Role of Angiopoietin-like protein 4 (ANGPTL4) as a Predictive marker for Diabetic Nephropathy in type 2 Diabetes

This table shows:

• Highly statistically significant (p-value < 0.001) increased Creat in group II (2.7 ± 1.1 mg/dl) when compared with group I (0.7 ± 0.2 mg/dl) and group III (0.7 ± 0.2 mg/dl).
• Highly statistically significant (p-value < 0.001) increased ALB/Creat ration in group II (1695 ± 488.3 mg ALB/g Creat) when compared with group I (14.05 ± 4.5 mg ALB/g Creat) and group III (8.3 ± 4.7 mg ALB/g Creat).

Fig. 2: comparisons between studied groups as regard ALB/Creat ratio.

Table 3: Post-Hoc test for multiple comparisons between studied groups as regard Creat and ALB/Creat ratio.

As regard Creat, there was:

• Highly statistically significant difference (p-value < 0.001) between groups I & II.
• Highly statistically significant difference (p-value < 0.001) between groups II & III.

As regard ALB/Creat ratio, there was:

• Highly statistically significant difference (p-value < 0.001) between groups I & II.
• Highly statistically significant difference (p-value < 0.001) between groups II & III.

Table 4: comparisons between studied groups as regard blood glucose assessment

This table shows:

• Highly statistically significant (p-value < 0.001) increased FBS in group II (198 ± 46.6 mg/dl) when compared with group I (108.8 ± 7 mg/dl) and group III (77 ± 6.6 mg/dl).
• Highly statistically significant (p-value < 0.001) increased PPBS in group II (260.9 ± 43.8 mg/dl) when compared with group I (154.7 ± 14 mg/dl) and group III (103.3 ± 10.8 mg/dl).
• Highly statistically significant (p-value < 0.001) increased HbA1C in group II (9.8 ± 1.5 %) when compared with group I (9.2 ± 1.5%) and group III (4.6 ± 0.3 %).

Fig. 3: comparisons between studied groups as regard HbA1C.

Table 5: comparisons between studied groups as regard ANGPTL4

This table shows: highly statistically significant (p-value < 0.001) increased ANGPTL4 in group II (230.3 ± 18.7 ug/ml) when compared with group I (174 ± 14.7 ug/ml) and group III (179.3 ± 15.5 ug/ml).

Fig. 4: Positive correlation between ANGPTL4 and HbA1C in group II.

Fig. 5: Positive correlation between ANGPTL4 and ALB/Creat ratio in group II.

DISCUSSION

Diabetes-related kidney disease (DKD) represents a major cause of end-stage renal disease (ESRD), with a 44% rise in the global frequency expected by 2030. ⁸    It is distinguished by higher urine albumin excretion, proteinuria, and a decrease in estimated glomerular filtration rate (eGFR) in the absence of other renal disorders. The risk of kidney damage is reduced by half when DKD is detected and managed early. ⁹

Angiopoietins are vascular growth factors that help blood vessels develop and repair. In both physiology and pathology, angiopoietins play a critical function in glomerular capillaries. Glomerular capillaries are distinguished by a fenestrated endothelium that lies on a basal membrane as well as specialized epithelial cells (podocytes) that coat the glomerular filter's exterior layers with their interdigitating foot processes. ¹⁰

Angiopoietin-like proteins are released proteins involved in energy metabolism. Adipocytes, hepatocytes, (cardio) myocytes, endothelial cells, and macrophages are among the cell types that express ANGPTL4.¹¹

As a result, ANGPTLs shield triglyceride-rich lipoproteins (TRLs) from LPL-mediated lipid hydrolysis, or lipolysis, in the bloodstream. In the opposite direction, LPL becomes resistant to ANGPTL inhibition after binding the endothelial membrane protein glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1).¹²

The goal of this research was to investigate the ANGPTL4 role in diabetic nephropathy as well as assess the risk factors associated with diabetic nephropathy.

In this study, 40 T2 diabetic patients and 20 healthy volunteers participated (normoglycemic individuals with normal renal function).

The participants have been allocated into 3 groups: Group 1 is made up of 20 diabetics who have normoalbuminuria (30 mg/g). Group 2 is made up of 20 diabetics with albuminuria (more than 30 mg/g). Group 3 is made up of 20 healthy, non-diabetic people.

According to the current study's findings, poor glycemic control is linked to a significantly higher likelihood of diabetic nephropathy.

When compared to groups I (108.8 mg/dl) and III (77 6.6 mg/dl), FBS levels in group II (198 46.6 mg/dl) increased statistically significantly (p-value 0.001).

Furthermore, when comparing groups I (9.2 percent) and III (9.2 percent), a statistically significant (p value 0.001) increase in HbA1C was seen in group II (9.8 percent). 4.6 percent.

AlRubeaan performed a randomized cross-sectional observational study in which 54,670 T2D patients above the age of 25 were recruited from the Saudi National Diabetes Registry and assessed for DN.

