The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome
Open accessAbstract
We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by ≈60% in young, lean, insulin-resistant subjects compared with a similar cohort of age–weight–body mass index–activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an ≈20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-α, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.
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Written from the paper’s full text.
TL;DR
In young, lean, insulin-resistant subjects, skeletal muscle insulin resistance diverted postprandial carbohydrate away from muscle glycogen synthesis and into hepatic de novo lipogenesis, producing atherogenic dyslipidemia. These changes occurred without differences in intraabdominal fat or circulating TNF-α, IL-6, HMW adiponectin, resistin, or RBP-4.
Key findings
- Net muscle glycogen synthesis after two high-carbohydrate mixed meals was 61% lower in insulin-resistant subjects than in matched insulin-sensitive controls, while net liver glycogen synthesis did not differ.
- Hepatic de novo lipogenesis was increased 2.2-fold in insulin-resistant subjects (15.7 ± 1.5% vs. 7.2 ± 0.7%, P = 0.00005), and net hepatic triglyceride synthesis was ≈2.5-fold greater.
- Plasma triglycerides were increased by 60% and HDL cholesterol was ≈20% lower in insulin-resistant subjects; small VLDL and large LDL particles were decreased by 38% and 30%, respectively.
- There were no differences between groups in plasma TNF-α, IL-6, HMW adiponectin, resistin, RBP-4, or intraabdominal fat volume; uric acid was ≈30% higher in insulin-resistant subjects.
Methods
- The authors screened ≈400 young, healthy, lean, sedentary volunteers with a 3-hr, 75-g oral glucose tolerance test and the insulin sensitivity index (ISI), then studied 12 insulin-resistant subjects (lowest ISI quartile) and 12 insulin-sensitive subjects (highest ISI quartile) matched for age, weight, BMI, and activity.
- After two high-carbohydrate mixed meals, liver and muscle glycogen and triglyceride synthesis were assessed by 1H and 13C magnetic resonance spectroscopy; hepatic de novo lipogenesis was assessed by deuterium incorporation from deuterium-labeled water into plasma triglycerides; intraabdominal fat was measured by MRI.
- Statistical comparisons used Wilcoxon rank sum or unpaired Student’s t tests, with paired t tests within individuals; data are mean ± SEM.
Limitations
- The paper does not state limitations explicitly.
- Evident from the text: the study is a small cross-sectional comparison (12 per group) in young, lean, sedentary volunteers, so causal direction is inferred rather than established by intervention, and findings may not generalize to older, obese, or more clinically advanced populations.
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- Findingown data§ Results
Fasting plasma glucose concentrations were higher in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“Fasting plasma glucose, triglyceride, and insulin concentrations were higher in the insulin-resistant subjects compared with the insulin-sensitive subjects (Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
Following ingestion of two high-carbohydrate mixed meals, hepatic triglyceride synthesis was increased by more than 2-fold in the insulin-resistant subjects compared with insulin-sensitive subjects.
“In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The increase in hepatic de novo lipogenesis and hepatic triglyceride synthesis in insulin-resistant subjects was associated with an approximately 20% reduction in plasma high-density lipoprotein concentrations.
“These changes were associated with a 60% increase in plasma triglyceride concentrations and an ≈20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Following ingestion of two high-carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with age-, weight-, BMI-, and activity-matched insulin-sensitive control subjects.
“Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by ≈60% in young, lean, insulin-resistant subjects compared with a similar cohort of age–weight–body mass index–activity-matched, insulin-sensitive, control subjects.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The increase in hepatic de novo lipogenesis and hepatic triglyceride synthesis in insulin-resistant subjects was associated with a 60% increase in plasma triglyceride concentrations.
“These changes were associated with a 60% increase in plasma triglyceride concentrations and an ≈20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume.”
Quote in the paperSubstantial claim
- Findingown data§ Abstract
Following ingestion of two high-carbohydrate mixed meals, hepatic de novo lipogenesis was increased by more than 2-fold in the insulin-resistant subjects compared with insulin-sensitive subjects.
“In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects.”
