Juurinen Leena, Kotronen Anna, Granér Marit, Yki-Järvinen Hannele
Department of Medicine, Division of Diabetes, University of Helsinki, PO Box 700, Room C418B, FIN-00029 HUCH Helsinki, Finland.
J Clin Endocrinol Metab. 2008 Jan;93(1):118-24. doi: 10.1210/jc.2007-1825. Epub 2007 Oct 23.
Liver fat is an important determinant of insulin requirements during insulin therapy. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists reduce liver fat. We therefore hypothesized that type 2 diabetic patients using exceptionally high doses of insulin might respond well to addition of a PPARgamma agonist.
We determined the effect of the PPARgamma agonist rosiglitazone on liver fat and directly measured hepatic insulin sensitivity in 14 patients with type 2 diabetes (aged 51 +/- 3 yr, body mass index 36.7 +/- 1.1 kg/m2), who were poorly controlled (glycosylated hemoglobin A 1c (HbA 1c) 8.9 +/- 0.4%) despite using high doses of insulin (218 +/- 22 IU/d) in combination with metformin. Liver fat content (1H-magnetic resonance spectroscopy), hepatic insulin sensitivity [6 h hyperinsulinemic euglycemic clamp (insulin 0.3 mU/kg.min) combined with [3-3H]glucose], body composition (magnetic resonance imaging), substrate oxidation rates (indirect calorimetry), clinical parameters, and liver enzymes were measured before and after rosiglitazone treatment (8 mg/d) for 8 months.
During rosiglitazone, HbA(1c) decreased from 8.9 +/- 0.4% to 7.8 +/- 0.3% (P = 0.007) and insulin requirements from 218 +/- 22 to 129 +/- 20 IU/d (P = 0.002). Liver fat content decreased by 46 +/- 9% from 20 +/- 3% to 11 +/- 3% (P = 0.0002). Hepatic insulin sensitivity, measured from the percent suppression of endogenous glucose production by insulin, increased from -40 +/- 7% to -89 +/- 12% (P = 0.001). The percent change in liver fat correlated with the percent decrease in HbA 1c (r = 0.53, P = 0.06), insulin dose (r = 0.66, P = 0.014), and suppression of endogenous glucose production (r = 0.76, P = 0.003).
Our results suggest that rosiglitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses. The mechanism is likely to involve reduced liver fat and enhanced hepatic insulin sensitivity.
肝脏脂肪是胰岛素治疗期间胰岛素需求量的重要决定因素。过氧化物酶体增殖物激活受体（PPAR）-γ激动剂可减少肝脏脂肪。因此，我们推测使用极高剂量胰岛素的2型糖尿病患者可能对添加PPARγ激动剂反应良好。
我们确定了PPARγ激动剂罗格列酮对肝脏脂肪的影响，并直接测量了14例2型糖尿病患者（年龄51±3岁，体重指数36.7±1.1kg/m2）的肝脏胰岛素敏感性，这些患者尽管联合使用高剂量胰岛素（218±22IU/d）和二甲双胍，但血糖控制不佳（糖化血红蛋白A1c（HbA1c）8.9±0.4%）。在罗格列酮治疗（8mg/d）8个月前后，测量肝脏脂肪含量（1H-磁共振波谱法）、肝脏胰岛素敏感性[6小时高胰岛素正常血糖钳夹试验（胰岛素0.3mU/kg·min）联合[3-3H]葡萄糖]、身体成分（磁共振成像）、底物氧化率（间接测热法）、临床参数和肝酶。
在罗格列酮治疗期间，HbA1c从8.9±0.4%降至7.8±0.3%（P=0.007），胰岛素需求量从218±22IU/d降至129±20IU/d（P=0.002）。肝脏脂肪含量从20±3%下降了46±9%至11±3%（P=0.0002）。通过胰岛素对内源性葡萄糖生成的抑制百分比来衡量的肝脏胰岛素敏感性从-40±7%增加到-89±12%（P=0.001）。肝脏脂肪的变化百分比与HbA1c的下降百分比（r=0.53，P=0.06）、胰岛素剂量（r=0.66，P=0.014）以及内源性葡萄糖生成的抑制（r=0.76，P=0.003）相关。
我们的结果表明，罗格列酮可能对尽管使用高剂量胰岛素但血糖控制不佳的2型糖尿病患者特别有效。其机制可能涉及肝脏脂肪减少和肝脏胰岛素敏感性增强。
