Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht Universtiy, Maastricht, Netherlands.
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands.
Front Endocrinol (Lausanne). 2020 Sep 30;11:575070. doi: 10.3389/fendo.2020.575070. eCollection 2020.
Type 2 diabetes mellitus is a metabolic disorder characterized by insulin resistance. Previous studies in patients demonstrated that plasma levels of cathepsin D (CTSD), which is optimally active in the acidic environment of lysosomes, correlate with insulin resistance. As plasma pH is slightly reduced in type 2 diabetic patients and we have previously shown that plasma CTSD activity is causally linked to insulin levels , it is likely that the activity of CTSD in plasma will be increased in type 2 diabetes compared to healthy individuals. However, so far the interaction between CTSD activity and levels to postprandial metabolic derangements in type 2 diabetes is not known.
Eighteen type 2 diabetes and 16 age-matched healthy males were given 2 consecutive standardized mixed meals, after which blood samples were collected. Plasma metabolic parameters as well as CTSD levels and activity were measured, and changes in plasma pH was assessed.
In line with the elevation of plasma free fatty acids (FFA) levels in male type 2 diabetics patients, plasma pH in type 2 diabetic individuals was decreased compared to male healthy individuals. While plasma CTSD levels were similar, plasma CTSD activity was increased in male type 2 diabetic compared to male healthy individuals. Besides, plasma CTSD activity rather than levels significantly correlated with indicators of type 2 diabetes (HbA1c, HOMA-IR and glucose). Furthermore, FFA was also independently associated with plasma CTSD activity (standardized β = 0.493, p = 0.007).
Despite similar plasma CTSD levels, type 2 diabetic male individuals showed increased plasma CTSD activity compared to healthy males, which was independently linked to plasma FFA levels. Our data therefore point toward plasma CTSD as a metabolic regulator in male type 2 diabetes.
2 型糖尿病是一种以胰岛素抵抗为特征的代谢紊乱。先前在患者中的研究表明，组织蛋白酶 D（CTSD）的血浆水平与胰岛素抵抗相关，而 CTSD 在溶酶体的酸性环境中具有最佳活性。由于 2 型糖尿病患者的血浆 pH 值略有降低，并且我们之前已经表明，血浆 CTSD 活性与胰岛素水平有因果关系，因此与健康个体相比，2 型糖尿病患者的血浆 CTSD 活性可能会增加。然而，迄今为止，CTSD 活性与 2 型糖尿病患者餐后代谢紊乱之间的相互作用尚不清楚。
给 18 名 2 型糖尿病男性和 16 名年龄匹配的健康男性连续服用 2 次标准混合餐，之后采集血样。测量血浆代谢参数以及 CTSD 水平和活性，并评估血浆 pH 值的变化。
与 2 型糖尿病男性患者血浆游离脂肪酸（FFA）水平升高一致，与健康男性相比，2 型糖尿病个体的血浆 pH 值降低。虽然血浆 CTSD 水平相似，但与健康男性相比，2 型糖尿病男性的血浆 CTSD 活性增加。此外，血浆 CTSD 活性而非水平与 2 型糖尿病的指标（HbA1c、HOMA-IR 和葡萄糖）显著相关。此外，FFA 也与血浆 CTSD 活性独立相关（标准化β=0.493，p=0.007）。
尽管血浆 CTSD 水平相似，但与健康男性相比，2 型糖尿病男性个体的血浆 CTSD 活性增加，这与血浆 FFA 水平独立相关。因此，我们的数据表明，血浆 CTSD 是 2 型男性糖尿病的代谢调节剂。