Quote in the paperSubstantial claim - Findingown data§ Results
There were no differences between the insulin-resistant and insulin-sensitive groups in net liver glycogen synthesis after ingestion of the meals.
“In contrast, there were no differences between the two groups in basal liver glycogen concentration (insulin-sensitive, 131.6 ± 9.2 mmol per liter of liver, vs. insulin-resistant, 125.0 ± 17.7 mmol per liter of liver; P = 0.74) or net liver glycogen synthesis after ingestion of the meals (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
Hepatic triglyceride synthesis is increased in these insulin-resistant subjects after high-carbohydrate meals.
“and that hepatic triglyceride synthesis is increased in these insulin-resistant subjects after high-carbohydrate meals”
Quote in the paperSubstantial claim - Findingown data§ Results
There were no differences in total cholesterol concentrations between the insulin-resistant and insulin-sensitive groups.
“Fasting plasma high-density lipoprotein (HDL) cholesterol concentrations were 20% lower in the insulin-resistant subjects (Table 2), but there were no differences in total cholesterol or low-density lipoprotein (LDL) between the two groups.”
Quote in the paperNot a substantial claim - Findingown data§ Results
The mean and distribution of intraabdominal fat volume assessed by MRI were similar between the insulin-resistant and insulin-sensitive groups, whether or not the single outlier in each group was excluded from analysis.
“The mean (Table 1) and distribution (Fig. 3C) of intraabdominal fat volume assessed by MRI were similar between the two groups, whether or not the single outlier in each group was excluded from analysis.”
Quote in the paperNot a substantial claim - Findingown data§ Results
Fasting plasma insulin concentrations were higher in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“Fasting plasma glucose, triglyceride, and insulin concentrations were higher in the insulin-resistant subjects compared with the insulin-sensitive subjects (Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Postprandial plasma insulin concentrations were markedly increased in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“In contrast, postprandial plasma concentrations of insulin and triglycerides were markedly increased in the insulin-resistant subjects (Fig. 1 B and C).”
Quote in the paperSubstantial claim - Findingown data§ Results
There were no differences in plasma concentrations of high-molecular-weight adiponectin, IL-6, resistin, plasminogen activator inhibitor-1, retinol binding protein-4, or TNF-α between the insulin-resistant and insulin-sensitive groups.
“In contrast, there were no differences in plasma concentrations of high-molecular-weight (HMW) adiponectin, IL-6, resistin, plasminogen activator inhibitor-1, retinol binding protein-4 (RBP-4), or TNF-α between the two groups (Table 3).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Fasting plasma high-density lipoprotein cholesterol concentrations were 20% lower in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“Fasting plasma high-density lipoprotein (HDL) cholesterol concentrations were 20% lower in the insulin-resistant subjects (Table 2), but there were no differences in total cholesterol or low-density lipoprotein (LDL) between the two groups.”
Quote in the paperNot a substantial claim - Findingown data§ Results
There were no differences in low-density lipoprotein concentrations between the insulin-resistant and insulin-sensitive groups.
“Fasting plasma high-density lipoprotein (HDL) cholesterol concentrations were 20% lower in the insulin-resistant subjects (Table 2), but there were no differences in total cholesterol or low-density lipoprotein (LDL) between the two groups.”
Quote in the paperNot a substantial claim - Findingown data§ Results
Net hepatic triglyceride synthesis was approximately 2.5-fold greater in the insulin-resistant subjects than in the insulin-sensitive subjects after the carbohydrate meals.
“There were no differences in the basal concentrations of hepatic triglyceride in the two groups (insulin-sensitive, 0.65 ± 0.14%, vs. insulin-resistant, 0.76 ± 0.20%; P = 0.63); however, net hepatic triglyceride synthesis was ≈2.5-fold greater in the insulin-resistant subjects than the insulin-sensitive subjects after the carbohydrate meals (Fig. 2D).”
Quote in the paperSubstantial claim - Findingown data§ Results
There were no differences in basal hepatic triglyceride concentrations between the insulin-resistant and insulin-sensitive groups.
