Cited by 141Liver Disease Diagnosis and TreatmentDiabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

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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·2007·American Journal of Physiology-Endocrinology and Metabolism

DOI 10.1152/ajpendo.00133.2006

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Abstract

UNLABELLED: We determined whether insulin therapy changes liver fat content (LFAT) or hepatic insulin sensitivity in type 2 diabetes. Fourteen patients with type 2 diabetes (age 51+/-2 yr, body mass index 33.1+/-1.4 kg/m2) treated with metformin alone received additional basal insulin for 7 mo. Liver fat (proton magnetic resonance spectroscopy), fat distribution (MRI), fat-free and fat mass, and whole body and hepatic insulin sensitivity (6-h euglycemic hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose) were measured. The insulin dose averaged 75+/-10 IU/day (0.69+/-0.08 IU/kg, range 24-132 IU/day). Glycosylated hemoglobin A1c (Hb A1c) decreased from 8.9+/-0.3 to 7.4+/-0.2% (P<0.001). Whole body insulin sensitivity increased from 2.21+/-0.38 to 3.08+/-0.40 mg/kg fat-free mass (FFM).min (P<0.05). This improvement could be attributed to enhanced suppression of hepatic glucose production (HGP) by insulin (HGP 1.04+/-0.28 vs. 0.21+/-0.19 mg/kg FFM.min, P<0.01). The percent suppression of HGP by insulin increased from 72+/-8 to 105+/-11% (P<0.01). LFAT decreased from 17+/-3 to 14+/-3% (P<0.05). The change in LFAT was significantly correlated with that in hepatic insulin sensitivity (r=0.56, P<0.05). Body weight increased by 3.0+/-1.1 kg (P<0.05). Of this, 83% was due to an increase in fat-free mass (P<0.01). Fat distribution and serum adiponectin concentrations remained unchanged while serum free fatty acids decreased significantly. CONCLUSIONS: insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.

