Despite 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 study therefore was focused on hepatocytes as the vital organ contributing in glucose homeostasis during fasting and postprandial stage. Serum ALT, AST, and GGT were taken from each participant and used for this work. Additionally, most people aged ≥45 years in developing countries suffer from diabetes . These findings were convenient with our study showed that T2D patients had significantly higher mean age compared to healthy control subjects (Table 1).
Besides, our present findings also observed significantly increased BMI, systolic BP, and diastolic BP in T2D patients than healthy control subjects. The present findings also showed that serum FBG, total cholesterol, and LDL-C were significantly higher in T2D patients than healthy control subjects, while, no significantly difference was found among both groups for serum triglyceride. In contrast, HDL-C was significantly lower in T2D patients. Our study further revealed higher levels of GGT in T2D patients. While, AST was significantly lower in T2D patients. Besides, no significantly difference was found among both groups for ALT.
Our study also revealed positive correlations between GGT with FBG, total cholesterol, triglyceride, and LDL-C across the combined group before and after adjustment for age and BMI, whilst, the association between ALT with FBG and triglyceride was no longer significant after adjustment for age and BMI. Such a positive relationship between liver enzymes and blood lipids profile in T2D patients has been observed in previous studies [4, 28-31]. This finding supports the role of hepatic IR in the pathogenesis of NAFLD 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]. Triglyceride is a major form of lipids stored in the liver of patients with NAFLD.
In addition to its effect on lipid metabolism, insulin also contributes a proinflammatory effect to liver abrasion . Thus, inflammation contributes to hepatic IR. Additionally, pro-inflammatory cytokines and transcription factors are highly expressed in white adipose tissue and liver. Obesity is defined as a state of chronic low-grade inflammation and a highly risk factor for hepatic IR and NAFLD. Thus, 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 production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) . In addition, various adipose tissue-derived proteins, such as adiponectin and leptin, are considered to be major links between obesity, hepatic 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 [38-41] and hyperlipidemia . These findings are in agreement with our study; GGT was significantly associated with the hyperglycemic and hyperlipidemic 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 [39-40, 43]. Although 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 are in agreement with our findings as AST does not show considerable relationship with the studied parameters. Besides, Clark et al. also suggested that mild or chronic elevations of these aminotransferases may be due to NAFLD [46-47]. However, our study is limited to the standard method of liver biopsy for the prediction of NAFLD but it goes with the analysis of the Third National Health and Nutritional Examination Survey where individuals with NAFLD are known to have elevated aminotransferases.
In addition, our study also found that increased ALT and GGT levels improve prediction of T2D risk, and this was supported by several previous studies: a meta-analysis reported a pooled relative risk of 1.34 (95% CI 1.27 to 1.42) comparing 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 an evidence for the relationship between higher GGT levels and hepatic IR study . In contrast, our study did not observe any relationship of AST incident T2D risk, which was consistent with previous studies [18, 30, 38, 51], and this may be due to lack of specificity of AST for liver diseases . However, one Korean study showed 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 measures of NAFLD . NAFLD also, may indicate fat deposition in other organs such as skeletal muscle, the myocardium, and the pancreas, which predispose individuals to T2D risk . Moreover, research evidence showed that the relations of GGT and ALT with T2D risk were also independent of other important pathologies in T2D development such as whole-body insulin resistance [3, 45 ] and blood lipids profile [3, 14-16].
The strength of the present study 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. First, our sample size may be small and thus underpowered to detect the interaction with ALT and GGT. Second, we measured liver enzymes only once and may not represent long-term profile. Third, we did not measure hepatitis B and C infection, which could result in elevated liver enzymes. Fourth, we did not measure insulin, CRP, leptin, and adiponectin as predictive biomarkers links between obesity, hepatic IR and related inflammatory disorders in T2D patients. Thus, further large sample size with measurement of insulin, hs-CRP, leptin, adiponectin, and interleukins are required to confirm these correlations. In conclusion, increased levels of ALT and GGT are positively associated with higher risk of T2D in Yemeni patients. Thus, routine screening of liver enzymes in T2D patients is recommended for the early detection of liver abnormalities.