“There were no differences in the basal concentrations of hepatic triglyceride in the two groups (insulin-sensitive, 0.65 ± 0.14%, vs. insulin-resistant, 0.76 ± 0.20%; P = 0.63); however, net hepatic triglyceride synthesis was ≈2.5-fold greater in the insulin-resistant subjects than the insulin-sensitive subjects after the carbohydrate meals (Fig. 2D).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
The insulin-resistant subjects in this study did not have hepatic steatosis.
“The absence of hepatic steatosis in this group of insulin-resistant subjects”
Quote in the paperSubstantial claim - Findingown data§ Discussion
The pattern of stored energy distribution derived from two high-carbohydrate meals was markedly different in young, lean, insulin-resistant individuals compared with young, lean, insulin-sensitive individuals.
“We found that the pattern of stored energy distribution derived from two high-carbohydrate meals was markedly different in young, lean, insulin-resistant individuals compared with young, lean, insulin-sensitive individuals.”
Quote in the paperSubstantial claim - Findingown data§ Results
There were no differences between the insulin-resistant and insulin-sensitive groups in basal liver glycogen concentration.
“In contrast, there were no differences between the two groups in basal liver glycogen concentration (insulin-sensitive, 131.6 ± 9.2 mmol per liter of liver, vs. insulin-resistant, 125.0 ± 17.7 mmol per liter of liver; P = 0.74) or net liver glycogen synthesis after ingestion of the meals (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data§ Results
After the mixed meals, net muscle glycogen synthesis was 61% lower in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“After the mixed meals, however, net muscle glycogen synthesis was 61% lower in the insulin-resistant subjects compared with the insulin-sensitive subjects (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data§ Results
There were no changes in intramyocellular triglyceride content after the meals in either the insulin-resistant or insulin-sensitive group.
“There were no changes in intramyocellular triglyceride content after the meals in either group (Fig. 2C).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Postprandial plasma glucose concentrations were similar in the insulin-resistant and insulin-sensitive groups after the mixed meals.
“After the mixed meals, postprandial plasma glucose concentrations were similar in the two groups (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data§ Results
The concentrations of large low-density lipoprotein particles were decreased by 30% in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“The concentrations of small very-low-density lipoprotein (VLDL) and large LDL particles were decreased by 38% and 30%, respectively, in the insulin resistant subjects (Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Postprandial fractional hepatic de novo triglyceride lipogenesis, assessed by incorporation of deuterated water into plasma triglyceride, was increased by 2.2-fold in the insulin-resistant subjects (15.7 ± 1.5%) compared with the insulin-sensitive subjects (7.2 ± 0.7%).
“Postprandial fractional hepatic de novo triglyceride lipogenesis, as assessed by the incorporation of deuterated water into plasma triglyceride, was increased by 2.2-fold in the insulin-resistant subjects (15.7 ± 1.5%) compared with the insulin-sensitive subjects (7.2 ± 0.7%, P = 0.00005) (Fig. 4).”
Quote in the paperSubstantial claim - Findingown data§ Results
Fasting plasma triglyceride concentrations were higher in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“Fasting plasma glucose, triglyceride, and insulin concentrations were higher in the insulin-resistant subjects compared with the insulin-sensitive subjects (Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Basal muscle glycogen content was similar in the insulin-sensitive and insulin-resistant subjects.
“Basal concentrations of muscle glycogen content were similar in the insulin-sensitive (87.1 ± 5.7 mmol/liter muscle) and insulin-resistant (84.1 ± 4.6 mmol per liter of muscle, P = 0.69) subjects.”
Quote in the paperNot a substantial claim - Findingown data§ Results
Plasma concentrations of uric acid were increased by approximately 30% in the insulin-resistant subjects compared with the insulin-sensitive control subjects.
“Plasma concentrations of uric acid were increased by ≈30% in the insulin-resistant subjects compared with the insulin-sensitive control subjects (Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Results
Postprandial plasma triglyceride concentrations were markedly increased in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“In contrast, postprandial plasma concentrations of insulin and triglycerides were markedly increased in the insulin-resistant subjects (Fig. 1 B and C).”
Quote in the paperNot a substantial claim - Findingown data§ Results
The concentrations of small very-low-density lipoprotein particles were decreased by 38% in the insulin-resistant subjects compared with the insulin-sensitive subjects.
