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.
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
Claims the paper makes
0 of 21 cited sources checked · 0 supported · 0 flagged
- Findingown data
PKCε associates with the insulin receptor in vivo.
“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.”
Quote in the paperSubstantial claim - Also stated in: § PKCε interferes with insulin receptor activation. · plain
- Findingown data
The reduction in PKCε mRNA translated into a similar reduction in PKCε protein content relative to saline-treated animals.
“The reduction in mRNA translated into a similar reduction in PKCε protein content relative to that in saline-treated animals (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Knocking down PKCε expression protects rats from fat-induced hepatic insulin resistance.
“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.”
Quote in the paperSubstantial claim - Also stated in: § PKCε ASO treatment does not alter liver lipids but lowers plasma insulin. · plain
- Findingown data
PKCε ASO treatment did not alter muscle PKCε expression.
“In contrast, PKCε ASO treatment did not alter muscle PKCε expression.”
Quote in the paperSubstantial claim - Findingown data
Knocking down PKCε expression reverses fat-induced defects in hepatic insulin signaling.
“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.”
Quote in the paperSubstantial claim - Also stated in: § PKCε ASO treatment improves insulin signaling. · plain
- Findingown data
The amount of PKCδ was unchanged by PKCε ASO treatment.
“The amount of PKCδ was unchanged by PKCε ASO treatment.”
Quote in the paperSubstantial claim - Findingown data
Insulin receptor tyrosine phosphorylation was similarly increased above basal by approximately 50% in all 3 groups.
“Insulin receptor tyrosine phosphorylation was similarly increased above basal by approximately 50% in all 3 groups.”
Quote in the paperNot a substantial claim - Findingown data
There was a modest but significant increase in insulin-stimulated whole-body glucose disposal in the PKCε ASO-treated animals.
“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).”
Quote in the paperSubstantial claim - Findingown data
Analysis of the insulin signaling pathway demonstrated that insulin signaling was improved in PKCε-treated rats.
“Moreover, analysis of the insulin signaling pathway demonstrated that insulin signaling was improved in PKCε-treated rats.”
Quote in the paperSubstantial claim - Findingown data
The lower insulin concentration approaches values seen in rats on regular (low-fat) chow.
“The lower insulin concentration approaches values seen in rats on regular (low-fat) chow and suggests improved hepatic insulin sensitivity.”
Quote in the paperSubstantial claim - Findingown data
Plasma insulin concentration was approximately 50% lower in PKCε ASO-treated rats compared with saline- and control ASO-treated rats.
“Though fasting plasma glucose was identical across all 3 groups (Figure 2A), plasma insulin concentration was approximately 50% lower in PKCε ASO-treated rats compared with saline-and control ASO-treated rats (Figure 2B).”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · plain
“Despite the lack of differences in these parameters, fasting plasma insulin concentrations were approximately 50% lower in PKCε ASO-treated rats compared with saline-and control ASO-treated rats.”
Quote in the paperSubstantial claim - Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · plain
- Findingown data
Basal rates of glucose production under fasted conditions were identical among the 3 groups.
“Basal rates of glucose production under fasted conditions were identical among the 3 groups.”
Quote in the paperNot a substantial claim - Findingown data
The diminished activation was also present in high-fat-fed rats treated with control ASO.
“The diminished activation was also present in high-fat-fed rats treated with control ASO.”
Quote in the paperSubstantial claim - Findingown data
PKCε ASO improved adipose insulin action.
“In addition to the improvements in hepatic insulin action, PKCε ASO improved adipose insulin action.”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in plasma concentrations of IL-6, leptin, adiponectin, or resistin among the groups.
“Finally, there were no differences in plasma concentrations of IL-6 (saline, 150 ± 40 pg/ml; control, 112 ± 34 pg/ml; PKCε, 97 ± 25 pg/ml), leptin (saline, 1,346 ± 274 pg/ml; control, 1,368 ± 223 pg/ml; PKCε, 1,548 ± 225 pg/ml), adiponectin (saline, 21.9 ± 3.2 μg/ml; control, 19.75 ± 3.0 μg/ml; PKCε, 17.6 ± 3.4 μg/ml), or resistin (saline, 26.9 ± 5.7 ng/ml; control, 32.9 ± 6.3 ng/ml; PKCε, 35.7 ±”
Quote in the paperNot a substantial claim - Findingown data
In the PKCε ASO-treated rats, glucose uptake in the epididymal white adipose tissue increased nearly 2-fold compared with that in saline and control ASO rats.
