The article "Sex-based differences in insulin resistance" by Gado et al. (2024) explores the sexual dimorphism in insulin resistance, a key factor in metabolic diseases such as diabetes and obesity. The authors highlight that women generally have higher insulin sensitivity compared to men, but this advantage diminishes after menopause or when insulin resistance progresses to hyperglycemia and diabetes. The review covers the pathophysiology of insulin resistance, epidemiological evidence, and biological factors contributing to sexual dimorphism in insulin sensitivity. Key points include: 1. **Pathophysiology of Insulin Resistance**: Insulin resistance is characterized by impaired insulin signaling in tissues like adipose tissue, skeletal muscle, and liver. This impairment leads to hyperglycemia and the development of type 2 diabetes (T2DM). The PI3K-AKT/PKB pathway is crucial for insulin signaling, and defects in this pathway contribute to insulin resistance. 2. **Epidemiological Evidence**: Pre-menopausal women have lower prevalence of T2DM and prediabetes compared to men of the same age, but this advantage diminishes after menopause. Menopause is associated with increased risk of impaired glucose tolerance and metabolic syndrome. 3. **Main Causes of Sex-Based Differences**: - **Sex Hormones**: Estrogens and androgens play significant roles in insulin sensitivity. Estrogen replacement therapy can improve insulin sensitivity in postmenopausal women, while testosterone levels are linked to visceral obesity and insulin resistance in men. - **Body Fat Amount and Distribution**: Women have a higher proportion of subcutaneous fat and lower visceral fat compared to men, which contributes to their higher insulin sensitivity. Menopause leads to a shift towards visceral fat, increasing insulin resistance. - **Skeletal Muscle Mass and Composition**: Women have a higher proportion of type I muscle fibers, which are more insulin-sensitive, and a higher capillary density per muscle surface area, enhancing insulin action. - **Inflammation**: Metaflammation, a chronic low-grade inflammatory state, is more prevalent in males and is associated with insulin resistance. Studies show that male-derived macrophages produce higher levels of inflammatory mediators compared to female-derived cells. 4. **Sex-Based Differences in Insulin Sensitivity in Key Organs**: - **Liver**: Pre-menopausal women have lower fasting glucose levels and higher hepatic insulin sensitivity. Estrogen replacement therapy improves hepatic insulin sensitivity. - **Adipose Tissue**: Women have higher capacity for non-oxidative clearance of free fatty acids and preferential storage of excess lipids in subcutaneous fat depots, providing metabolic protection. - **Skeletal Muscle**: Women have higher muscle insulin sensitivity, which deteriorates with obesity. Estrogens and differences in muscle fiber composition contribute to these differences. The article concludes by discussing open research questions and the importance of sex-based differences in the development and progression of metabolic diseases.The article "Sex-based differences in insulin resistance" by Gado et al. (2024) explores the sexual dimorphism in insulin resistance, a key factor in metabolic diseases such as diabetes and obesity. The authors highlight that women generally have higher insulin sensitivity compared to men, but this advantage diminishes after menopause or when insulin resistance progresses to hyperglycemia and diabetes. The review covers the pathophysiology of insulin resistance, epidemiological evidence, and biological factors contributing to sexual dimorphism in insulin sensitivity. Key points include: 1. **Pathophysiology of Insulin Resistance**: Insulin resistance is characterized by impaired insulin signaling in tissues like adipose tissue, skeletal muscle, and liver. This impairment leads to hyperglycemia and the development of type 2 diabetes (T2DM). The PI3K-AKT/PKB pathway is crucial for insulin signaling, and defects in this pathway contribute to insulin resistance. 2. **Epidemiological Evidence**: Pre-menopausal women have lower prevalence of T2DM and prediabetes compared to men of the same age, but this advantage diminishes after menopause. Menopause is associated with increased risk of impaired glucose tolerance and metabolic syndrome. 3. **Main Causes of Sex-Based Differences**: - **Sex Hormones**: Estrogens and androgens play significant roles in insulin sensitivity. Estrogen replacement therapy can improve insulin sensitivity in postmenopausal women, while testosterone levels are linked to visceral obesity and insulin resistance in men. - **Body Fat Amount and Distribution**: Women have a higher proportion of subcutaneous fat and lower visceral fat compared to men, which contributes to their higher insulin sensitivity. Menopause leads to a shift towards visceral fat, increasing insulin resistance. - **Skeletal Muscle Mass and Composition**: Women have a higher proportion of type I muscle fibers, which are more insulin-sensitive, and a higher capillary density per muscle surface area, enhancing insulin action. - **Inflammation**: Metaflammation, a chronic low-grade inflammatory state, is more prevalent in males and is associated with insulin resistance. Studies show that male-derived macrophages produce higher levels of inflammatory mediators compared to female-derived cells. 4. **Sex-Based Differences in Insulin Sensitivity in Key Organs**: - **Liver**: Pre-menopausal women have lower fasting glucose levels and higher hepatic insulin sensitivity. Estrogen replacement therapy improves hepatic insulin sensitivity. - **Adipose Tissue**: Women have higher capacity for non-oxidative clearance of free fatty acids and preferential storage of excess lipids in subcutaneous fat depots, providing metabolic protection. - **Skeletal Muscle**: Women have higher muscle insulin sensitivity, which deteriorates with obesity. Estrogens and differences in muscle fiber composition contribute to these differences. The article concludes by discussing open research questions and the importance of sex-based differences in the development and progression of metabolic diseases.