“The concentrations of small very-low-density lipoprotein (VLDL) and large LDL particles were decreased by 38% and 30%, respectively, in the insulin resistant subjects (Table 2).”
Quote in the paperNot a substantial claim - Interpretationown data§ Abstract
Insulin resistance in the young, lean, insulin-resistant subjects was independent of changes in plasma concentrations of TNF-α, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity.
“Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-α, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations.
“These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concent”
Quote in the paperSubstantial claim - Interpretationcitation§ Discussion
Increased export of triglyceride from the liver to peripheral and visceral adipose tissue in the form of VLDL may predispose these insulin-resistant individuals to abdominal obesity.
“Increased export of triglyceride from the liver to the peripheral and visceral adipose tissue in the form of VLDL may also predispose these insulin-resistant individuals to abdominal obesity (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Eckel RH, Hernandez TL, Bell ML, Weil KM, Shepard TY, Grunwald GK, Sharp TA, Francis CC, Hill JO. Am J Clin Nutr. 2006;83:803–808. doi: 10.1093/ajcn/83.4.803. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Discussion
Mice with muscle-specific inactivation of the insulin receptor gene have increased plasma triglycerides and increased adiposity as a result of muscle-specific insulin resistance.
“This hypothesis is further supported by studies in mice with muscle-specific inactivation of the insulin receptor gene, which have been shown to have increased plasma triglycerides and increased adiposity as a result of muscle-specific insulin resistance (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Kim JK, Michael MD, Previs SF, Peroni OD, Mauvais-Jarvis F, Neschen S, Kahn BB, Kahn CR, Shulman GI. J Clin Invest. 2000;105:1791–1797. doi: 10.1172/JCI8305. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Premisecitation§ Discussion
Our previous findings show similar basal and insulin-suppressed rates of whole body and subcutaneous fat lipolysis in similar groups of insulin-sensitive and insulin-resistant subjects.
“This hypothesis is supported by our previous findings of similar basal and insulin suppressed rates of whole body and subcutaneous fat lipolysis in similar groups of insulin-sensitive and insulin-resistant subjects (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. N Engl J Med. 2004;350:664–671. doi: 10.1056/NEJMoa031314. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationnone given§ Discussion
Insulin resistance in skeletal muscle is due to decreased muscle glycogen synthesis.
“insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, promotes atherogenic dyslipidemia”
Quote in the paperNot a substantial claim - Interpretationcitation§ Discussion
Increased hepatic de novo lipogenesis resulting in hypertriglyceridemia can explain the lower HDL levels in the insulin-resistant subjects through cholesteryl ester transfer protein-mediated exchange of VLDL triglycerides for HDL cholesterol, leading to triglyceride-rich, cholesterol-depleted HDL particles that are cleared more rapidly.
“Second, increased hepatic de novo lipogenesis resulting in hypertriglyceridemia also can explain the lower HDL levels in the insulin-resistant subjects by the following mechanism”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Krauss RM, Siri PW. Endocrinol Metab Clin N Am. 2004;33:405–415. doi: 10.1016/j.ecl.2004.03.016. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ Discussion
The data are consistent with the hypothesis that insulin resistance in skeletal muscle promotes atherogenic dyslipidemia by promoting the conversion of energy derived from ingested carbohydrate into hepatic de novo lipogenesis and increased VLDL production.
“First, the data are consistent with the hypothesis that insulin resistance in skeletal muscle promotes atherogenic dyslipidemia by promoting the conversion of energy derived from ingested carbohydrate into hepatic de novo lipogenesis and increased VLDL production.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Insulin resistance in skeletal muscle promotes atherogenic dyslipidemia by diverting energy derived from ingested carbohydrate away from muscle glycogen synthesis into increased hepatic de novo lipogenesis.
“insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, promotes atherogenic dyslipidemia by diverting energy derived from ingested carbohydrate away from muscle glycogen synthesis into increased hepatic de novo lipogenesis”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
The observed alterations in the concentrations of these adipocytokines in the metabolic syndrome and T2DM are likely to be secondary to other factors, such as obesity.
