INTRODUCTION:

Diabetes mellitus (DM) refers to a group of metabolic disorders identified by a chronic hyperglycemic state brought on by insulin secretion, insulin action, or a combination of the two¹. Type 1 DM (T1DM) and type 2 DM (T2DM) are the two primary kinds of DM². In Iraq, the number of diabetes cases was predicted to be over 3.5 million in 2013. Furthermore, it is expected that the number of patients who suffer from diabetics would rise from 171 million in 2000 to 366 million by 2030 all over the world³.

As a result, to establish control measures, it is important to identify persons with prediabetes.

If a person's blood glucose levels grow over normal but are not yet high enough to be diagnosed with diabetes (type 2), they are said to have prediabetes (PD) (World Health Organization. 2006)⁴. There is an inability to digest insulin in prediabetics, resulting in decreased fasting glucose or glucose tolerance⁵. Prediabetes is a disease characterized by mild hyperglycemia that can result in aberrant intracellular metabolism in most tissues and organs, including the liver⁶. The liver regulates glucose homeostasis, but lipids in the liver make it less sensitive to insulin, resulting in an excess of glucose in the blood, which can lead to prediabetes or T2DM in extreme instances⁷. As a result, the liver has been linked to the development of T2DM⁸. Hepatic damage caused by insulin resistance syndrome is thought to be a major factor in the development of type 2 diabetes(T2DM). The liver's role in glucose regulation is critical⁹. The liver is also particularly vulnerable to diseases like diabetes because it regulates carbohydrate metabolism and maintains glucose homeostasis¹⁰. In hyperglycemia, intracellular glycogen accumulates in hepatocytes as a result of increased glycogen production, which might result in a moderate rise in hepatic enzymes and liver damage¹¹.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) are hepatic enzymes that are utilized as surrogate indicators for the function of liver¹². T2DM has been linked to abnormally high levels of AST and ALT in the blood¹³. However, it is not apparent if liver enzymes best predict T2DM if the associations hold in prediabetes, or whether hepatic markers have a substantial predictive value in T2DM¹⁴.

As a result, the main goal of the current research was to find out the prognostic relevance of the AST, ALT, and ALP in Iraqi adults with prediabetes.

MATERIALS AND METHODS:

Populations studied:

From December 2020 to May 2021, a prospective research was conducted on three groups of people. The first group included30apparently healthy individuals (Normoglycemia), the second group included 58 prediabetics and the third group included 30 T2DM patients. The definition of normoglycemia, prediabetes, and diabetes was due to the American Diabetes Association (ADA) criteria, which are based on assessing fasting blood glucose (FBG: Less than 100, 100-125 and ≥ 126 mg/dL, respectively) and glycated hemoglobin (HbA1c: Less than 5.7, 5.7-6.4and ≥ 6.5%, respectively) (American Diabetes Association Standards of medical care in diabetes 2016)¹⁵. Only people who met these criteria were included. Patients with hepatitis B and C viral infections were excluded from the research when they were diagnosed with the viruses. Patients under medication (hepatotoxic and anti-tuberculosis drugs), unwilling to participate in the study, or who had liver diseases were also excluded. Besides, pregnant women with gestational diabetes were also excluded. All participants were distinguished by the characteristics presented in Table 1.

Laboratory methods:

Blood samples were collected by vein puncture after 10 – 12 hours of fasting. We split the blood (5mL) into two equal halves and aliquoted them. The first aliquot of ethylene-diamine tetra-aceticacid (2mL) was poured into the tube (EDTA). This blood was processed in less than three hours and utilized for HbAlc measurement in the same manner as stated earlier. Afterward, the second portion (3mL) was transferred to a plain tube, which was centrifuged at 3000rpm for 15 minutes to collect serum after it had clotted. The serum was assessed for FBG, ALT, AST, and ALP usingCobas c311 analyzer (Cobas-Roche, Germany) preloaded with the respective reagent kits.

Statistical analysis:

The mean ± standard deviation (SD) were used to express metric (normally distributed) variables (SD). The analysis of variance (ANOVA) and the least significant difference (LSD) or Duncan multiple range test were used to assess the significance of variations between the means. The median and interquartile range (IQR: 25–75%) were employed to represent non-parametric (skewed) variables, and the Kruskal-Wallis test and Mann-Whitney U test were used to compare the medians. For the odds ratio (OR) and 95% confidence interval (CI), the individuals were split into two groups based on their ALT, AST, and ALP median values (> and ≤ median). In pre-diabetes and diabetes, the predictive usefulness of the enzymes ALT, AST, and ALP was studied using ROC curve analysis. This importance was addressed in terms of area under the curve (AUC), 95% CI, cut-off value, sensitivity, and particularly. A probability (p) value of ≤ 0.05 was regarded significant. IBM SPSS version 25 (Armonk, NY: IBM Corp.) was used for the statistical analysis.

