Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes

Juurinen, Leena; Tiikkainen, Mirja; Häkkinen, Anna‐Maija; Hakkarainen, Antti; Yki‐Järvinen, Hannele

doi:10.1152/ajpendo.00133.2006

Cited by 119 publications

(104 citation statements)

References 56 publications

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“…These findings are consistent with studies demonstrating increased TG synthesis from dietary fatty acids in fat-fed mice (31,32). Our hypothesis would also explain the apparently paradoxical finding of unchanged or decreased hepatic fat content in T2D patients treated with insulin (33)(34)(35). If insulin was the primary driving force for hepatic TG synthesis in disorders of hepatic insulin resistance, then one would expect insulin therapy to potentially exacerbate NAFLD rather than having a neutral or beneficial effect (33)(34)(35).…”

Section: Discussionsupporting

confidence: 89%

“…Our hypothesis would also explain the apparently paradoxical finding of unchanged or decreased hepatic fat content in T2D patients treated with insulin (33)(34)(35). If insulin was the primary driving force for hepatic TG synthesis in disorders of hepatic insulin resistance, then one would expect insulin therapy to potentially exacerbate NAFLD rather than having a neutral or beneficial effect (33)(34)(35). Our data, demonstrating the insulin-independent substrate-dependent nature of hepatic TG synthesis, explain the beneficial effect of insulin in the progression of hepatic steatosis in insulin-resistant patients (34,36).…”

Section: Discussionmentioning

confidence: 85%

“…If insulin was the primary driving force for hepatic TG synthesis in disorders of hepatic insulin resistance, then one would expect insulin therapy to potentially exacerbate NAFLD rather than having a neutral or beneficial effect (33)(34)(35). Our data, demonstrating the insulin-independent substrate-dependent nature of hepatic TG synthesis, explain the beneficial effect of insulin in the progression of hepatic steatosis in insulin-resistant patients (34,36). Insulin therapy protects the liver from excess fatty acid delivery, both by increasing fat delivery to peripheral stores through increased synthesis and secretion of lipoprotein lipase and plasma membrane translocation of the FATP1 fatty acid transporter in the white adipose tissue and through the suppression of adipose tissue lipolysis (37).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids

Vatner¹,

Majumdar²,

Kumashiro³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

181

134

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A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance-wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-13 C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2′-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.nonalcoholic fatty liver disease | hepatic insulin resistance | lipogenesis | esterification | mass spectrometry

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids

Vatner¹,

Majumdar²,

Kumashiro³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

181

134

View full text Add to dashboard Cite

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“…Therefore, a CT L-S of less than 1 HU could be used as a conservative criterion for diagnosing hepatic steatosis with nonenhanced CT more consistently. diagnosis of hepatic steatosis and is widely generalizable, the low sensitivity of this approach considerably limits the capability of nonenhanced CT in the detection of hepatic steatosisparticularly nonalcoholic fatty liver disease and nonalcoholic steatohepatitisas patients with these conditions frequently have a mild degree of hepatic steatosis (25)(26)(27). Although the CT fi ndings of hepatic steatosis should not be neglected when interpreting CT data, it may be inappropriate to perform nonenhanced CT to diagnose mild hepatic steatosis.…”

Section: Discussionmentioning

confidence: 99%

Biopsy-proven Nonsteatotic Liver in Adults: Estimation of Reference Range for Difference in Attenuation between the Liver and the Spleen at Nonenhanced CT