“However, in the PKCε ASO-treated rats, glucose uptake in the epididymal white adipose tissue increased nearly 2-fold compared with that in saline and control ASO rats (Figure 3F).”
Quote in the paperNot a substantial claim - Findingown data
Fasting plasma glucose was identical across all 3 groups.
“Though fasting plasma glucose was identical across all 3 groups (Figure 2A), plasma insulin concentration was approximately 50% lower in PKCε ASO-treated rats compared with saline-and control ASO-treated rats (Figure 2B).”
Quote in the paperNot a substantial claim - Findingreasoning
Insulin-stimulated AKT2 activity was increased approximately 400% in PKCε ASO-treated rats, compared with approximately 50% in saline and control ASO groups.
“These differences in IRS2 tyrosine phosphorylation resulted in an approximately 400% increase in insulin-stimulated AKT2 activity, as compared with the approximately 50% increase in the saline and control ASO groups.”
Quote in the paperSubstantial claim - Findingown data
Under hyperinsulinemic conditions, suppression of hepatic glucose production was markedly greater in the PKCε group compared with the saline and control ASO groups.
“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).”
Quote in the paperSubstantial claim - Findingown data
Suppression of plasma fatty acid concentration during hyperinsulinemic-euglycemic clamping was increased in PKCε ASO-treated rats.
“The augmented adipose insulin sensitivity is corroborated by an increased suppression of plasma fatty acid concentration during the hyperinsulinemic-euglycemic clamping (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
Liver triglyceride content and DAG content were similar in all 3 groups.
“Liver triglyceride content and diacylglycerol (DAG) content were similar in all 3 groups (Figure 2, C and D).”
Quote in the paperSubstantial claim - Findingown data
The mean insulin concentration in the PKCε rats was similar to that seen in normal rats on a low-fat diet.
“The mean insulin concentration in the PKCε rats was similar to that seen in normal rats on a low-fat diet.”
Quote in the paperSubstantial claim - Findingown data
In rats treated with PKCε ASO, insulin increased IRS2 tyrosine phosphorylation approximately 300% above basal.
“In contrast, in rats treated with PKCε ASO, insulin increased IRS2 tyrosine phosphorylation approximately 300% above basal (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Decreasing expression of PKCε preserves the ability of the insulin receptor to tyrosine-phosphorylate IRS2.
“Specifically, the finding that decreasing expression of PKCε preserves the ability of the insulin receptor to tyrosinephosphorylate IRS2 suggests that PKCε interferes with this critical step.”
Quote in the paperSubstantial claim - Findingown data
None of the treatments altered liver lipid content (i.e., triglyceride and DAG).
“In addition, none of the treatments altered liver lipid content (i.e., triglyceride and DAG).”
Quote in the paperSubstantial claim - Findingown data
Fasting plasma fatty acid concentration was similar across all groups.
“Fasting plasma fatty acid concentration was also similar across all groups (saline, 0.69 ± 0.11; control, 0.66 ± 0.08; PKCε, 0.59 ± 0.08; ANOVA P = 0.68).”
Quote in the paperNot a substantial claim - Findingown data
ASO treatment was not associated with any adverse events.
“ASO treatment was not associated with any adverse events.”
Quote in the paperNot a substantial claim - Findingown data
Increasing molar ratios of PKCε to insulin receptor-β resulted in a dose-dependent decrease in insulin receptor-β tyrosine kinase activity.
“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).”
Quote in the paperSubstantial claim - Findingown data
Insulin receptor obtained from PKCε ASO-treated rats had preserved activation of the insulin receptor kinase.
“In contrast, insulin receptor obtained from PKCε ASO-treated rats had preserved activation of the insulin receptor kinase.”
Quote in the paperSubstantial claim - Findingown data
In adipose tissue, insulin-stimulated AKT2 activity was increased 221% ± 16% in PKCε ASO-treated rats as compared with 32% ± 11% and 23% ± 20% in saline- and control ASO-treated rats.
“In adipose tissue, insulin-stimulated AKT2 activity was increased 221% ± 16% in PKCε ASO-treated rats as compared with 32% ± 11% and 23% ± 20% in saline-and control ASO-treated rats.”
