Although the incidence of diabetes is increasing worldwide and its prevalence is higher in developing countries, no studies have examined the relationship between elevated liver enzymes and T2D risk in Yemeni patients. Our research, therefore, was focused on the liver as the vital organ contributing to glucose homeostasis during the fasting and postprandial stage. Also, most people aged ≥45 years in developing countries have diabetes . These findings were convenient with our study showed that T2D patients had significantly higher mean age compared to healthy control subjects (Table 1).
Our present findings also observed significantly increased BMI, systolic BP, and diastolic BP in T2D patients than healthy control subjects. The current results also showed that serum FBG, total cholesterol, and LDL-C were significantly higher in T2D patients than healthy control subjects. At the same time, no significant difference among both groups for serum triglycerides was found. In contrast, HDL-C was significantly lower in T2D patients. Our study further revealed higher levels of GGT in T2D patients. At the same time, AST was considerably lower in T2D patients. Besides, no significant difference between both groups for ALT was observed.
Our study also revealed positive correlations between GGT with FBG, total cholesterol, triglycerides, and LDL-C across the combined group before and after adjustment for age and BMI. The association between ALT with FBG and triglycerides was no longer significant after adjustment for age and BMI. Such a positive relationship between liver enzymes and blood lipid profile in T2D patients has been observed in previous studies [4, 28-31]. This finding supports the role of hepatic IR in NAFLD's pathogenesis in patients with T2D [6, 32]. Moreover, Cho et al. reported a correlation between ALT activity and increased fatty liver . The impairment of the normal process of synthesis and elimination of triglycerides may progress to fibrosis, cirrhosis, and hepatocellular carcinoma [33,34]. A triglyceride is a significant form of lipids stored in the liver of patients with NAFLD.
In addition to its effect on lipid metabolism, insulin also contributes a pro-inflammatory effect to liver abrasion . Thus, inflammation contributes to IR. Moreover, Pro-inflammatory cytokines and transcription factors are highly expressed in white adipose tissue and the liver. In contrast, obesity, a state of chronic low-grade inflammation and a risk factor for IR and NAFLD, is induced by overnutrition. It is a primary cause of decreased insulin sensitivity. Obesity leads to lipid accumulation and activates the c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways, which consequently increase the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) . Besides, various adipose tissue-derived proteins, such as adiponectin and leptin, are considered significant links between obesity, IR, and related inflammatory disorders .
GGT is known as a marker of hepatobiliary disorders and is associated with other pathological conditions like diabetes. Free radicals generated by diabetes consume glutathione which induces the increased expression of GGT in hepatocytes. Various studies have suggested the association of GGT concentrations with T2D [37-40], and hyperlipidemia . These findings agree with our study; GGT was significantly associated with the hyperglycemic and hyperlipidemia profile. We observed ALT and GGT together were positively correlated. Moreover, some data also reported elevated GGT levels with ALT in T2D patients with dyslipidemia [38,39,42]. Even though we did not confirm the presence of fatty liver by ultrasound techniques, we showed the relationship of ALT, AST, and GGT with the predictors of diabetes and lipid profile parameters, presenting hepatocellular injury.
A study of male Korean workers found that AST was independently associated with diabetes , while in a study of male Japanese office workers, AST was not associated with T2D risk . Some studies also reported that ALT is a significant predictor of diabetes while AST is not . These findings agree with our conclusions as AST does not show a considerable relationship with the studied parameters. Besides, Clark et al. also suggested that mild or chronic elevation of these aminotransferases may be due to NAFLD [45,46]. However, our study is limited to the standard method of liver biopsy for the prediction of NAFLD. Still, it goes with the Analysis of the Third National Health and Nutritional Examination Survey, where individuals with NAFLD have elevated aminotransferases.
Besides, our study also found that increased ALT and GGT levels improve the prediction of T2D risk. Several previous studies supported this: a meta-analysis reported a pooled relative risk of 1.34 (95% CI 1.27 to 1.42) comparing the highest versus lowest tertiles of GGT levels  and 1.66 (95% CI 1.31 to 2.09) for ALT . Besides, a case-control study in a Chinese population also reported higher levels of ALT and GGT with increased risk of T2D 2.00 (1.01 to 3.96; ALT) and 2.38 (1.21 to 4.66; GGT) . A Mendelian randomization study further provided evidence for the relationship between higher GGT levels and the hepatic IR studies . In contrast, our study did not observe any relationship of AST incident T2D risk, which was consistent with previous studies [18, 30,37,50]. This may be due to a lack of specificity of AST for liver diseases . However, one Korean study showed a positive correlation between GGT/ALT and T2D risk among patients without fatty liver, suggesting alternative pathways exist . Thus, increased GGT and ALT levels were linked to T2D development as surrogate NAFLD measures . NAFLD also may indicate fat deposition in other organs such as skeletal muscle, myocardium, and the pancreas, which predispose individuals to T2D risk . Moreover, research evidence showed that GGT and ALT's relations with T2D risk were also independent of other vital pathologies in T2D development, such as whole-body insulin resistance [3,44] and blood lipid profile [3, 14,15,16].
The present study's strength included adjustment for well-established diabetes risk factors, including BMI, blood lipids, and hypertension, and using comprehensive statistical methods (Pearson correlation coefficient and regression analysis) to explore the predictive utility of liver enzymes with other risk factors. However, there are some limitations: Our sample size may be small and thus underpowered to detect the interaction with ALT and GGT. We measured liver enzymes only once and may not represent a long-term profile. We did not measure hepatitis B and C infection, resulting in elevated liver enzymes. We did not measure CRP, insulin, leptin, and adiponectin as predictive biomarkers linked between obesity, hepatic IR, and related inflammatory disorders in T2D patients. Thus, a further large sample size with measurements of insulin, hs-CRP, leptin, adiponectin, and interleukins are required to confirm these correlations. In conclusion, higher ALT and GGT are positively associated with a higher risk of T2D in Yemeni patients. Thus, routine screening of liver enzymes in T2D patients is recommended to detect liver disorders.