Type 2 diabetes, sex and metabolic dysfunction-associated steatotic liver disease

Table 3 Evidence that sex-specific associations link metabolic dysfunction, liver health and cardiovascular risk in humans

Method	Findings	Conclusion	Risk of bias	Ref.
Of 158 women (47 normal and 111 with IGT) and 148 men (74 normal and 74 with IGT) were enrolled. They underwent a hyperinsulinemic normoglycemic clamp to determine M3, besides liver enzymes (ALT, AST, and GGT), metabolic and anthropometric parameters	Significant bivariate correlations were found between clamp measured M3 and all three liver enzymes in both sexes. After adjustment for possible metabolic confounders, correlations ceased in the male population alone. Feature selection analysis showed that ALT is an important attribute for M3 among women alone. MRA confirmed that BMI (P < 0.0001) and ALT (P = 0.00991) significantly and independently predicted clamp measured muscle glucose uptake in women [R (2) = 0.5259], while in men serum fasting insulin (P = 0.0210) and leptin levels (P = 0.0294) but none of the liver enzymes were confirmed as significant independent predictors of M3 [R (2) = 0.4989]	The existing sex-specific association between insulin sensitivity, MRFs, and ALT might explain the sex difference in the predictive role of ALT elevation for CVD. Accordingly, ALT may be used as a simple biomarker of IR in women	Moderate	Buday et al[83]
A cohort with T2D (n = 64, 30 male/34 female) and a sample of healthy subjects (n = 25, 13 male/12 female) were enrolled. Intraorgan and visceral fat were quantified by MR and VLDL1-TG export by intralipid infusion techniques	Intrahepatic and intrapancreatic TG content was elevated among those with T2D, irrespective of sex. In non-diabetic subjects, fat levels in both organs were significantly lower in women than men [1.0% (0.9%-1.7%) vs 4.5% (1.9%-8.0%), P = 0.005, and 4.7% ± 0.4% vs 7.6% ± 0.5%, P < 0.0001, respectively]. T2D women had higher hepatic VLDL1-TG production rate and plasma VLDL1-TG than healthy women [559.3 ± 32.9 mg/kg/day vs 403.2 ± 45.7 mg/kg/day, P = 0.01, and 0.45 (0.26-0.77) mmol/L vs 0.25 (0.13-0.33) mmol/L, P = 0.02], whereas there were no differences in men [548.8 ± 39.8 mg/kg/day vs 506.7 ± 29.2 mg/kg/day, P = 0.34, and 0.72 (0.53-1.15) mmol/L vs 0.50 (0.32-0.68) mmol/L, P = 0.26]. Weight loss decreased intraorgan fat content and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of T2D remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively	In T2D, women have liver and pancreas fat accumulation like men, associated with raised hepatic VLDL1-TG production rates. Dynamics of TG turnover differ between sexes in T2D and after weight loss. Collectively, these changes may explain the raised CVR among women with T2D	High	Jesuthasan et al[84]
This cross-sectional observational study enrolled n = 16126 adult participants from the KNHANES. Absolute and body size-adjusted HGS indices were evaluated	Prevalence of T2D in all, younger, and older groups were 131%, 4.2%, and 21.4%, respectively. Proportions of cardiometabolic diseases were all higher in those with than without T2D in sex-stratified age groups, whereas obesity and MASLD were higher in younger T2D, and HTN was higher in older T2D in both sexes. Adjusted HGS significantly correlated with cardiometabolic parameters, and thus, high ORs for T2D in low tertiles of adjusted HGS were shown in all groups, whereas high ORs for T2D in low tertiles of absolute HGS were observed only in older men	Obesity and MASLD were more prevalent in younger T2D, while HTN was more prevalent in older T2D in both sexes. Low adjusted HGS was associated with higher T2D risk in all groups, whereas low absolute HGS was associated with higher T2D risk in older men, indicating that adjusted HGS might be useful in screening, especially for younger or obese individuals with T2D	Low	Bae et al[85]
