Yu Tian, Sungelo Mitchell J, Goldberg Ira J, Wang Hong, Eckel Robert H
Division of Endocrinology, Metabolism, & Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, NYU Langone Medical Center, New York, New York, USA.
Horm Metab Res. 2017 May;49(5):400-406. doi: 10.1055/s-0042-110934. Epub 2017 Apr 10.
The pharmacological effects of type 2 diabetes (T2DM) medications on lipoprotein metabolism are difficult to assess in preclinical models because those created failure to replicate the human condition in which insulin deficiency is superimposed on obesity-related insulin resistance. To create a better model, we fed mice with high fat (HF) diet and treated the animals with low dose streptozotocin (STZ) to mimic T2DM. We used this model to evaluate the effects of canagliflozin (CANA), a drug that reduces plasma glucose by inhibiting the sodium-glucose transporter 2 (SGLT2), which mediates ~90% of renal glucose reabsorption] on lipid and lipoprotein metabolism. After 6 weeks of CANA (30 mg/kg/day) treatment, the increase in total plasma cholesterol in HF-STZ diabetic mice was reversed, but plasma triglycerides were not affected. Lipoprotein fractionation and cholesterol distribution analysis showed that CANA kept HDL-Cholesterol, LDL-Cholesterol, and IDL-Cholesterol levels steady while these lipoprotein species were increased in placebo- and insulin-treated control groups. CANA treatment of HF-STZ mice reduced post-heparin plasma lipoprotein lipase (LPL) activity at 2 (-40%) and 5 (-30%) weeks compared to placebo. Tissue-specific LPL activity following CANA treatment showed similar reduction. In summary, CANA prevented the total cholesterol increase in HF-STZ mice without effects on plasma lipids or lipoproteins, but did decrease LPL, implying a potential role of LPL-dependent lipoprotein metabolism in CANA action. These effects did not recapitulate the effect of SGLT2 inhibitors on lipids and lipoproteins in human, suggesting that a better murine T2DM model (such as the ApoB100 humanized CETP-overexpressing mouse) is needed next.
2型糖尿病（T2DM）药物对脂蛋白代谢的药理作用在临床前模型中难以评估，因为这些模型无法复制人类那种胰岛素缺乏叠加在肥胖相关胰岛素抵抗之上的状况。为了建立一个更好的模型，我们用高脂肪（HF）饮食喂养小鼠，并用低剂量链脲佐菌素（STZ）处理动物以模拟T2DM。我们使用这个模型来评估卡格列净（CANA）的作用，卡格列净是一种通过抑制钠-葡萄糖转运蛋白2（SGLT2）来降低血糖的药物，SGLT2介导约90%的肾脏葡萄糖重吸收，该药物对脂质和脂蛋白代谢的影响。在接受CANA（30mg/kg/天）治疗6周后，HF-STZ糖尿病小鼠血浆总胆固醇的升高得到逆转，但血浆甘油三酯未受影响。脂蛋白分级和胆固醇分布分析表明，CANA使高密度脂蛋白胆固醇（HDL-胆固醇）、低密度脂蛋白胆固醇（LDL-胆固醇）和中间密度脂蛋白胆固醇（IDL-胆固醇）水平保持稳定，而在安慰剂和胰岛素治疗的对照组中这些脂蛋白种类增加。与安慰剂相比，CANA治疗HF-STZ小鼠在第2周（-40%）和第5周（-30%）降低了肝素后血浆脂蛋白脂肪酶（LPL）活性。CANA治疗后的组织特异性LPL活性也有类似程度的降低。总之，CANA可防止HF-STZ小鼠总胆固醇升高，对血浆脂质或脂蛋白无影响，但确实降低了LPL，这意味着LPL依赖的脂蛋白代谢在CANA作用中可能发挥作用。这些作用并未重现SGLT2抑制剂对人类脂质和脂蛋白的影响，这表明接下来需要一个更好的小鼠T2DM模型（如载脂蛋白B100人源化、胆固醇酯转运蛋白过表达小鼠）。