“and that the observed alterations in the concentrations of these adipocytokines in the metabolic syndrome and T2DM are likely to be secondary to other factors, such as obesity.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Increased hepatic triglyceride synthesis in these insulin-resistant subjects may predispose them to nonalcoholic fatty liver disease (NAFLD).
“which may predispose them to nonalcoholic fatty liver disease (NAFLD).”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Skeletal muscle insulin resistance predates hepatic insulin resistance.
“These data also demonstrate that skeletal muscle insulin resistance predates hepatic insulin resistance”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Alterations in the concentrations of plasma adipocytokines (HMW adiponectin, IL-6, resistin, TNF-α, RBP-4) do not play a primary role in the early development of insulin resistance and atherogenic dyslipidemia in these young, lean, insulin-resistant subjects.
“Taken together these data suggest that alterations in the concentrations in these plasma adipocytokines do not play a primary role in the early development of insulin resistance and atherogenic dyslipidemia in these young, lean, insulin-resistant subjects”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM.
“recent studies have demonstrated that NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM (18–23).”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [18] Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. J Biol Chem. 2000;275:8456–8460. doi: 10.1074/jbc.275.12.8456. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [19] Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, et al. Proc Natl Acad Sci USA. 2001;98:7522–7527. doi: 10.1073/pnas.121164498. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
- cites [21] Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. J Biol Chem. 2004;279:32345–32353. doi: 10.1074/jbc.M313478200. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [22] Neschen S, Morino K, Hammond LE, Zhang D, Liu ZX, Romanelli AJ, Cline GW, Pongratz RL, Zhang XM, Choi CS, et al. Cell Metab. 2005;2:55–65. doi: 10.1016/j.cmet.2005.06.006. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [23] Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, et al. J Clin Invest. 2006;116:817–824. doi: 10.1172/JCI27300. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationcitation§ Discussion
The cellular signal driving increased hepatic de novo lipogenesis can most likely be attributed to hyperinsulinemia promoting increased expression of sterol regulatory element binding protein-1c in the liver, which coordinately regulates transcription of all key enzymes involved in lipogenesis.
“The cellular signal driving this increased hepatic de novo lipogenesis can most likely be attributed to hyperinsulinemia promoting increased expression of the sterol regulatory element binding protein-1c in the liver, which coordinately regulates transcription of all of the key enzymes involved in lipogenesis (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Horton JD, Goldstein JL, Brown MS. J Clin Invest. 2002;109:1125–1131. doi: 10.1172/JCI15593. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- The authors state this as an assumption: A portal vein–artery concentration gradient for insulin of approximately 3.
- Premisecitation§ Discussion
NAFLD is strongly linked to hepatic insulin resistance.
“NAFLD is strongly linked to hepatic insulin resistance”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [18] Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. J Biol Chem. 2000;275:8456–8460. doi: 10.1074/jbc.275.12.8456. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [19] Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, et al. Proc Natl Acad Sci USA. 2001;98:7522–7527. doi: 10.1073/pnas.121164498. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [20] Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI. J Clin Invest. 2002;109:1345–1350. doi: 10.1172/JCI15001. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. J Biol Chem. 2004;279:32345–32353. doi: 10.1074/jbc.M313478200. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [22] Neschen S, Morino K, Hammond LE, Zhang D, Liu ZX, Romanelli AJ, Cline GW, Pongratz RL, Zhang XM, Choi CS, et al. Cell Metab. 2005;2:55–65. doi: 10.1016/j.cmet.2005.06.006. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [23] Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, et al. J Clin Invest. 2006;116:817–824. doi: 10.1172/JCI27300. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- May combine two claims. 10
- Classified as probably not a substantial claim. 2
May combine two claims.
Findingown data§ AbstractThere were no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume between insulin-resistant and insulin-sensitive subjects.
“These changes were associated with a 60% increase in plasma triglyceride concentrations and an ≈20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsThere were no differences in fasting or postprandial plasma fatty acid concentrations between the insulin-resistant and insulin-sensitive groups, except from 10 to 11 p.m., when plasma fatty acid concentrations were lower in the insulin-resistant subjects.