The study comprised 332 hospitalized patients. The following data on leading CVD and risks related to CV drug administration were collected: Age, hyperlipidemia, T2D, CKD, CLD, HF, HTN, MI, and S. The amount of the CV drugs administered during hospitalization was expressed as the sex-specific DDD/100 BD	During hospitalization in the ICU, women were less likely to be treated with statins than male patients (30.1 DDD/100 BD vs 57.5 DDD/100 BD, P < 0.05). There was no difference between sexes regarding the use of antihypertensive drugs. Women were less likely to be treated with ASA (30.4 DDD/100 BD vs 36.9 DDD/100 BD, P < 0.05)	This study identifies sex differences in CV drug administration, and it is possible that these discrepancies mirror differences in primary care	Moderate	Drakul et al[86]
HTG was prospectively assessed among 2331 individuals using 1H MRS magnetic resonance spectroscopy, and plasma concentrations of TG, T-chol, LDL-chol, HDL-chol, and UA	The 95th percentile for HTG in lean non-AI individuals was 1.85%. Plasma insulin, TG, T-chol, LDL-chol, and UA concentrations were increased, and HDL-chol was decreased in individuals with HTG content > 1.85% and ≤ 5.56% compared to those individuals with HTG content ≤ 1.85%, and these altered parameters were associated with increased IR. Lean non-AI women had lower mean HTG than lean non-AI men, but both lean AI men and women showed a 40%-100% increase in HTG compared to their non-AI counterparts, with this rise linked to higher CMRFs	HTG concentrations > 1.85% (the 95th percentile of HTG in lean non-AI individuals) were associated with IR and CVR factors. Premenopausal women were protected from these changes, while young, lean AI men and women showed increased HTG levels and related CMRFs	Low	Petersen et al[87]
Of 5027 men were enrolled in this population-based study conducted in China. Low eGFR was defined as 60 mL/minute/1.73 m2	After adjusting for age, smoking, metabolic factors, and testosterone, through increasing quartiles of SHBG, a significantly positive association between SHBG quartiles and eGFR was detected in men (Q1 vs Q4, β = -2.53, 95%CI: -3.89 to -1.17, P < 0.001). Compared to the highest quartile of SHBG, SHBG in the lowest quartile was associated with 96% higher odds of low eGFR (OR = 1.96, 95%CI: 1.10 to 3.48) in the fully adjusted model. At stratified analyses, the associations between a 1-SD increase in serum SHBG and the prevalence of low eGFR were significant in men aged ≥ 60 years old, WC, diabetes, HTN, dyslipidemia, and MASLD	Reduced serum SHBG levels were independently associated with decreased eGFR and an increased prevalence of low eGFR among Chinese men, after adjusting for demographic characteristics, lifestyle factors, MRFs, and testosteronemia	Low	Zhang et al[88]
This cross-sectional study included data from 33216 randomly selected Spanish adult workers submitted to occupational medical check-ups. Sociodemographic, anthropometric, and clinical parameters were recorded, and MASLD was identified with FLI ≥ 60. MetS was diagnosed according to the IDF criteria, and CVR was determined with the REGICOR-Framingham equation	The global prevalence of MASLD was 19.1%, 27.9% (95%CI: 23.3%-28.5%) for men and 6.8% (95%CI: 6.4%-7.3%) for women, and increasing across age intervals. Compared to women, men had worse cardiometabolic and anthropometric profiles. At MVA, SLD was strongly associated with age, HDL-chol, social class, prediabetes, diabetes, preHTN, HTN, and smoking in both sexes. The association between diabetes, HTN, and MASLD was stronger in women than in men	Compared to women, men had a higher prevalence of MASLD, a worse cardiometabolic profile and a higher CVR. Nevertheless, MASLD was more strongly associated with T2D or HTN in women than in men, suggesting that metabolic dysfunction poses a more severe threat to liver health in women than in men	Low	Fresneda et al[89]
This retrospective longitudinal study of 92997 patients seen between January 2017 to January 2019 used electronic medical records to abstract data back to April 1997	Globally, 59323 individual without known CLD received an ALT test. Age, ethnicity, and metabolic factors were associated with higher odds of ALT testing (P < 0.01). At MVA, female sex (OR = 2.7), Latinx ethnicity (OR = 2.6), API race (OR = 1.3), overweight/obesity (OR = 1.8, OR = 2.6), and dyslipidemia (OR = 1.3) were associated with abnormal ALT (P ≤ 0.001)	Among individuals without any known CLD, women, Latinx, API, and persons with excess BMI had greater risks of abnormal ALT	Low	Kim and Khalili[90]
