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.
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Claims the paper makes
37 Own result · 10 Not checked yet · 10 Own interpretation · 1 No basis given
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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 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.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
boosteddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Biochemical analysis and calculations.
“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).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Biochemical analysis and calculations.
“GlucoseM+2 enrichment was determined from the m/z ratio 202:200.”
Citations
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“The contrasting interpretations of the role of PKCε in hepatic insulin action arising from these studies might be explained by differences in both the type and the duration of the fat diets used (42,44).”
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“insulin resistance [14, 15, 41–43], other data suggest that they may not be related to chronic insulin resistance [44–46].”
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BackgroundMechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
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Self-citationThe Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance
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“The elevated DAG activates protein kinase C , a serine/threonine kinase that then binds to the insulin receptor and inhibits its tyrosine kinase activity (183).”
BackgroundTargeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
Kumashiro, N., Beddow, S. A., Vatner, D. F., Majumdar, S. K., Cantley, J. L., Guebre‐Egziabher, F., Fat, I., Guigni, B. A., Jurczak, M. J., Birkenfeld, A. L., et al. (2013) · Diabetes · doi:10.2337/db12-1311 · Cited by 157
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“That PKCε is responsible for the observed effect on insulin resistance is supported by the fact that antisense oligonucleotide-mediated inhibition of PKCε in the liver improved insulin resistance, independent of DAG levels [61].”
BackgroundMechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice
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“An elegant study conducted by Samuel et al investigated PKC-ε and how it may link NAFLD and insulin resistance [22].”
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“This finding is of particular interest given that Protein Kinase C (PKC) epsilon activation is implicated in hepatic insulin resistance [41,42].”
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“Indeed, several PKC isoforms have been implicated in insulin resistance in models of elevated blood FFA caused by lipid infusion or obesity (Dey et al., 2006; Griffin et al., 1999; Kim et al., 2004; Lam et al., 2002; Samuel et al., 2007).”
BackgroundNon-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids
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“There is considerable associative evidence to support a role for diacylglycerol in mediating hepatic insulin resistance, with the demonstration of concurrent reductions in diacylglycerol, PKCe activity and improved insulin receptor substrate signalling following various experimental manipulations [ 34 , 36, 37].”
BackgroundExercise therapy in Type 2 diabetes
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“Experimental research now suggests that hepatic insulin resistance arises from DAG-induced activation of protein kinase Ce, which directly binds to and inhibits insulin receptor tyrosine kinase activity [75].”
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“inflammatory cytokines and protein kinase C (PKC) ( 18-20 ).”
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“Activation of novel PKCs, especially PKCs δ, ε, and θ, by hormones, hyperglycemia, and lipids, especially diacylglycerol, has been shown to contribute to insulin resistance (Bezy et al., 2011; Li et al., 2004; Samuel et al., 2007).”
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“First, decreased expression of CREB led to reduced intrahepatic DAG content and decreased PKCε activation (Samuel et al., 2007).”
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Nonalcoholic Fatty Liver: A Possible New Target for Type 2 Diabetes Prevention and Treatment
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Ectopic fat and insulin resistance
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“insulin resistance is strongly associated with NAFLD [3,4,6].”
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“In this sense, high-fat diet mice accumulate more liver diacylglycerol than wildtype mice, which causes insulin resistance by activating PKCe, a specific isoform of PKC [37,38].”
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“sociated activation of novel protein kinase C (15, 16), generation of reactive oxygen species (17), and activation of the I B kinase/nuclear factor- B pathway (18).”
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Self-citationHypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis
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Inhibition of PKCɛ Improves Glucose-Stimulated Insulin Secretion and Reduces Insulin Clearance
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Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease
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Self-citationMechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes
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“…shown that lipid-induced hepatic insulin resistance is mediated in part through DAG activation of PKC 3resulting in phosphorylation of the insulin receptor tyrosine kinase (IRTK) on threonine 1160, which in turn leads to decreased IRTK activity (Petersen et al., 2016; Samuel et al., 2004, 2007).”
Self-citationKumashiro, N., Yoshimura, T., Cantley, J. L., Majumdar, S. K., Guebre‐Egziabher, F., Kursawe, R., Vatner, D. F., Fat, I., Kahn, M., Erion, D. M., et al. (2012) · Hepatology · doi:10.1002/hep.26170 · Cited by 89
Self-citationMARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels
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Self-citationPathogenesis of Insulin Resistance and Atherogenic Dyslipidemia in Nonalcoholic Fatty Liver Disease
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TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1
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“Among family members, PKC3 is known to be involved in reducing 240 Cell Metabolism 9, 240–251, March 4, 2009 ª2009 Elsevier Inc. insulin receptor (IR) kinase activity, thus inhibiting insulinmediated signaling cascades in liver (Samuel et al., 2004, 2007).”
