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
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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.
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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.
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
“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.”
§ 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.
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · 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
“Basal rates of glucose production under fasted conditions were identical among the 3 groups.”
§ 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.
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
“The diminished activation was also present in high-fat-fed rats treated with control ASO.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε interferes with insulin receptor activation.
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
“In addition to the improvements in hepatic insulin action, PKCε ASO improved adipose insulin action.”
§ 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: 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
“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 ±”
§ 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: 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
“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).”
§ 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: 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
“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).”
§ 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.
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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO treatment improves insulin signaling.
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
“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).”
§ 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
“The augmented adipose insulin sensitivity is corroborated by an increased suppression of plasma fatty acid concentration during the hyperinsulinemic-euglycemic clamping (Figure 3G).”
§ 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
“Liver triglyceride content and diacylglycerol (DAG) content were similar in all 3 groups (Figure 2, C and D).”
§ 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.
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
“The mean insulin concentration in the PKCε rats was similar to that seen in normal rats on a low-fat diet.”
§ 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.
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, in rats treated with PKCε ASO, insulin increased IRS2 tyrosine phosphorylation approximately 300% above basal (Figure 4B).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO treatment improves insulin signaling.
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
“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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
hedgeddirect- 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
“In addition, none of the treatments altered liver lipid content (i.e., triglyceride and DAG).”
§ 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.
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
“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).”
§ 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.
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
“ASO treatment was not associated with any adverse events.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO is specific and effective.
plaincorrelational- 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
“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).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε interferes with insulin receptor activation.
hedgeddirect- 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
“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 > PKCε interferes with insulin receptor activation.
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
“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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε ASO treatment improves insulin signaling.
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
“Insulin failed to increase IRS2 tyrosine phosphorylation in high-fat-fed rats treated with saline or control ASO.”
§ 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: 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
“There were no differences in gastrocnemius or soleus 14 C-2-deoxyglucose uptake (Figure 3, D and E).”
§ 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.
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 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
“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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
hedgeddirect- 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: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > Abstract
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.
- Also stated in: § Introduction · plain
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
“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.”
§ 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: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“Preventing fat accumulation in rodents preserves hepatic insulin action (7,10,12).”
§ 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.
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
“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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > PKCε interferes with insulin receptor activation.
hedgedconditional- 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: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
In the paper
“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).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
What the sources say
- Not checked yetcites [26] Considine, 1995, J. Clin. Invest. source
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.
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
“This observation, in and of itself, suggests that knockdown of PKCε expression improves insulin sensitivity in high-fat fed 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
hedgeddirect- 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 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
“The protective ability of PKCε ASO suggests that PKCε plays a crucial role in the pathogenesis of fat-induced hepatic insulin resistance.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
hedgeddirect- 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.
In the paper
“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).”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
What the sources say
- Not checked yetcites [26] Considine, 1995, J. Clin. Invest. source
hedgedconditional- 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 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
“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.”
§ 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.
- Also stated in: § NAFLD is strongly linked to hepatic insulin resistance, and T2DM · hedged
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, 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 > 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.
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, 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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
hedgeddirect- 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 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
“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.”
§ Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease > NAFLD is strongly linked to hepatic insulin resistance, and T2DM
hedgeddirect- 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
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751
A new mathematical model for relative quantification in real-time RT-PCR
Pfaffl, M. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.e45 · Cited by 34,610
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) · Diabetes Care · doi:10.2337/diacare.27.5.1047 · Cited by 15,297
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769
Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome
Kadowaki, T. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29126 · Cited by 2,824
Özcan, U., Yilmaz, E., Özcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O., Görgün, C. Z., & Hotamisligil, G. S. (2006) · Science · doi:10.1126/science.1128294 · Cited by 2,413
Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561
Self-citationGlobal Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030
Wild, S. H., Roglić, G., Green, A., Sicree, R. A., & King, H. O. M. (2004) · Diabetes Care · doi:10.2337/diacare.27.10.2569-a · Cited by 1,477
Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322
Self-citationPetersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005) · Diabetes · doi:10.2337/diabetes.54.3.603 · Cited by 911
Self-citation
Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Self-citationDeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Self-citationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002
“Lowering PKCε expression in the liver protects rats from lipid-induced hepatic insulin resistance and preserves IRTK activity despite increases in liver lipid content (Samuel et al., 2007).”
BackgroundSelf-citationStanhope, K. L., Schwarz, J. M., Keim, N. L., Griffen, S. C., Bremer, A. A., Graham, J. L., Hatcher, B., Cox, C. L., Dyachenko, A., Zhang, W., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37385 · Cited by 1,765
Adipose tissue dysfunction as determinant of obesity-associated metabolic complications
Longo, M., Zatterale, F., Naderi, J., Parrillo, L., Formisano, P., Raciti, G. A., Beguinot, F., & Miele, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092358 · Cited by 1,575
Metadata
- Authors
- Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-03-01
- Volume
- 117
- Issue
- 3
- Pages
- 739-745
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1797607
- OpenAlex
- W2094051977
- Semantic Scholar
- 26809f321fcb7f6db237dd2f0abf76fa612e6a2f
- Cited by
- 497
- References
- 39
- Citations by year
- 2026: 17 · 2025: 10 · 2024: 24 · 2023: 14 · 2022: 19 · 2021: 12 · 2020: 25 · 2019: 26 · 2018: 36 · 2017: 21 · 2016: 37 · 2015: 29 · 2014: 28 · 2013: 25 · 2012: 27
- FWCI
- 24.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (P30 DK45735, R01 DK-40936, DK40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, U24DK059635, P30DK045735)
- National Center for Research Resources (K23RR017404, K23 RR-17404)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- protein kinase C epsilon, hepatic insulin resistance, non-alcoholic fatty liver disease, hepatic steatosis, high-fat feeding, insulin receptor, antisense oligonucleotide knockdown, type 2 diabetes, insulin signaling, therapeutic target
- MeSH terms
- Animals, Fatty Liver, Insulin, Insulin Resistance, Male, Receptor, Insulin, Signal Transduction, Oligonucleotides, Antisense, Rats, Sprague-Dawley, Lipid Metabolism, Rats, Protein Kinase C-epsilon
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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