“There were no differences in fasting or postprandial plasma fatty acid concentrations between the two groups, except from 10 to 11 p.m., when plasma fatty acid concentrations were lower in the insulin-resistant subjects compared with the insulin-sensitive subjects (Fig. 1D).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown data§ ResultsThe insulin-resistant and insulin-sensitive volunteers were similar in age, body mass index, lean body mass, fat mass, and monitored physical activity despite large differences in the insulin sensitivity index.
“Despite having large differences in the ISI, the insulin-resistant and insulin-sensitive volunteers were similar in age, body mass index, lean body mass, fat mass, and monitored physical activity (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown data§ ResultsThere were no differences in systolic or diastolic blood pressure between the insulin-resistant and insulin-sensitive groups.
“There also were no differences in systolic or diastolic blood pressure between the groups.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown data§ AbstractTNF-α, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, and intraabdominal obesity do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.
“suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationcitation§ DiscussionIncreased hepatic de novo lipogenesis precedes the development of adipose tissue insulin resistance, which subsequently leads to increased flux of fatty acids to the liver.
“these results suggest that increased hepatic de novo lipogenesis precede the development of adipose tissue insulin resistance, which subsequently leads to increased flux of fatty acids to the liver (16, 17).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Klein S. J Clin Invest. 2004;113:1530–1532. doi: 10.1172/JCI22028. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [17] Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD. Diabetes. 1988;37:1020–1024. doi: 10.2337/diab.37.8.1020. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ DiscussionInsulin resistance in skeletal muscle promotes the development of the metabolic syndrome, NAFLD, T2DM, and the associated cardiovascular disease.
“These findings have important implications for understanding the mechanism by which insulin resistance in skeletal muscle promotes the development of the metabolic syndrome, NAFLD, T2DM, and the associated cardiovascular disease.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation§ Materials and MethodsThe ISI measures the overall effects of insulin to stimulate glucose disposal and inhibit glucose production.
“The ISI measures the overall effects of insulin to stimulate glucose disposal and inhibit glucose production.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. N Engl J Med. 2004;350:664–671. doi: 10.1056/NEJMoa031314. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
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Not checked in the free run.
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Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Study design and conductnone given§ AbstractHealthy, young, lean, insulin-resistant individuals have none of the other confounding factors typically associated with obesity and T2DM.
“The advantage of examining this question in healthy, young, lean, insulin-resistant individuals is that they have none of the other confounding factors that are typically associated with obesity and T2DM”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown data§ DiscussionThe young, lean, insulin-resistant subjects had a marked defect in muscle glycogen synthesis and diverted much more of their ingested energy into hepatic de novo lipogenesis, resulting in increased plasma triglycerides, lower HDL, and increased hepatic triglyceride synthesis.
“In contrast to the young, lean, insulin-sensitive subjects, who stored most of their ingested energy in liver and muscle glycogen, the young lean insulin-resistant subjects had a marked defect in muscle glycogen synthesis and diverted much more of their ingested energy into hepatic de novo lipogenesis, resulting in increased plasma triglycerides, lower HDL, and increased hepatic triglyceride synth”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ DiscussionAbdominal obesity develops later in the course of the metabolic syndrome along with NAFLD and is likely more a consequence of insulin resistance in skeletal muscle rather than a primary cause of insulin resistance and atherogenic dyslipidemia.
“These data suggest that abdominal obesity develops later in the course of the metabolic syndrome along with NAFLD and that it is likely more a consequence of insulin resistance in skeletal muscle rather than a primary cause of insulin resistance and atherogenic dyslipidemia (5–7).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Peiris AN, Sothmann MS, Hoffmann RG, Hennes MI, Wilson CR, Gustafson AB, Kissebah AH. Ann Intern Med. 1989;110:867–872. doi: 10.7326/0003-4819-110-11-867. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [6] Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. J Clin Invest. 1995;96:88–98. doi: 10.1172/JCI118083. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [7] Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE. Diabetes. 2004;53:2087–2094. doi: 10.2337/diabetes.53.8.2087. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Premisecitation§ DiscussionRecent studies by our group demonstrate a relatively low prevalence of hepatic steatosis in young, lean, healthy subjects of different ethnic backgrounds, with the important exception of Asian Indian males who have a marked increase in the prevalence of hepatic steatosis.