Quote in the paperSubstantial claim - Findingown data
Insulin failed to increase IRS2 tyrosine phosphorylation in high-fat-fed rats treated with saline or control ASO.
“Insulin failed to increase IRS2 tyrosine phosphorylation in high-fat-fed rats treated with saline or control ASO.”
Quote in the paperSubstantial claim - Findingown data
There were no differences in gastrocnemius or soleus 14C-2-deoxyglucose uptake.
“There were no differences in gastrocnemius or soleus 14 C-2-deoxyglucose uptake (Figure 3, D and E).”
Quote in the paperNot a substantial claim - Interpretationown data
PKCε inhibition is a novel therapeutic strategy/target for treating hepatic insulin resistance in patients with NAFLD and T2DM.
“These data support the hypothesis that PKCε plays a critical role in mediating fat-induced hepatic insulin resistance and represents a novel therapeutic target for type 2 diabetes.”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
“Taken together, these data suggest that PKCε inhibition is a novel therapeutic strategy for treatment of hepatic insulin resistance in patients with NAFLD and T2DM.”
Quote in the paperSubstantial claim - Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
- Premisecitation
Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance.
“Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance.”
- Also stated in: § Introduction · plain
“Rats fed a high-fat diet for 3 days develop hepatic steatosis and hepatic insulin resistance in the absence of the confounding effects of peripheral insulin resistance (10,13).”
Quote in the paperSubstantial claim0 of 2 sources checked - Also stated in: § Introduction · plain
- Interpretationown data
PKCε plays a critical role in mediating fat-induced hepatic insulin resistance.
“These data support the hypothesis that PKCε plays a critical role in mediating fat-induced hepatic insulin resistance and represents a novel therapeutic target for type 2 diabetes.”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · boosted
“Taken together, these data strongly support an important role for PKCε in mediating fat-induced hepatic insulin resistance.”
Quote in the paperSubstantial claim - Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · boosted
- Premisecitation
Preventing fat accumulation in rodents preserves hepatic insulin action.
“Preventing fat accumulation in rodents preserves hepatic insulin action (7,10,12).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
PKCε could directly inhibit insulin receptor kinase activity.
“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: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
“Second, we demonstrate that incubation of active PKCε with active insulin receptor-β led to a dose-dependent decrease in insulin receptor-β kinase activity, thereby suggesting that PKCε may constrain insulin signaling by hindering the ability of the insulin receptor kinase to tyrosine-phosphorylate its substrates.”
Quote in the paperSubstantial claim - Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
- Premisecitation
PKCε is activated in the livers of obese diabetic patients compared with lean, normoglycemic control subjects.
“A similar mechanism may be present in patients with diabetes; this is supported by Considine et al., who observed activation of PKCε in the livers of obese diabetic patients compared with lean, normoglycemic control subjects (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Considine, 1995, J. Clin. Invest. source
Not checked in the free run.
- Interpretationown data
Knockdown of PKCε expression improves insulin sensitivity in high-fat fed rats.
“This observation, in and of itself, suggests that knockdown of PKCε expression improves insulin sensitivity in high-fat fed rats.”
Quote in the paperSubstantial claim - Interpretationown data
The protective ability of PKCε ASO suggests that PKCε plays a crucial role in the pathogenesis of fat-induced hepatic insulin resistance.
“The protective ability of PKCε ASO suggests that PKCε plays a crucial role in the pathogenesis of fat-induced hepatic insulin resistance.”
Quote in the paperSubstantial claim - Interpretationcitation
A similar mechanism may be present in patients with diabetes.
“A similar mechanism may be present in patients with diabetes; this is supported by Considine et al., who observed activation of PKCε in the livers of obese diabetic patients compared with lean, normoglycemic control subjects (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Considine, 1995, J. Clin. Invest. source
Not checked in the free run.
- Interpretationreasoning
The lower insulin concentration suggests improved hepatic insulin sensitivity.
“The lower insulin concentration approaches values seen in rats on regular (low-fat) chow and suggests improved hepatic insulin sensitivity.”
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
“This observation, in and of itself, suggests that knockdown of PKCε expression improves insulin sensitivity in high-fat fed rats.”
Quote in the paperSubstantial claim - Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
- Interpretationown data
PKCε ASO treatment prevents the defects in insulin signaling that lead to the development of hepatic insulin resistance.
