Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
Diabetes Obes Metab. 2013 Oct;15(10):915-22. doi: 10.1111/dom.12112. Epub 2013 May 1.
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).
Sixteen patients [body mass index (BMI): 28 ± 1 kg/m(2) ; 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/m(2)] 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.
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.
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.
噻唑烷二酮通过其胰岛素增敏作用降低血糖。在这里，我们研究了吡格列酮加那格列奈（PIO）是否会干扰肝细胞脂质（HCL）含量和/或改善血糖控制良好的非肥胖 2 型糖尿病（T2DM）患者的胰岛素敏感性。
16 名患者[体重指数（BMI）：28±1kg/m²；糖化血红蛋白（HbA1c）：7.1±0.6%]进行了一项随机、双盲、12 周平行组试验研究，而匹配的健康人[非糖尿病对照受试者（CON），BMI：26±1kg/m²]则进行了一次研究。用吡格列酮（30mg/天）加那格列奈（PIO 组）治疗来控制格列美脲诱导的胰岛素分泌，与格列美脲（2mg/天）加安慰剂（GLI 组）治疗进行比较。多核磁共振波谱（MRS）与胰腺正常血糖双相胰岛素钳夹和稳定同位素相结合，以评估葡萄糖周转率、葡萄糖转运/磷酸化、HCL 和肌内脂质（IMCL）含量、非酯化脂肪酸（NEFA）和脂肪因子。
在基线时，T2DM 患者的 HCL 大约高 5.6 倍（p<0.05 与 CON 相比）。这与瘦素增加约两倍相对应：脂联素比率（p<0.05）。PIO 治疗后 HCL 降低约 39%（p<0.05），GLI 治疗后仅呈下降趋势（p=0.12）。PIO 治疗并未影响瘦素：脂联素比率，但略微改善（p<0.05）胰岛素介导的 NEFA 抑制作用，这与较低的 HCL 有关。PIO 还进一步防止了胰岛素诱导的比目鱼肌和胫骨前肌 IMCL 含量的增加。两组的外周和肝脏胰岛素敏感性、葡萄糖转运和血糖控制均未改变。
短期、低剂量噻唑烷二酮治疗可改善脂肪分解和 HCL 的胰岛素敏感性，而不影响肌肉和肝脏的胰岛素敏感性。似乎 T2DM 中代谢性 PIO 作用主要是通过降低与脂肪分解对胰岛素敏感性增加相关的 HCL 来介导的。