Diabetic nephropathy affected 10.8 percent of the population, with microalbuminuria accounting for 1.2 percent, macroalbuminuria accounting for 8.1 percent, and ESRD accounting for 1.5 percent.

Poor glycemic control was found to be significantly greater in nephropathic individuals, microalbuminuria patients, macroalbuminuria patients, and ESRD patients, with 60.6 percent, 61.1 percent, 59.5 percent, and 63.6 percent, respectively, as measured by the percentage of patients with a HbA1c of more than 8%. ¹³

Nephropathic patients had significantly higher HbA1c levels (p value =0.0001) than non-nephropathic individuals.

The Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) researchers discovered that patients who received an intensive glycemic strategy showed a significantly lower risk of poor renal function than those who received a conventional glycemic control strategy. ¹⁴. In another study, strict blood glucose control (target HbA1c of 7.1%) delayed microalbuminuria when compared to standard therapy (target HbA1c of < 9.1 percent). ¹⁵

The current study's findings revealed a highly statistically significant (p-value 0.001) increase in ANGPTL4 in group II (239.3 18.7 ug/ml) when compared to groups I (174 14.7 ug/ml) and III (179.3 15.5 ug/ml). This means that in T2D patients, ANGPTL4 acts as a biochemical indicator for diabetic nephropathy.

In their study, Al Shawaf and her colleagues discovered a significant rise in plasma ANGPTL4 levels in DN cases when compared to those with T2D and healthy people.

The study included 36 healthy people and 86 people with T2D, 37 of whom had a normal renal function and 49 of whom had DN. ¹⁶

ANGPTL4 levels were higher in DN patients (241:56, 14:1 g/ml) than in the control group (178:43, 24:09 g/ml). Surprisingly, the levels of ANGPTL4 in T2D patients and healthy people were comparable.

Yu examined 1207 T2DM patients in a cross-sectional study. Patients having UACRs of 30 mg/g, 30–300 mg/g, or > 300 mg/g have been classified as having normal to mild, moderate, or severe albuminuria. According to the researchers, increased ANGPTL4 levels have been linked to a greater risk of CKD and albuminuria in T2DM patients. ¹⁷

The findings of this study matched those of Ma et al., who studied diabetics with normoalbuminuria (n = 40), microalbuminuria (n = 40), and macroalbuminuria (n = 40). For example, urine ACRs of 30 lg/mg, 30-299 lg/mg, and C300 lg/mg, for example, were utilized to differentiate between normoalbuminuria, microalbuminuria, and macroalbuminuria. ¹⁸

The researchers discovered that diabetics with microalbuminuria and macroalbuminuria had significantly higher Angptl4 levels than cases with normal-albuminuria and healthy people. ¹⁸

Data from the National Health and Nutrition Examination Survey (NHANES) in the United States, which included a large sample of diabetics, supported these findings. Diabetes affected 2,894 adults (13.6 percent) of the 21,205 study participants. Diabetics, on average, were 59 years old, had a FBG of 1552 mg/dl, and a HbA1c level of 7.2 percent; 80.3 % were overweight (BMI 25), and 49.1 % were obese (BMI 30). Diabetes was found to be more prevalent in adults as weight classes increased, rising from 8% in normal-weight people to 43% in obese class 3 people. ¹⁹

According to the findings of a recent study, obesity has a deleterious effect on kidney function in diabetes patients. In terms of BMI, we discovered statistically significant (p-value 0.001) differences among groups I and II (29.9 2.7 kg/m2 versus 34.1 5.5 kg/m2)

Chenl did research in China that comprised 264 people with T2D and biopsy confirmed DN, which was similar to ours. The mean age of DN patients was 53–19.06 years (range 31–80). Individuals have been allocated into 3 groups based on their BMI: obese (28.0 kg/m2 (n = 59), overweight (25–30 kg/m2 (n = 83), and lean (18–25 kg/m2 (n = 122). The three groups had the same mean ages and sex ratios, as well as comparable FBG, HbA1c, average blood pressure, and previous treatment. Obesity has been linked to an increased risk of proteinuria. ²⁰

Another recent study found a total of 1077 sufferers with T2D participated in the observational prospective longitudinal follow-up research. Patients with T2D were 58.3 years old on average and had diabetes for a mean of 11 years. Nephropathy was discovered to affect 90.7 percent of the population in a multiple logistic regression study. The development of diabetic nephropathy was found to be strongly linked to BMI. ²¹.

CONCLUSION

Our findings demonstrated the levels of circulating ANGPTL4 in individuals having DN were found to be significantly higher.

We propose ANGPTL4 as a novel biomarker for predicting the risk of nephrotic syndrome. Increased ANGPTL4 levels in T2DM patients indicate the severity of nephropathy. There this positive correlation between A1c and nephropathy in type 2 DM.