“Thus, PKCε ASO treatment prevents the defects in insulin signaling that lead to the development of hepatic insulin resistance.”
Quote in the paperSubstantial claim - Interpretationown data
The diminished tyrosine phosphorylation of IRS2 seen in steatotic livers is a consequence of PKCε-mediated inhibition of the insulin receptor kinase.
“Thus, these data suggest that the diminished tyrosine phosphorylation of IRS2 seen in steatotic livers is a consequence of PKCε-mediated inhibition of the insulin receptor kinase.”
Quote in the paperSubstantial claim - Interpretationreasoning
PKCε interferes with the ability of the insulin receptor to tyrosine-phosphorylate IRS2.
“Specifically, the finding that decreasing expression of PKCε preserves the ability of the insulin receptor to tyrosinephosphorylate IRS2 suggests that PKCε interferes with this critical step.”
Quote in the paperSubstantial claim
- May combine two claims. 10
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataPKCε ASO treatment specifically reduced PKCε expression in liver and white adipose tissue after 4 weeks of treatment at 75 mg/kg per week.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPKCε impairs insulin receptor kinase activity in vivo and in vitro.
“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.”
Quote in the paperSubstantial claim- Also stated in: § PKCε interferes with insulin receptor activation. · hedged
May combine two claims.
Findingown dataNeither fasting plasma glucose concentrations nor basal hepatic glucose production rates were affected by PKCε ASO therapy.
“Neither fasting plasma glucose concentrations nor basal hepatic glucose production rates were affected by PKCε ASO therapy.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataImmunoprecipitation of insulin receptor from liver protein extracts pulled down PKCε, and immunoprecipitation of PKCε also pulled down insulin receptor.
“Immunoprecipitation of insulin receptor from liver protein extracts pulled down PKCε, and immunoprecipitation of PKCε also pulled down insulin receptor (Figure 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPKCε ASO specifically inhibits PKCε, without altering the levels of other PKC isoforms.
“PKCε ASO specifically inhibits PKCε, without altering the levels of other PKC isoforms.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRats remained free of hepatotoxicity, as reflected by the absence of transaminase elevation, and exhibited similar weight gain across all 3 groups.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationAmelioration of NAFLD in patients with T2DM by weight reduction is associated with reversal of hepatic insulin resistance and a return to normoglycemia.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Petersen, 2005, Diabetes. source
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted).
PremisecitationHepatic steatosis per se causes hepatic insulin resistance.
“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).”
Quote in the paperNot a substantial claim0 of 3 sources checked- Also stated in: § Introduction · boosted
May combine two claims.
PremisecitationPreventing fat accumulation by inhibiting lipid synthesis via disruption of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase or promoting fat oxidation using either mitochondrial uncoupler 2,4-dinitrophenol or inhibition of acetyl-CoA carboxylase-1 and -2 prevents PKCε activation and hepatic insulin resistance.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIn this setting, PKCε, but not other isoforms of PKC, is activated.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDAG concentrations have closely paralleled insulin resistance in other models.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationDAG is a known activator of classic and novel isoforms of PKC.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataIn this model system, we specifically inhibit PKCε without altering other PKC isoforms or the concentration of PKC activators.
“Thus, in this model system, we specifically inhibit PKCε without altering other PKC isoforms or the concentration of PKC activators.”
Quote in the paperSubstantial claim
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?
Nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.
“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]
Increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of protein kinase C epsilon, resulting in reduced insulin signaling and hepatic insulin resistance.
“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.”
