · Cited by 259
“While PKCe ASO treatment did not prevent hepatic steatosis in fat-fed rats, it did preserve hepatic insulin signaling [95].”
Self-citationPathogenesis of Lipid Disorders in Insulin Resistance: a Brief Review
Bjornstad, P., & Eckel, R. H. (2018) · Current Diabetes Reports · doi:10.1007/s11892-018-1101-6 · Cited by 262
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance
Petersen, M. C., Madiraju, A. K., Gassaway, B. M., Marcel, M., Nasiri, A. R., Butrico, G. M., Marcucci, M., Zhang, D., Abulizi, A., Zhang, X., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86013 · Cited by 260
Self-citationBenefits of lifestyle modification in NAFLD
Harrison, S. A., & Day, C. P. (2007) · Gut · doi:10.1136/gut.2006.112094 · Cited by 246
Cardio-Metabolic Effects of High-Fat Diets and Their Underlying Mechanisms—A Narrative Review
Wali, J. A., Jarzebska, N., Raubenheimer, D., Simpson, S. J., Rodionov, R. N., & O’Sullivan, J. (2020) · Nutrients · doi:10.3390/nu12051505 · Cited by 256
Perry, R. J., Kim, T.-H., Zhang, X., Lee, H., Pesta, D. H., Popov, V., Zhang, D., Rahimi, Y., Jurczak, M. J., Cline, G. W., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.004 · Cited by 230
“…in heart and quadriceps muscle, [14C]2-deoxyglucose was injected at the conclusion of the clamp, and tissues were processed as described previously (Samuel et al., 2007). nProtein Kinase C Translocation PKCε translocation in liver and PKCq translocation in muscle from 6 hr fasted rats in the NAFLD…”
MethodSelf-citationThe role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD)
Liu, Q., Bengmark, S., & Qu, S. (2010) · Lipids in Health and Disease · doi:10.1186/1476-511x-9-42 · Cited by 233
Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications
Sangwung, P., Petersen, K. F., Shulman, G. I., & Knowles, J. W. (2020) · Endocrinology · doi:10.1210/endocr/bqaa017 · Cited by 232
Self-citationBirkenfeld, A. L., Lee, H., Guebre‐Egziabher, F., Alves, T. C., Jurczak, M. J., Jornayvaz, F. R., Zhang, D., Hsiao, J. J., Martín‐Montalvo, A., Fischer‐Rosinsky, A., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.06.009 · Cited by 217
“Increased DAG content in turn results in activation of protein kinase Cs (nPKCs) and subse- quent impairment in insulin signaling (Shulman, 2000; Samuel et al., 2004, 2007, 2010; Erion and Shulman, 2010).”
BackgroundSelf-citationSantoro, N., Kursawe, R., D’Adamo, E., Dykas, D. J., Zhang, C. K., Bale, A. E., Cali, A. M. G., Narayan, D., Shaw, M. M., Pierpont, B. M., et al. (2010) · Hepatology · doi:10.1002/hep.23832 · Cited by 219
Self-citationWang, Q. A., Jiang, L., Wang, J., Li, S., Yu, Y., You, J., Zeng, R., Gao, X., Rui, L., Li, W., et al. (2008) · Hepatology · doi:10.1002/hep.22774 · Cited by 215
Jornayvaz, F. R., Jurczak, M. J., Lee, H., Birkenfeld, A. L., Frederick, D. W., Zhang, D., Zhang, X., Samuel, V. T., & Shulman, G. I. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00361.2010 · Cited by 213
“In this case, hepatic insulin resistance could be attributed to a more than threefold increase in hepatic DAG content, resulting in PKCε activation and, in turn, decreased insulin signaling at the level of IRS-2 tyrosine phosphorylation (33, 34), although a potential role of triglycerides and/or ceramide in this proce…”
BackgroundSelf-citationThe role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease
Nomura, K., & Yamanouchi, T. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2011.09.006 · Cited by 218
Nandipati, K. C., Subramanian, S., & Agrawal, D. K. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2878-8 · Cited by 214
Liver and diabetes. A vicious circle
Loria, P., Lonardo, A., & Anania, F. A. (2012) · Hepatology Research · doi:10.1111/j.1872-034x.2012.01031.x · Cited by 208
Mells, J. E., Fu, P. P., Sharma, S., Olson, D., Cheng, L., Handy, J. A., Saxena, N. K., Sorescu, D., & Anania, F. A. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00274.2011 · Cited by 202
Nagai, Y., Yonemitsu, S., Erion, D. M., Iwasaki, T., Stark, R., Weismann, D., Dong, J., Zhang, D., Jurczak, M. J., Löffler, M. G., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.01.011 · Cited by 203
“These reductions in insulin responsiveness could be attributed to decreased mitochondrial fatty acid oxidation resulting in increased DAG content and to increased PKC3 activation resulting in decreased insulin signaling (Samuel et al., 2007).”
