Here, we revealed the associations of plasma levels of the secreted protein acidic and rich in cysteine (SPARC), an inflammatory factor highly expressed in fat tissues, and insulin sensitivity improvement in a 6-month randomized controlled, calorie-restricted feeding trial recruiting 235 Chinese adults with overweight/obesity and prediabetes: the Mediterranean diet (MD) group (<i>n </i>= 81), the traditional Jiangnan diet (TJD) group (<i>n </i>= 81), and the control diet (CD) group (<i>n </i>= 73). Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.