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Background
Hepatopathy Associated With Type 1 Diabetes: Distinguishing Non-alcoholic Fatty Liver Disease From Glycogenic Hepatopathy
Mertens, J., Block, C. E. M. D., Spinhoven, M. J., Driessen, A. L. C., Francque, S., & Kwanten, W. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.768576 · Cited by 48
Randomized, double‐blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3
Bergenstal, R. M., Lunt, H., Franek, E., Travert, F., Mou, J., Qu, Y., Antalis, C. J., Hartman, M. L., Rosilio, M., Jacober, S. J., et al. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12698 · Cited by 47
“Several studies have demonstrated a reduction in liver fat content (LFC) associated with initiation of GL [20] or other conventional basal insulins [21,22].”
Background
Basal insulin peglispro versus insulin glargine in insulin‐naïve type 2 diabetes: IMAGINE 2 randomized trial
Davies, M. J., Russell-Jones, D. L., Selam, J. L., Bailey, T. S., Kerényi, Z., Luo, J., Bue‐Valleskey, J. M., Iványi, T., Hartman, M. L., Jacobson, J. G., et al. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12712 · Cited by 46
Liver-targeting drugs and their effect on blood glucose and hepatic lipids
Gastaldelli, A., Stefan, N., & Häring, H. (2021) · Diabetologia · doi:10.1007/s00125-021-05442-2 · Cited by 48
Randomized double‐blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 2 diabetes: IMAGINE 4
Blevins, T., Pieber, T. R., Vega, G. C., Zhang, S., Bastyr, E. J., Chang, A. M., & on behalf of the IMAGINE 4 Investigators (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12696 · Cited by 44
“Previous studies in insulin-naïve patients with T2D have shown decreases in LFC with initiation of currently available basal and pre-mixed insulins, similar to those reported in IMAGINE 2 [35,36].”
Result
Role of nonalcoholic fatty liver disease in the development of insulin resistance and diabetes
Grønbæk, H., Thomsen, K. L., Rungby, J., Schmitz, O., & Vilstrup, H. (2008) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/17474124.2.5.705 · Cited by 44
Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes
Cusi, K. J., Sanyal, A. J., Zhang, S., Hoogwerf, B. J., Chang, A. M., Jacober, S. J., Bue-Valleskey, J. M., Higdon, A. N., Bastyr, E. J., Haupt, A., et al. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12751 · Cited by 40
“Treatment periods in these studies ranged from 3 to 7 months.(5,6,8) Data from the current studies demonstrate that no further reductions in LFC occur with glargine treatment between 26 and 52 weeks in insulin-naïve T2D patients.”
Result
Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action
Jacober, S. J., PRINCE, M. J., Beals, J. M., Hartman, M. L., Qu, Y., Linnebjerg, H., Garhyan, P., & Haupt, A. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12744 · Cited by 39
Environmental and Genetic Determinants of Fatty Liver in Humans
Kantartzis, K., Schick, F., Häring, H., & Stefan, N. (2010) · Digestive Diseases · doi:10.1159/000282082 · Cited by 32
“On the other hand, exogenous hyperinsulinemia in type 2 diabetic patients resulted in a reduction, not an increase, in hepatic fat content after 7 months [”
Background
Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year Prospective Study
Lallukka, S., Sädevirta, S., Kallio, M. T., Luukkonen, P. K., Zhou, Y., Hakkarainen, A., Lundbom, N. M. I., Orho‐Melander, M., & Yki‐Järvinen, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-14706-0 · Cited by 31
Liver insulinization as a driver of triglyceride dysmetabolism
Cook, J. R., Hawkins, M. A., & Pajvani, U. B. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00843-6 · Cited by 33
Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes
Skovsø, S., Damgaard, J., Fels, J. J., Olsen, G. S., Wolf, X. A., Rolin, B., & Holst, J. J. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.92 · Cited by 30
The potential role of fatty liver in paediatric metabolic syndrome: a distinct phenotype with high metabolic risk?
Nobili, V., Bedogni, G., Canani, R. B., Brambilla, P., Cianfarani, S., Pietrobelli, A., & Agostoni, C. V. (2012) · Pediatric Obesity · doi:10.1111/j.2047-6310.2012.00089.x · Cited by 27
“In the first stages of IR, insulin may continue to inhibit the hepatic secretion of very-low density lipoproteins (VLDLs) but, once the liver has become infiltrated with fat, the overproduction of VLDL produces high triglyceride and low HDL levels (12).”
Background
Suppression of Rho-kinase 1 is responsible for insulin regulation of the AMPK/SREBP-1c pathway in skeletal muscle cells exposed to palmitate
Tang, S., Wu, W., Tang, W., Ge, Z., Wang, H., Hong, T., Zhu, D., & Bi, Y. (2017) · Acta Diabetologica · doi:10.1007/s00592-017-0976-z · Cited by 27
Role of Insulin Resistance and Diabetes in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease
Portillo-Sánchez, P., Yavuz, S., Bril, F., & Cusi, K. J. (2014) · Current Hepatology Reports · doi:10.1007/s11901-014-0229-3 · Cited by 25
Phagocytic function of Kupffer cells in mouse nonalcoholic fatty liver disease models: Evaluation with superparamagnetic iron oxide
Cheong, H., Lee, S. S., Lee, J. S., Kim, J., Kim, S. W., & Lee, W. J. (2014) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.24674 · Cited by 25
“NAFLD is also closely related to insulin resistance and is now regarded as a hepatic manifestation of metabolic syndrome (5,6).”
Background
Modulation of gut microbiota contributes to effects of intensive insulin therapy on intestinal morphological alteration in high-fat-diet-treated mice
Wang, H., Tang, W., Zhang, P., Zhang, Z., He, J., Zhu, D., & Bi, Y. (2019) · Acta Diabetologica · doi:10.1007/s00592-019-01436-0 · Cited by 24
Non-alcoholic fatty liver disease in diabetes: When to refer to the hepatologist?
Khandelwal, R., Dassanayake, A. S., Conjeevaram, H. S., & Singh, S. P. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i9.1479 · Cited by 25
NAFLD vs MASLD (Metabolic Dysfunction–Associated Steatotic Liver Disease)—Why the Need for a Change of Nomenclature?
Gastaldelli, A., & Newsome, P. N. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf094 · Cited by 24
Lower mean blood glucose during short‐term intensive insulin therapy is associated with long‐term glycemic remission in patients with newly diagnosed type 2 diabetes: Evidence‐based recommendations for standardization
Liu, L., Liu, J., Xu, L., Ke, W., Wan, X., Li, H., He, X., Wang, L., Cao, X., Xiao, H., et al. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12782 · Cited by 24
Inhibition of obesity-induced hepatic ER stress by early insulin therapy in obese diabetic rats
Sun, W., Bi, Y., Liang, H., Cai, M., Chen, X. '., Zhu, Y., Li, M., Xu, F. L., Yu, Q.-Q., He, X., et al. (2010) · Endocrine · doi:10.1007/s12020-010-9429-y · Cited by 21
Correlational Study of Nonalcoholic Fatty Liver Disease Diagnosed by Ultrasonography with Lipid Profile and Body Mass Index in Adult Nepalese Population
Khanal, U. P., Paudel, B., Gurung, G., Hu, Y.-S., & Kuo, C.-W. (2019) · Journal of Medical Ultrasound · doi:10.4103/jmu.jmu_53_18 · Cited by 19