BackgroundGassaway, B. M., Petersen, M. C., Surovtseva, Y. V., Barber, K. W., Sheetz, J. B., Aerni, H. R., Merkel, J. S., Samuel, V. T., Shulman, G. I., & Rinehart, J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1804379115 · Cited by 93
Self-citationThe Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats
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“…in liver and skeletal muscle commensurate with reduced PKC3 and PKCq activity, respectively, which have been shown to cause insulin resistance in these tissues (Griffin et al., 1999; Yu et al., 2002; Samuel et al., 2004; Neschen et al., 2005; Savage et al., 2006; Samuel et al., 2007) (Figure 5).”
BackgroundSelf-citationMitochondrial Dysfunction in Obesity and Reproduction
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Perspectives on Treatment for Nonalcoholic Steatohepatitis
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Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice
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Mammalian TOR signaling to the AGC kinases
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“Inhibition of nPKCε prevents insulin resistance in the liver (Samuel et al., 2007). nPKCθ was also shown to inhibit insulin signaling via phosphorylation of IRS1 at Ser1101 (Li et al., 2004).”
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Self-citationDysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease
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“PKCepsilon then suppresses insulin-induced phosphorylation of insulin receptor beta at Y1162 and promotes inhibitory phosphorylation of threonine at residue 1160, suggesting that lipid accumulation inhibits insulin signaling [34,56–59].”
BackgroundPostprandial Lipemia Associates with Liver Fat Content
Matikainen, N., Mänttäri, S., Westerbacka, J., Vehkavaara, S., Lundbom, N. M. I., Yki‐Järvinen, H., & Taskinen, M. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0187 · Cited by 76
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Self-citationThe immunopathogenesis of alcoholic and nonalcoholic steatohepatitis: two triggers for one disease?
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“High-fat feeding causes hepatic fat accumulation associated with inflammation and liver injury even before inducing obesity and systemic insulin resistance [ 74 ].”
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Early Hepatic Insulin Resistance in Mice: A Metabolomics Analysis
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Polysaccharides influence human health via microbiota-dependent and -independent pathways
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Lipin — The bridge between hepatic glycerolipid biosynthesis and lipoprotein metabolism
Khalil, M. B., Blais, A., Figeys, D., & Yao, Z. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.07.008 · Cited by 68
“Targeted inactivation of PKCε in nonalcoholic fatty liver disease reverses hepatic insulin resistance [74].”
BackgroundShinjo, S., Jiang, S. S., Nameta, M., Suzuki, T., Kanai, M., Nomura, Y., & Goda, N. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.08.006 · Cited by 74
XBP1s Is an Anti-lipogenic Protein
Herrema, H., Zhou, Y., Zhang, D., Lee, J., Hernández, M. A. S., Shulman, G. I., & Özcan, U. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.728949 · Cited by 67
“PKC directly interacts with and inhibits insulin receptor kinase activity, and depletion of hepatic PKC improves hepatic insulin action in HFD-fed rats (28).”
BackgroundSelf-citationRaddatz, K., Turner, N. A., Frangioudakis, G., Liao, B. M., Pedersen, D. J., Cantley, J., Wilks, D. L., Preston, E., Hegarty, B. D., Leitges, M., et al. (2011) · Diabetologia · doi:10.1007/s00125-011-2073-0 · Cited by 69
“The delineation of this novel progression helps to reconcile the findings reported for the ablation of PKCe in acute [ 8 ] and longer term [9] models of lipid excess, and provides mechanistic insights into the role of the kinase in glucose homeostasis, as discussed below.”
BackgroundResultInfluentialHepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia
Visser, M. E., Lammers, N. M., Nederveen, A. J., van der Graaf, M., Heerschap, A., Ackermans, M. T., Sauerwein, H. P., Stroes, E. S. G., & Serlie, M. J. M. (2011) · Diabetologia · doi:10.1007/s00125-011-2157-x · Cited by 71
“In addition, results of animal studies have shown that hepatic fat accumulation may interfere with insulin signalling in the liver through activation of protein kinase Ce [9, 10 ], suggesting a direct causal relationship between hepatic fat accumulation and insulin resistance.”
Result
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
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