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 · see citing works
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 · see citing works
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) · Diabetes Care · doi:10.2337/diacare.27.5.1047 · Cited by 15,297 · see citing works
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citationTissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121164498 · Cited by 753 · see citing works
Self-citationRegulation of Fasted Blood Glucose by Resistin
Banerjee, R. R., Rangwala, S. M., Shapiro, J. S., Rich, A. S., Rhoades, B., Qi, Y., Wang, J., Rajala, M. W., Pocai, A., Scherer, P. E., et al. (2004) · Science · doi:10.1126/science.1092341 · Cited by 727 · see citing works
Alessi, D. R., Barry Caudwell, F., Andjelkovic, M., Hemmings, B. A., & Cohen, P. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01370-1 · Cited by 628 · see citing works
Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Hundal, R. S., Petersen, K. F., Mayerson, A. B., Randhawa, P. S., Inzucchi, S. E., Shoelson, S. E., & Shulman, G. I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14955 · Cited by 623 · see citing works
Self-citationLeptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy
Petersen (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215001 · Cited by 622 · see citing works
Self-citationDevelopment of Muscle Insulin Resistance After Liver Insulin Resistance in High-Fat–Fed Rats
Kraegen, E. W., Clark, P. W., Jenkins, A. B., Daley, E. A., Chisholm, D. J., & Storlien, L. H. (1991) · Diabetes · doi:10.2337/diab.40.11.1397 · Cited by 601 · see citing works
The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease
McCullough, A. J. (2004) · Clinics in Liver Disease · doi:10.1016/j.cld.2004.04.004 · Cited by 578 · see citing works
Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z., & Ruderman, N. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3458 · Cited by 528 · see citing works
Savage, D. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27300 · Cited by 447 · see citing works
Kabir, M., Catalano, K. J., Ananthnarayan, S., Kim, S. P., Van Citters, G. W., Dea, M. K., & Bergman, R. N. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00203.2004 · Cited by 327 · see citing works
Takayama, S., White, M. F., & Kahn, C. R. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)69090-8 · Cited by 317 · see citing works
Neschen, S., Morino, K., Hammond, L. E., Zhang, D., Liu, Z.-X., Romanelli, A. J., Cline, G. W., Pongratz, R. L., Zhang, X.-M., Choi, C. S., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.006 · Cited by 261 · see citing works
Self-citationCharacterization of the insulin receptor kinase purified from human placental membranes.
Kasuga, M., Fujita‐Yamaguchi, Y., Blithe, D., White, M. F., & Kahn, C. R. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44373-0 · Cited by 195 · see citing works
Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ
Lam, T. K. T., Yoshii, H., Haber, C. A., Bogdanovic, E., Lam, L., Fantus, I. G., & Giacca, A. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00038.2002 · Cited by 195 · see citing works
Considine, R. V., Nyce, M. R., Allen, L. E., Morales, L. M., Triester, S., Serrano, J., Colberg, J., Lanza-Jacoby, S., & Caro, J. F. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118001 · Cited by 141 · see citing works
Graham, M. J., Crooke, S. T., Monteith, D., Cooper, S. R., Lemonidis, K. M., Stecker, K., Martin, M. J., & Crooke, R. M. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37605-0 · Cited by 140 · see citing works
Qu, X.-Q., Seale, J., & Donnelly, R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1620207 · Cited by 123 · see citing works
Biological Variation in HbA1c Predicts Risk of Retinopathy and Nephropathy in Type 1 Diabetes
Twomey, P. J., Viljoen, A., Reynolds, T., & Wierzbicki, A. S. (2004) · Diabetes Care · doi:10.2337/diacare.27.10.2569 · Cited by 106 · see citing works
Lewis, R. E., Cao, L., Perregaux, D. G., & Czech, M. P. (1990) · Biochemistry · doi:10.1021/bi00459a020 · Cited by 90 · see citing works
Youn, J. H., & Buchanan, T. A. (1993) · Diabetes · doi:10.2337/diab.42.5.757 · Cited by 64 · see citing works
Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Hundal, R. S., Petersen, K. F., Mayerson, A. B., Randhawa, P. S., Inzucchi, S. E., Shoelson, S. E., & Shulman, G. I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci200214955 · Cited by 49 · see citing works
Self-citationFrevert, E. U., & Kahn, B. B. (1996) · Biochemical Journal · doi:10.1042/bj3160865 · Cited by 41 · see citing works
Anderson, C. M., & Olefsky, J. M. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54701-3 · Cited by 40 · see citing works
Coghlan, M., Pillay, T. S., Tavaré, J. M., & Siddle, K. (1994) · Biochemical Journal · doi:10.1042/bj3030893 · Cited by 33 · see citing works
Kellerer, M., Coghlan, M., Capp, E., Mühlhöfer, A., Kroder, G., Mosthaf, L., Galante, P., Siddle, K., & Häring, H.-U. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118073 · Cited by 27 · see citing works
Webb, P. R., Doyle, C., & Anderson, N. G. (2003) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-003-2337-z · Cited by 24 · see citing works
Pillay, T. S., Xiao, S., Keranen, L. M., & Olefsky, J. M. (2003) · Cellular Signalling · doi:10.1016/s0898-6568(03)00090-1 · Cited by 21 · see citing works
PKCε induces interleukin-6 expression through the MAPK pathway in 3T3-L1 adipocytes
Ohashi, K., Kanazawa, A., Tsukada, S., & Maeda, S. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.12.072 · Cited by 12 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-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 · see citing works
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 · see citing works
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 1,475 · see citing works
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 · see citing works
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 · see citing works
Postic, C., & Girard, J. R. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34275 · Cited by 1,200 · see citing works
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 · see citing works
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 · see citing works
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 1,131 · see citing works
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 1,136 · see citing works
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 · see citing works
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 1,179 · see citing works
Copps, K. D., & White, M. F. (2012) · Diabetologia · doi:10.1007/s00125-012-2644-8 · Cited by 1,017 · see citing works
“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 · see citing works
Fullerton, 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 · see citing works