Two-hundred and twelve T2D patients, equally assigned to oral or subcutaneous semaglutide (n = 106 per group), were enrolled. The primary endpoint was the change in HbA1c. Secondary endpoints included variations in anthropometric and metabolic parameters.	A total of 208 patients completed the study. In men, sc semaglutide significantly reduced Δ weight (P = 0.010), Δ HbA1c (P = 0.037), and Δ LDL-chol (P = 0.038) compared to oral semaglutide. In women, sc semaglutide caused a significant decrease in Δ HSI (P = 0.024) and also led to a greater Δ GOT reduction (P = 0.035) than in men	This real-world study indicates that sc semaglutide offers superior metabolic benefits compared to the oral formulation, especially among male patients	High	Piccione et al[91]
This retrospective study included 6107 subjects submitted to annual health check-ups. CMI was calculated by multiplying the ratio of TG and HDL-chol (TG/HDL-C) by WHtR	MAFLD prevalence rose with higher CMI quartiles in both sexes. Higher CMI independently increased MAFLD risk (per SD: OR = 2.72 for males, OR = 3.26 for females). Those in the highest CMI quartile had the greatest odds of MAFLD (males: OR = 15.82; females: OR = 22.60), with significant trends (P < 0.001). CMI showed a non-linear association with MAFLD and had the largest AUC among obesity indexes for identifying MAFLD (males: 0.796; females: 0.853). FLD in males (AUC = 0.796, 95%CI: 0.782-0.810) and females (AUC = 0.853, 95%CI: 0.834-0.872)	CMI served as an effective marker for MAFLD screening in Chinese adults. The diagnostic value of CMI for MAFLD was higher in women than in men	Low	Gu et al[92]
A total of 7950 Taiwan Biobank participants were enrolled; 6478 had anthropometric, biochemical, and hematologic data, and 4185 underwent abdominal sonography for MASLD assessment	High PCSK9 levels were linked to older age, female sex, adverse cardiometabolic factors, and changes in blood markers. In women, associations with platelet count were stronger. Increasing PCSK9 quartiles correlated with higher odds of IR, MetS, DM, and MASLD, particularly for women. Elevated PCSK9 predicted higher risks of all-cause, non-cardiovascular, and cancer mortality, mainly affecting women	Elevated PCSK9 levels are linked to higher risks of IR, MetS, DM, MASLD, and mortality, reflecting poorer metabolic health among Taiwanese individuals. These effects are more pronounced in women, emphasizing the need for sex-specific risk assessment in metabolic disorders	Low	Yeh et al[56]

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma glutamyl transferase; IGT: Impaired glucose tolerance; VLDL: Very low density lipoproteins; T2D: Type 2 diabetes; TG: Triglycerides; MR: Magnetic resonance; CVD: Cardiovascular disease; HGS: Hand-grip strength; CKD: Chronic kidney disease; CLD: Chronic liver disease; CV: Cardiovascular; HF: Heart failure; HTN: Arterial hypertension; MI: Myocardial infarction; S: Stroke; DDD: Defined daily dose; BD: Bed-days; HTG: Hepatic triglycerides; MRS: Magnetic resonance spectroscopy; T-chol: Total cholesterol; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; chol: Cholesterol; UA: Uric acid; eGFR: Estimated glomerular filtration rate; MASLD: Metabolic dysfunction-associated steatotic liver disease; FLI: Fatty liver index; MetS: Metabolic syndrome; IDF: International diabetes federation; CVR: Cardiovascular risk; HbA1c: Glycated hemoglobin; CMI: Cardiometabolic index; WHtR: Waist-to-height ratio; MRA: Magnetic resonance angiography; BMI: Body mass index; OR: Odds ratio; CI: Confidence interval; ICU: Intensive care unit; ASA: Acetylsalicylic acid; AI: Asian Indians; CMRFs: Cardiometabolic risk factors; IR: Insulin resistance; KNHANES: Korea National Health and Nutrition Examination Survey; SHBG: Sex hormone-binding globulin; WC: Waist circumference; MVA: Multivariate analysis; SLD: Steatotic liver disease; API: Asian/pacific islander; HIS: Hepatic steatosis index; GOT: Glutamic oxalacetic transaminase; MAFLD: Metabolic dysfunction-associated fatty liver disease; AUC: Area under the curve; FLD: Fatty liver disease; pre-HTN: Prehypertension; PCSK9: Proprotein convertase subtilisin/kexin type 9; DM: Diabetes mellitus; MRFs: Metabolic risk factors; M3: Muscle glucose uptake; Q: Quartile; sc: Subcutaneous.