et al. 2011

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Purpose:To establish the reference range for hepatic attenuation minus splenic attenuation difference (CT L 2 S ) values on nonenhanced computed tomographic (CT) images obtained in adults with a biopsy-proved nonsteatotic liver and determine the CT L 2 S criterion for diagnosing hepatic steatosis. Materials and Methods:This retrospective study was institutional review board approved, and all subjects had provided written informed consent. The CT L 2 S was measured in 315 liver donor candidates (207 men, 108 women; mean age, 31.5 years 6 10.1 [standard deviation]) who underwent nonenhanced CT of the liver and subsequent ultrasonographically guided liver biopsy on the same day. Nonenhanced liver CT was performed with a 16-section multidetector scanner in 154 individuals and with a 64-section multidetector scanner in 161 individuals. Biopsy specimens were analyzed for degree of hepatic steatosis and iron deposition. The CT L 2 S reference range was determined according to Clinical and Laboratory Standards Institute guideline C28-A3 in individuals with a histologically proved nonsteatotic liver. The sensitivity of nonenhanced CT for the diagnosis of 5% or greater and 30% or greater hepatic steatosis with use of the lower limit of the reference range as the diagnostic cutoff was determined. The effects of subject age and sex, CT scanner type, and hepatic iron on the CT L 2 S were evaluated by using multiple linear regression analysis. Results:Ninety-six subjects (48 men, 48 women) were found to have a histologically proved nonsteatotic liver, with an estimated reference range for CT L 2 S values of 1-18 HU. With a CT L 2 S of less than 1 HU as the criterion for hepatic steatosis, the sensitivities of nonenhanced CT for 5% or greater and 30% or greater hepatic steatosis were 18.6% (29 of 156 subjects) and 67 % (26 of 39 subjects), respectively. Subject age had a signifi cant but negligible effect on CT L 2 S (0.076-HU increase per year of age, P = .009), subject sex and scanner type had no effects on CT L 2 S , and hepatic iron deposition signifi cantly increased the CT L 2 S (1.434-HU increase per increase in iron deposition grade, P = .011). Conclusion:The histologically proved reference range of CT L 2 S values for nonsteatotic livers was 1-18 HU. A CT L 2 S of less than 1 HU could be used as a conservative criterion for diagnosing hepatic steatosis with nonenhanced CT more consistently.q RSNA, 2011

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“…Yet, prior studies that have used imaging techniques for fat quantification have shown a reduction in liver fat with insulin therapy (6)(7)(8)(9). The mechanisms by which insulin therapy may reduce liver fat include inhibition of lipolysis, which may reduce free fatty acid flux to the liver (7), and decreased production of endogenous insulin passing through the liver to stimulate hepatic lipogenesis (6).…”

mentioning

confidence: 99%

Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

et al. 2015

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OBJECTIVEThis study determined the effects of insulin versus liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy, including metformin. RESEARCH DESIGN AND METHODSThirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications were randomized to receive insulin glargine or liraglutide therapy for 12 weeks. The liver proton density fat fraction (PDFF) was measured by MRS. The mean liver PDFF, the total liver volume, and the total liver fat index were measured by MRI. The Student t test, the Fisher exact test, and repeated-measures ANOVA were used for statistical analysis. RESULTSInsulin treatment was associated with a significant improvement in glycated hemoglobin (7.9% to 7.2% [62.5 to 55.2 mmol/mol], P = 0.005), a trend toward a decrease in MRS-PDFF (12.6% to 9.9%, P = 0.06), and a significant decrease in liver mean MRI-PDFF (13.8% to 10.6%, P = 0.005), liver volume (2,010.6 to 1,858.7 mL, P = 0.01), and the total liver fat index (304.4 vs. 209.3 % · mL, P = 0.01). Liraglutide treatment was also associated with a significant improvement in glycated hemoglobin (7.6% to 6.7% [59.8 to 50.2 mmol/mol], P < 0.001) but did not change MRS-PDFF (P = 0.80), liver mean MRI-PDFF (P = 0.15), liver volume (P = 0.30), or the total liver fat index (P = 0.39). CONCLUSIONSThe administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes. However, the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group.To reduce the risk of long-term microvascular and macrovascular complications, diabetes therapy should aim for tight glucose control as assessed by glycated hemoglobin (HbA 1c ) below 7% (53 mmol/mol) while minimizing hypoglycemia (1,2). However, most patients still do not achieve glycemic targets and thus require

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Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes

Abstract: insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.

Cited by 119 publications

References 56 publications

Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids

Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids

Biopsy-proven Nonsteatotic Liver in Adults: Estimation of Reference Range for Difference in Attenuation between the Liver and the Spleen at Nonenhanced CT

Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

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