Effects of pioglitazone versus glimepiride exposure on hepatocellular fat content in type 2 diabetes

Authors

  • E. Phielix,

    1. Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany
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  • A. Brehm,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical Unviersity of Vienna, Vienna, Austria
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  • E. Bernroider,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical Unviersity of Vienna, Vienna, Austria
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  • M. Krssak,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical Unviersity of Vienna, Vienna, Austria
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  • C.-H. Anderwald,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical Unviersity of Vienna, Vienna, Austria
    2. Metabolic Unit, Istituto di Ingegneria Biomedica-Consiglio Nazionale delle Ricerche (ISIB-CNR), Padova, Italy
    3. Specialized Hospital Complex Agathenhof, Micheldorf, Austria
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  • M. Krebs,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical Unviersity of Vienna, Vienna, Austria
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  • A. I. Schmid,

    1. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical Unviersity of Vienna, Vienna, Austria
    2. Center of Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria
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  • P. Nowotny,

    1. Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany
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  • M. Roden

    Corresponding author
    1. Department of Endocrinology, University Clinics Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
    • Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany
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Correspondence to: Dr Michael Roden, Department of Endocrinology, Institute for Clinical Diabetology, German Diabetes Center, Heinrich-Heine University, Aufm Hennekamp 65, D-40225 Düsseldorf, Germany.

E-mail: michael.roden@ddz.uni-duesseldorf.de

Abstract

Aims

Thiazoledinediones decrease blood glucose by their insulin-sensitizing properties. Here, we examined whether pioglitazone plus nateglinide (PIO) interferes with hepatocellular lipid (HCL) content and/or improves insulin sensitivity in well-controlled non-obese patients with type 2 diabetes mellitus (T2DM).

Methods

Sixteen patients [body mass index (BMI): 28 ± 1 kg/m2; HbA1c: 7.1 ± 0.6%] were studied in a randomized, double-blind, 12-week parallel group trial, whereas matched healthy humans [non-diabetic control subjects (CON), BMI: 26 ± 1 kg/m2] were studied once. Treatment with pioglitazone (30 mg/day) plus nateglinide (PIO arm) to control for glimepiride-induced insulin secretion was compared to treatment with glimepiride (2 mg/day) plus placebo (GLI arm). Multinuclei magnetic resonance spectroscopy (MRS) was combined with pancreatic normoglycaemic-two-step-insulin clamps and stable isotopes to assess glucose turnover, glucose transport/phosphorylation, HCL and intramyocellular lipid (IMCL) contents, non-esterified fatty acids (NEFA) and adipokines.

Results

At baseline, HCL was approximately 5.6-fold higher in T2DM (p < 0.05 vs. CON). This was paralleled by approximately doubled leptin : adiponectin ratios (p < 0.05). HCL decreased by approximately 39% (p < 0.05) after PIO and only tended to decrease after GLI (p = 0.12). Treatment with PIO did not affect leptin : adiponectin ratios, but slightly improved (p < 0.05) insulin-mediated NEFA suppression, which related to lower HCL. PIO further prevented the insulin-induced increase in IMCL content of soleus and tibialis anterior muscles. Peripheral and hepatic insulin sensitivity, glucose transport and glycaemic control did not change in both groups.

Conclusion

Short-term, low-dose thiazolidendione treatment improves insulin sensitivity of lipolysis and HCL, without affecting muscle and liver insulin sensitivity. It appears that metabolic PIO action in T2DM is primarily mediated via a decline in HCL associated with greater sensitivity of lipolysis to insulin.

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