“is consistent with recent studies by our group demonstrating the relatively low prevalence of hepatic steatosis in young, lean, healthy subjects of different ethnic backgrounds with the important exception of Asian Indian males who have a marked increase in the prevalence of hepatic steatosis (13).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Petersen KF, Dufour S, Feng J, Befroy D, Dziura J, Dalla Man C, Cobelli C, Shulman GI. Proc Natl Acad Sci USA. 2006;103:18273–18277. doi: 10.1073/pnas.0608537103. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
The paper relies on this without support.
The biologic mechanisms linking abdominal obesity, insulin resistance, and other metabolic risk factors to the metabolic syndrome are not fully understood.
“however, the biologic mechanisms linking these and other metabolic risk factors associated with the metabolic syndrome are not fully understood and appear to be complex.”
The authors state this as an assumption.
A portal vein–artery concentration gradient for insulin of approximately 3.
“assuming a portal vein–artery concentration gradient for insulin of ≈3”
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?
Insulin-resistant individuals had a large increase in liver triglyceride content, attributable to a roughly two-fold increase in hepatic de-novo lipogenesis.
“Furthermore, insulin-resistant individuals had a large increase in liver triglyceride content, attributable to a roughly two-fold increase in hepatic de-novo lipogenesis.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [89]
Visceral fat mass was identical in normal-weight, insulin-sensitive and insulin-resistant individuals, suggesting features of the metabolic syndrome can develop independently of increased visceral adiposity.
“Notably, visceral fat mass, as measured with abdominal MRI, was identical in these cohorts of normal-weight, insulin-sensitive and insulin-resistant individuals, which suggests these features of the metabolic syndrome can develop independently of increased visceral adiposity.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [89]
After a carbohydrate challenge, the insulin-resistant group had muscle glycogen synthesis 61% lower than controls.
“After a carbohydrate challenge, the insulin-resistant group had substantial elevations in plasma insulin but glycogen synthesis in muscle was 61% lower than in the controls, as measured with 13C–MRS.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [89]
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Hepatic expression and cellular distribution of the glucose transporter family
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- Authors
- Petersen, K. F., Dufour, S., Savage, D. B., Bilz, S., Solomon, G., Yonemitsu, S., Cline, G. W., Befroy, D., Zemany, L., Kahn, B. B., Papademetris, X., Rothman, D. L., & Shulman, G. I.
- Affiliations
- Departments of *Internal Medicine;
- Howard Hughes Medical Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Diagnostic Radiology and Biomedical Engineering;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-31
- Volume
- 104
- Issue
- 31
- Pages
- 12587-12594
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1924794
- OpenAlex
- W1970653898
- Cited by
- 759
- References
- 49
- Citations by year
- 2026: 19 · 2025: 34 · 2024: 36 · 2023: 30 · 2022: 45 · 2021: 52 · 2020: 27 · 2019: 45 · 2018: 36 · 2017: 49 · 2016: 47 · 2015: 34 · 2014: 50 · 2013: 41 · 2012: 49
- FWCI
- 27.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Yale University
- U.S. Public Health Service (P30 DK45735, R01 AG23686)
- National Institute on Aging (R01-AG-23686, R01AG023686)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01 DK43051, R01DK043051, P30DK045735, P01DK068229)
- National Institute of Biomedical Imaging and Bioengineering (R01EB006494)
- National Center for Research Resources (M01RR000125, M01 RR-00125)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- skeletal muscle insulin resistance, metabolic syndrome, atherogenic dyslipidemia, muscle glycogen synthesis, hepatic de novo lipogenesis, hepatic triglyceride synthesis, plasma triglycerides, HDL cholesterol, mixed meal, adipokines, TNF-α, interleukin-6, adiponectin, resistin, retinol-binding protein 4, intra-abdominal fat
- MeSH terms
- Fasting, Glycogen, Hormones, Humans, Insulin Resistance, Magnetic Resonance Imaging, Cytokines, Muscle, Skeletal, Metabolic Syndrome
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 ›
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