“Significant association with increasing grades of fatty liver was found with increasing levels of cholesterol (P = 0.028), low-density lipoprotein (LDL) (P = 0.017), liver size (P = 0.001), and body mass index (BMI) (P = 0.045) in patients diagnosed with NAFLD.”
BackgroundMethodInfluential
Frailty Is Associated with Oxidative Stress in Older Patients with Type 2 Diabetes
Alabadí, B., Civera, M., la Rosa, A. D., Martínez‐Hervás, S., Gómez‐Cabrera, M. C., & Real, J. T. (2021) · Nutrients · doi:10.3390/nu13113983 · Cited by 18
“showing an increase in total body weight and LM without significant changes in fat mass [47].”
Background
Effects of bed-time insulin versus pioglitazone on abdominal fat accumulation, inflammation and gene expression in adipose tissue in patients with type 2 diabetes
Hartemann, A., Halbron, M., Golmard, J., Jacqueminet, S., Bastard, J., Rouault, C., Ayed, A., Piéroni, L., Clément, K., & Grimaldi, A. (2009) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2009.06.028 · Cited by 17
Basal insulin combined incretin mimetic therapy with glucagon-like protein 1 receptor agonists as an upcoming option in the treatment of type 2 diabetes: a practical guide to decision making
Scholz, G. H., & Fleischmann, H. (2014) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018814556099 · Cited by 16
“This assumption is supported by the observation that in patients with poorly controlled T2DM, treated for 7 months with basal insulin as an add on to metformin, a reduction in liver fat was documented, although body weight increased [Juurinen et al. 2007].”
Result
Fat accumulates preferentially in the right rather than the left liver lobe in non-diabetic subjects
Hua, B., Hakkarainen, A., Zhou, Y., Lundbom, N. M. I., & Yki‐Järvinen, H. (2017) · Digestive and Liver Disease · doi:10.1016/j.dld.2017.08.030 · Cited by 16
Role of anti-diabetic medications in the management of MASLD
Isaacs, S. D., Farrelly, F. V., & Brennan, P. (2025) · Frontline Gastroenterology · doi:10.1136/flgastro-2024-102856 · Cited by 17
Approach to the Patient With Nonalcoholic Fatty Liver Disease
Belfort‐DeAguiar, R., Lomonaco, R., & Cusi, K. J. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac624 · Cited by 16
The effect of dioxidovanadium complex (V) on hepatic function in streptozotocin-induced diabetic rats
Sibiya, S., Msibi, B., Khathi, A., Sibiya, N. H., Booysen, I. N., & Ngubane, P. S. (2019) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2019-0369 · Cited by 15
“The ability of vanadium to protect against weight loss might be due to its glucose lowering effect and perhaps also other possible insulin mimetic effect (Juurinen et al. 2007).”
Background
Effect of Insulin versus Triple Oral Therapy on the Progression of Hepatic Steatosis in Type 2 Diabetes
Lingvay, I., Roe, E. D., Duong, J., Leonard, D. S., & Szczepaniak, L. S. (2012) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e3182621c5f · Cited by 14
Endogenous Chronic Hyperinsulinemia Does Not Increase the Production Rate of VLDL Apolipoprotein B: Proof from a Kinetic Study in Patients with Insulinoma
Duvillard, L., Florentin, E., Pont, F., Petit, J., Baillot-Rudoni, S., Penfornis, A., & Vergès, B. L. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2946 · Cited by 15
Insulin Resistance, Hepatic Lipid and Adipose Tissue Distribution in HIV-Infected Men
He, Q. W., Engelson, E. S., Ionescu, G. O., Glesby, M. J., Albu, J., & Kotler, D. P. (2008) · Antiviral Therapy · doi:10.1177/135965350801300309 · Cited by 13
Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon-like peptide-1 receptor agonists. A multicenter retrospective longitudinal study
Morieri, M. L., Targher, G., Lapolla, A., D'Ambrosio, M., Tadiotto, F., Rigato, M., Frison, V., Paccagnella, A., Simioni, N., Avogaro, A., et al. (2021) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2021.08.049 · Cited by 13
Assessment of fatty liver and its correlation with glycemic control in patients with type 2 diabetes mellitus attending Dessie Comprehensive Specialized Hospital, Northeast Ethiopia
Abebe, G., Ayanaw, D., Mengstie, T. A., Dessie, G., & Malik, T. (2022) · SAGE Open Medicine · doi:10.1177/20503121221124762 · Cited by 11
Pivotal Role of Timely Basal Insulin Replacement After Metformin Failure in Sustaining Long-Term Blood Glucose Control at a Target in Type 2 Diabetes
Bolli, G. B., Lucidi, P., Porcellati, F., & Fanelli, C. G. (2011) · Diabetes Care · doi:10.2337/dc11-s224 · Cited by 11
“Insulin is the only drug that directly reduces lipolysis and free fatty acid concentrations in blood (22), thus reducing lipotoxicity (23) and improving insulin action and secretion (24) and the liver fat accumulation in non-alcoholic steato-hepatitis (25).”
Background
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis
Goedeke, L., Strober, J. W., Suh, R., Paolella, L. M., Li, X., Rogers, J. C., Petersen, M. C., Nasiri, A. R., Casals, G., Kahn, M., et al. (2024) · iScience · doi:10.1016/j.isci.2024.111175 · Cited by 10
An overview of insulin therapy for the non‐specialist
Home, P. D. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16280 · Cited by 11
Comparison of size of the liver between patients with non-alcoholic fatty liver disease and healthy controls
Dorostghol, M., Gharibvand, M. M., Hanafi, M. G., & Motamedfar, A. (2024) · Journal of Family Medicine and Primary Care · doi:10.4103/jfmpc.jfmpc_94_23 · Cited by 10
“[18] ] However, these studies did not compare liver size between normal and NAFLD groups.”
Background
Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis
Gastaldelli, A., Scoditti, E., & Macedo, M. P. (2026) · Diabetologia · doi:10.1007/s00125-026-06774-7 · Cited by 11
“Furthermore, while therapeutic insulin can improve hepatic insulin sensitivity and reduce steatosis [80], it is frequently associated with weight gain and increased visceral and subcutaneous adiposity [80, 81].”
Current approaches to diagnosing and treating nonalcoholic fatty liver disease
Никонов, Е. Л., & Va, A. (2018) · Russian Journal of Preventive Medicine · doi:10.17116/profmed201831262 · Cited by 9
“Как СД2, так и повышенный риск СД тесно связаны с тяжестью НАЖБП и способствуют развитию НАСГ, выраженного фиброза и ГЦК [16, 17].”
The Effect of Early Intensive Insulin Therapy on Body Fat Distribution andβ-Cell Function in Newly Diagnosed Type 2 Diabetes
Son, J. W., Jeong, H. K., Lee, S. S., Kim, S. R., Cha, B., Son, H., & Yoo, S. J. (2013) · Endocrine Research · doi:10.3109/07435800.2012.745870 · Cited by 9
Effects of Exenatide and Humalog Mix25 on Fat Distribution, Insulin Sensitivity, and β-Cell Function in Normal BMI Patients with Type 2 Diabetes and Visceral Adiposity
Wang, X., Zhao, X., Gu, Y., Zhu, X., Yin, T., Tang, Z., Yuan, J., Chen, W., Ouyang, R., Yao, L., et al. (2020) · Journal of Diabetes Research · doi:10.1155/2020/9783859 · Cited by 9
“Furthermore, studies have reported conflicting results on the effectiveness of insulin therapy to reduce LFC and consequently increase hepatic insulin sensitivity in obese patients with T2DM [16, 17].”
Result
Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD
Jensen, V. S., Fledelius, C., Zachodnik, C., Damgaard, J., Nygaard, H., Tornqvist, K. S., Kirk, R. K., Viuff, B. M., Wulff, E. M., Lykkesfeldt, J., et al. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02729-1 · Cited by 11