Nonalcoholic fatty liver disease
Brunt, E., Wong, V., Nobili, V., Day, C., Sookoian, S., Maher, J., Bugianesi, E., Sirlin, C., Neuschwander-Tetri, B., & Rinella, M. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.80 · Cited by 591 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
Self-citationKammoun, 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 · see citing works
Nonalcoholic 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 740 · see citing works
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 · see citing works
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 685 · see citing works
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 678 · see citing works
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 681 · see citing works
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 619 · see citing works
The 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 · see citing works
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 · see citing works
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 542 · see citing works
Causes and Metabolic Consequences of Fatty Liver
Stefan, N., Kantartzis, K., & Häring, H. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0009 · Cited by 527 · see citing works
Pathophysiology 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 552 · see citing works
Diacylglycerol-mediated insulin resistance
Erion, D. M., & Shulman, G. I. (2010) · Nature Medicine · doi:10.1038/nm0410-400 · Cited by 493 · see citing works
Self-citationErtunc, M. E., & Hotamışlıgil, G. S. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r066514 · Cited by 485 · see citing works
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 461 · see citing works
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 · see citing works
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 436 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 384 · see citing works
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 · see citing works
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 365 · see citing works
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 · see citing works
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 · see citing works
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 331 · see citing works
Choi, 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 · see citing works
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 315 · see citing works
Self-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 315 · see citing works
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 310 · see citing works
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 305 · see citing works
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 299 · see citing works
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 · see citing works
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 · see citing works
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 281 · see citing works
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 · see citing works
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 263 · see citing works
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 267 · see citing works
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 261 · see citing works
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 249 · see citing works
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 245 · see citing works
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 242 · see citing works
Self-citationBenefits of lifestyle modification in NAFLD
Harrison, S. A., & Day, C. P. (2007) · Gut · doi:10.1136/gut.2006.112094 · Cited by 240 · see citing works
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 245 · see citing works
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 · see citing works
Self-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 229 · see citing works
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 223 · see citing works
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 212 · see citing works
Self-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 214 · see citing works
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 212 · see citing works
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 212 · see citing works
Self-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 213 · see citing works
Nandipati, K. C., Subramanian, S., & Agrawal, D. K. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2878-8 · Cited by 210 · see citing works
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 206 · see citing works
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 · see citing works
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 · see citing works
Self-citationMaher, J. J., León, P., & Ryan, J. C. (2008) · Hepatology · doi:10.1002/hep.22399 · Cited by 204 · see citing works
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 · see citing works
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 · see citing works
DNA 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 194 · see citing works
Hepatic Steatosis as a Marker of Metabolic Dysfunction
Fabbrini, E., & Magkos, F. (2015) · Nutrients · doi:10.3390/nu7064995 · Cited by 191 · see citing works
Increased 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 187 · see citing works
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 185 · see citing works
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 204 · see citing works
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 182 · see citing works
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 · see citing works
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 181 · see citing works
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 176 · see citing works
Leptin 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 · see citing works
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 · see citing works
Self-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 170 · see citing works
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 167 · see citing works
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 168 · see citing works
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 164 · see citing works
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 164 · see citing works
Self-citationNarasimhan, A., Mayilvanan, C., & Karundevi, B. (2015) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2015-0002 · Cited by 164 · see citing works
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 · see citing works
Self-citation
- 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 › Epidemiology › 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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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