RESULTS:

Among the characteristics given in Table 1, BMI was considerably high in people who suffer from prediabetes and diabetes in comparison to people with normoglycemia (30.7±3.2 and 30.3±3.4vs.26.7±2.8 kg/m², respectively; p = 0.001). More than 50% of prediabetics and diabetics were obese, while obesity accounted for 13.3% in normoglycemia. The assessments of FBG and HbA1c was compatible with the ADAcriteria;81.4±6.0mg/dL and 4.5±0.4%, 104.4±6.0 mg/dL and 6.0 ± 0.4% and 170.3 ± 54.1 mg/dL and 7.6± 1.4%, in normoglycemia, prediabetes and diabetes, respectively (Table 1).

Table 1: Baseline properties of normoglycemia, prediabetes, and diabetes

Characteristic	Mean ± SD or Number (%)			p-value
Characteristic	Normoglycemia (N = 30)	Prediabetes (N = 58)	Diabetes (N =30)	p-value
Age (years)	42.5 ± 12.9^A	45.7 ± 11.4^AB	49.8 ± 13.1^B	0.074
Age group (years)
< 35	8 (26.7)	6 (10.3)	4 (13.3)	0.168
35-50	12 (40.0)	33 (56.9)	12 (40.0)
> 50	10 (33.3)	19 (32.8)	14 (46.7)
Gender
Male	15 (50.0)	32 (55.2)	18 (60.0)	0.738
Female	15 (50.0)	26 (44.8)	12 (40.0)
Height (cm)	169.5 ± 7.5^A	169.2 ± 10.2^A	170.8 ± 9.9^A	0.706
Weight (kg)	77.5 ± 12.1^A	88.8 ± 14.8^B	88.3 ± 15.1^B	0.001
BMI (kg/m²)	26.7 ± 2.8^A	30.7 ± 3.2^B	30.3 ± 3.4^B	0.001
BMI groups
Normal	12 (40.0)	2 (3.4)	1 (3.3)	0.001
Overweight	14 (46.7)	23 (39.7)	14 (46.7)
Obese	4 (13.3)	33 (56.9)	15 (50.0)
Waist (cm)	86.6 ± 8.6^A	90.3 ± 7.8^B	93.6 ± 8.0^B	0.003
FBG mg/dL	81.4 ± 6.0^A	108.4 ± 6.0^B	170.3 ± 54.1^C	0.001
HbA1c (%)	4.5 ± 0.4^A	6.0 ± 0.4^B	7.6 ± 1.4^C	0.013

Table 2: Median levels of ALT, AST, and ALP in serum of normoglycemia, prediabetes, and diabetes

Variable	Median (IQR: 25-75%)			p-value
Variable	Normoglycemia (N =30)	Prediabetes (N = 58)	Diabetes (N =30)	p-value
ALT (IU/L)	13.3 (11.5-16.1)^A	19.7 (15.9-34.0)^B	12.0 (9.0-20.0)^A	0.001
AST (IU/L)	16.3 (14.9-25.0)^A	19.0 (15.3-27.9)^A	21.5 (15.1-25.1)^A	0.444
ALP (IU/L)	70.6 (65.5-86.1)^A	90.4 (75.9-111.6)^B	87.5 (64.2-123.2)^B	0.007

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; IQR: Interquartile range; p: Kruskal-Wallis test probability (significant p-value is indicated in bold); There is no substantial difference in the median between comparable superscript capital letters and dissimilar superscript uppercase letters, although the medians are significantly different. I did the Mann-Whitney U test.

Table 3: Receiver operating characteristic curve analysis of ALT, AST, and ALP in prediabetes and diabetes

Variable	AUC	95% CI	p-value	Cut-off value (IU/L)	Sensitivity (%)	Specificity (%)
Prediabetes
ALT	0.791	0.688 - 0.894	0.001	16.1	72.4	73.3
AST	0.573	0.448 - 0.699	0.262	18.7	55.2	53.3
ALP	0.724	0.621 - 0.828	0.001	80.2	67.2	66.7
Diabetes
ALT	0.422	0.272 - 0.573	0.301	12.6	46.7	46.7
AST	0.587	0.440 - 0.733	0.249	19.2	53.3	53.3
ALP	0.623	0.474 - 0.771	0.102	77.5	56.7	56.7

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; AUC: Area under curve; CI: Confidence interval; p: Probability (significant p-value is indicated in bold).

Table 4: Logistic regression analysis of ALT, AST and ALP in prediabetes and diabetes versus normoglycemia

Variable	Normoglycemia (N = 30)				Prediabetes (N = 58)				OR (95% CI)	p-value
	> Median		≤ Median		> Median		≤ Median
	N	%	N	%	N	%	N	%
Prediabetes
ALT	8	26.7	22	73.3	42	72.4	16	27.6	7.22 (2.71 - 19.22)	0.001
AST	14	46.7	16	53.3	29	50.0	29	50.0	1.14 (0.48 - 2.73)	0.824
ALP	7	23.3	23	76.7	36	62.1	22	37.9	5.38 (2.01 - 14.38)	0.001
Diabetes
ALT	8	26.7	22	73.3	9	30.0	21	70.0	1.18 (0.39 - 3.56)	1.000
AST	14	46.7	16	53.3	16	53.3	14	46.7	1.31 (0.48 - 3.54)	0.797
ALP	7	23.3	23	76.7	15	50.0	15	50.0	3.29 (1.11 - 9.77)	0.060

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; OR: Odds ratio; CI: Confidence interval; p: Probability (significant p-value is indicated in bold).