Authors: Juurinen, L., Tiikkainen, M., Häkkinen, A.-M., Hakkarainen, A., & Yki-Järvinen, H.
ORCID: Hakkarainen, Antti
Venue: American Journal of Physiology-Endocrinology and Metabolism
Publisher: American Physiological Society
Published: 2007-03
Volume: 292
Issue: 3
Pages: E829-E835
ISSN: 0193-1849 (ISSN-L)
1522-1555
DOI: 10.1152/ajpendo.00133.2006
OpenAlex: W2062583781
Cited by: 141
References: 54
Citations by year: 2026: 4 · 2025: 6 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 4 · 2019: 6 · 2018: 3 · 2017: 10 · 2016: 11 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 9
FWCI: 5.61
Type: journal article
Language: en
Open access: closed
Locations: American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: insulin therapy, type 2 diabetes, hepatic insulin sensitivity, liver fat, hepatic glucose production, basal insulin, metformin, fat-free mass, free fatty acids, adiponectin, weight gain, hyperinsulinemic-euglycemic clamp, 1H NMR
MeSH terms: Alanine Transaminase, Basal Metabolism, Diabetes Mellitus, Type 2, Drug Combinations, Fatty Acids, Nonesterified, Glucose, Humans, Insulin, Insulin Resistance, Lipids, Liver, Metformin, Middle Aged, Oxidation-Reduction

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

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