BackgroundSelf-citationMaher, J. J., León, P., & Ryan, J. C. (2008) · Hepatology · doi:10.1002/hep.22399 · Cited by 208
Kolczynska, K., Loza-Valdes, A., Hawro, I., & Sumara, G. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-01286-8 · Cited by 199
Adiels, M., Westerbacka, J., Soro‐Paavonen, A., Häkkinen, A. ‐., Vehkavaara, S., CASLAKE, M. J., Packard, C. J., Olofsson, S.-O., Yki‐Järvinen, H., Taskinen, M., et al. (2007) · Diabetologia · doi:10.1007/s00125-007-0790-1 · Cited by 197
“Importantly preventing liver fat accumulation in animal models is associated with reversal of hepatic insulin sensitivity [ 43 , 44].”
BackgroundDNA methylation in the pathogenesis of type 2 diabetes in humans
Davegårdh, C., García-Calzón, S., Bacos, K., & Ling, C. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.01.022 · Cited by 200
“PRKCE may induce insulin resistance interfering directly with the activation of the insulin receptor kinase activity [124].”
BackgroundHepatic Steatosis as a Marker of Metabolic Dysfunction
Fabbrini, E., & Magkos, F. (2015) · Nutrients · doi:10.3390/nu7064995 · Cited by 192
“PKC isoforms are protected from high-fat diet induced insulin resistance at the liver but also at the whole body level [37,39–41,43,44].”
BackgroundIncreased Expression and Activity of the Transcription Factor FOXO1 in Nonalcoholic Steatohepatitis
Valenti, L. V. C., Rametta, R., Dongiovanni, P., Maggioni, M., Fracanzani, A. L., Zappa, M. A., Lattuada, E., Roviaro, G., & Fargion, S. R. (2008) · Diabetes · doi:10.2337/db07-0714 · Cited by 186
Olive oil consumption and non-alcoholic fatty liver disease
Assy, N., Nassar, F., Nasser, G., & Grosovski, M. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.1809 · Cited by 190
Pathogenesis of MASLD and MASH – role of insulin resistance and lipotoxicity
Bansal, S., & Bansal, M. B. (2024) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.17930 · Cited by 211
Choi, C. S., Fillmore, J. J., Kim, J. K., Liu, Z., Kim, S., Collier, E. F., Kulkarni, A. S., Distefano, A. G., Hwang, Y.-J., Kahn, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci13579 · Cited by 183
Self-citationInsulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair
Nelson, T. J., Sun, M., Hongpaisan, J., & Alkon, D. L. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.051 · Cited by 184
Erion, D. M., Yonemitsu, S., Nie, Y., Nagai, Y., Gillum, M. P., Hsiao, J. J., Iwasaki, T., Stark, R., Weismann, D., Yu, X. X., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812931106 · Cited by 180
Self-citationElovl6: a new player in fatty acid metabolism and insulin sensitivity
Matsuzaka, T., & Shimano, H. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0449-0 · Cited by 183
“Several lines of evidence suggest that lipid metabolites, such as acyl-CoAs, diacylglycerol (DAG), and ceramides, rather than triglycerides themselves, are the determinants of the development of insulin resistance accompanying the accumulation of intracellular lipids [13–15].”
BackgroundLeptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation
Perry, R. J., Wang, Y., Cline, G. W., Rabin-Court, A., Song, J. D., Dufour, S., Zhang, X. M., Petersen, K. F., & Shulman, G. I. (2018) · Cell · doi:10.1016/j.cell.2017.12.001 · Cited by 171
“…TAG synthesis in an insulin-independent fashion (Vatner et al., 2015), as well as a causal role for hepatic DAG activation of PKCε in hepatic insulin resistance, through increased insulin receptor kinase threonine1160 (murine 1150) phosphorylation (Petersen et al., 2016; Samuel et al., 2004, 2007).”
Self-citationA Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu, K., Zhang, Y., Zhang, D., Kahn, M., ter Horst, K. W., Rodrigues, M. R. D. S., Gaspar, R. C., Hirabara, S. M., Luukkonen, P. K., Lee, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.08.001 · Cited by 173
“Consistent with our prior study (Samuel et al., 2007) Brandon et al. found that WAT PKCε has a role in the regulation of glucose metabolism.”
BackgroundResultInfluentialSelf-citationDoege, H., Grimm, D., Falcon, A., Tsang, B., Storm, T. A., Xu, H., Ortegon, A. M., Kazantzis, M., Kay, M. A., & Stahl, A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803510200 · Cited by 171
Lipid oversupply, selective insulin resistance, and lipotoxicity: Molecular mechanisms
Chavez, J. A., & Summers, S. A. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.09.015 · Cited by 170
Li, S., Sun, Y., Liang, C., Thorp, E. B., Han, S., Jehle, A. W., Saraswathi, V., Pridgen, B. C., Kanter, J. E., Li, R., et al. (2009) · Circulation Research · doi:10.1161/circresaha.109.199570 · Cited by 173
Guebre‐Egziabher, F., Alix, P. M., Koppe, L., Pelletier, C. C., Kalbacher, E., Fouque, D. P., & Soulage, C. O. (2013) · Biochimie · doi:10.1016/j.biochi.2013.07.017 · Cited by 168
Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2
Jornayvaz, F. R., Birkenfeld, A. L., Jurczak, M. J., Kanda, S., Guigni, B. A., Jiang, D. C., Zhang, D., Lee, H., Samuel, V. T., & Shulman, G. I. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103451108 · Cited by 169
Self-citationNarasimhan, A., Mayilvanan, C., & Karundevi, B. (2015) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2015-0002 · Cited by 166
ter Horst, K. W., Gilijamse, P. W., Versteeg, R. I., Ackermans, M. T., Nederveen, A. J., la Fleur, S. E., Romijn, J. A., Nieuwdorp, M., Zhang, D., Samuel, V. T., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.035 · Cited by 166
“For instance, short-term high-fat feeding promotes hepatic insulin resistance, which is associated with increases in cytosolic and membrane DAG content and activation of PKCε as reflected by translocation of PKCε from the cytosol to the plasma membrane (Samuel et al., 2004, 2007).”
Self-citation
Metadata
- Authors
- Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-03-01
- Volume
- 117
- Issue
- 3
- Pages
- 739-745
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1797607
- OpenAlex
- W2094051977
- Semantic Scholar
- 26809f321fcb7f6db237dd2f0abf76fa612e6a2f
- Cited by
- 497
- References
- 39
- Citations by year
- 2026: 17 · 2025: 10 · 2024: 24 · 2023: 14 · 2022: 19 · 2021: 12 · 2020: 25 · 2019: 26 · 2018: 36 · 2017: 21 · 2016: 37 · 2015: 29 · 2014: 28 · 2013: 25 · 2012: 27
- FWCI
- 24.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (P30 DK45735, R01 DK-40936, DK40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, U24DK059635, P30DK045735)
- National Center for Research Resources (K23RR017404, K23 RR-17404)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- protein kinase C epsilon, hepatic insulin resistance, non-alcoholic fatty liver disease, hepatic steatosis, high-fat feeding, insulin receptor, antisense oligonucleotide knockdown, type 2 diabetes, insulin signaling, therapeutic target
- MeSH terms
- Animals, Fatty Liver, Insulin, Insulin Resistance, Male, Receptor, Insulin, Signal Transduction, Oligonucleotides, Antisense, Rats, Sprague-Dawley, Lipid Metabolism, Rats, Protein Kinase C-epsilon
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