The importance of ALT and ALP in pre-diabetes was verified using a log-regression study. The ALT was related to an OR of 7.22 (95% CI = 2.71 - 19.22; p = 0.001). Pre-diabetes was also linked to ALP (OR = 5.38; 95% CI = 2.01 - 14.38; p = 0.001). Similarly, Diabetes-related levels of ALT and ALP had no connection to illness risk (Table 4).

DISCUSSION:

Insulin resistance and beta β-cell dysfunction coexist in individuals who suffer from prediabetes, and this occurs before any changes in blood glucose levels are apparent. Studies have shown that those with pre-diabetes are more likely to develop early-stage nephropathy as well as chronic kidney disease, diabetic eye disease, and an increased risk of heart disease and stroke. Individuals with prediabetes were also more likely than those with normoglycemia to acquire diabetes¹⁶. In the current investigation, the identification of prediabetes and diabetes was based on FBG and HbA1c as recommended by the American Diabetes Association (ADA) (American Diabetes Association Standards of medical care in diabetes 2016)¹⁵. Those at high risk of getting diabetes in the future can be identified by having blood glucose levels that are abnormally low (IFG: 100-125 mg/dL). HbA1c has also just been recommended by new recommendations as a way to recognize those at risk of progressed prediabetes¹⁷. There were several long-term predictors of IFG in a sample of persons with diabetes in their families, but just a few long-term predictors for T2DM including age, gender, fasting blood glucose, triglycerides, and uric acid¹⁸.

In the current investigation, BMI was significantly increased in pre-diabetes and diabetesin comparision to normoglycemia. These results are compatible with previous findings that indicated the risk potential of overweight/obesity in diabetes¹⁹. As a result of obesity insulin resistance can develop and hence impairment of glucose level and finally leads to pre-diabetes²⁰. In this regard, According to Neeland and colleagues, extra visceral fat and insulin resistance were found to be independently related to progress of prediabetes and diabetes in obese adult patients²¹. In addition, A higher body mass index (BMI) has been found to be related with higher incidences of pre-diabetes and diabetes in adults²². Accordingly, Obesity has been considered a strong predictor of T2DM in both genders and all ethnic groups^23,24. Besides BMI, the waist circumference was higher in prediabetes and diabetes than in people with normoglycemia, and this may indicate that both BMI and waist circumference are good predictors of prediabetes²⁵.

Early detection and treatment of diabetics with abnormal liver parameters by laboratory testing may assist to reduce liver-related morbidity and death²⁶. Abnormal liver function tests have been linked to an increased risk of developing prediabetes and diabetes, according to some research^{27, 28}. In thecurrent investigation, ALT and ALP were upregulated in prediabetics, and ROC curve and logistic regression analyses confirmed the significance of both hepatic enzymes in increasing the risk of developing prediabetes. Consistent with these observations previous studies suggested the role of ALT and ALP in predicting prediabetes^29,30. Studies have linked prediabetes with higher levels of ALT and ALP, and these results suggest that both enzymes are independent risk factors for developing diabetes, in both men and women^31,32,33.

In addition to obesity and insulin resistance in the whole body and the liver, high ALT levels have been linked to a decrease in hepatic insulin sensitivity and potential diabetes development. Furthermore, ALT has been found to be a risk factor for developing prediabetes, indicating that the liver may be involved in the disease's pathogenesis^34,35. Additionally, studies have shown that serum ALT levels are a good predictor of prediabetes in the general public, even in the absence of known risk factors for the condition³². ROC curve analysis was also performed by Hatano and colleagues and estimated an AUC of 0.71 for ALT in prediabetes^36,37. These findings were consistent with the findings of this research, in which the AUC for ALT was 0.79, which was published earlier this year^38,39.

In some cases, the rise in liver enzymes may be due to the insulin resistance syndrome's increased hepatic fat buildup, which has been identified as a symptom^40,41. Another possible pathophysiological mechanism has also been put forward, and elevated liver enzymes may reflect an inflammatory status, which has been accompaniedby local (the liver) and systemic impairment of insulin signaling^42,43. In this context, chronic alterations in transaminases and reduced hepatic functioning have been linked to prediabetes. As a result, frequent evaluation of liver parameters in patients at risk of diabetes may help to avoid future problems related to the liver caused by insulin resistance^44,45.

This study shows that ALT, ALP, and obesity are all good predictors of prediabetes, but further research is needed to understand the process by which the relationship between liver function enzymes and the risk of diabetes is established in the first place.

ACKNOWLEDGMENT:

The authors would like to acknowledge the Department of Biology /College of Science/Mustansiriyah University (WWW.uomustansiriyah.edu. Iq) Baghdad/Iraq and University of Baghdad for their help to achieve this research.

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Received on 17.10.2021 Modified on 30.11.2021

Research J. Pharm. and Tech. 2022; 15(8):3697-3702.

DOI: 10.52711/0974-360X.2022.00620