Study Reveals Betatrophin Rise and Sestrin 2 Decline in Diabetic Nephropathy Patients

The study, published in BMC Nephrology, found a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 levels among patients with DN, particularly the macroalbuminuria group.

"In diabetic nephropathy, Sestrin 2 function is impaired, but restoring it has been shown to reverse a cascade of molecular changes, leading to improved renal function, reduced albuminuria, and mitigation of structural damage," the researchers wrote.

Diabetic kidney disease is one of the most severe microvascular complications of diabetes mellitus and the primary contributor to chronic kidney disease (CKD) globally. Since T2D and obesity are considered inflammatory conditions, thus reducing their accompanied systemic inflammation may reduce their complications.

Sestrin 2 is part of a family of stress-induced proteins produced in response to oxidative stress, inflammation, and DNA damage. Betatrophin is a hormone that promotes the growth, proliferation, and mass expansion of pancreatic beta-cells, thereby enhancing glucose tolerance. Asmaa Mounir Emara, Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt, and colleagues aimed to evaluate serum Sestrin 2 and betatrophin levels in patients with different DN stages and compare results with healthy control.

For this purpose, the researchers conducted a cross-sectional study comprising 60 patients above 18 years old recruited from Tanta University hospitals out patients clinics and 20 healthy individuals of matched sex and age as a control group.

Participants were categorized into two groups: Group I comprised 20 normal subjects as the control group. Group II consisted of 60 patients diagnosed with T2D, further subdivided into three equal groups: Group IIA (20 patients) with normoalbuminuria (ACR < 30 mg/g), Group IIB (20 patients) with microalbuminuria (ACR = 30 to 300 mg/g), and Group IIC (20 patients) with macroalbuminuria (ACR > 300 mg/g).

They were subjected to detailed history taking, careful clinical examination, and laboratory investigations, including serum creatinine, blood urea, urinary albumin creatinine ratio, estimated glomerular filtration rate (eGFR), and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique.

The following were the key findings of the study:

· Serum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in the macroalbuminuric group compared to the control and other two diabetic groups.

· The cut-off value of serum sestrin 2 was 0.98 ng/ml with a sensitivity of 99%, and a specificity of 66%, while the cut-off value of serum betatrophin was > 98.25 ng/ml with a sensitivity of 98%, a specificity of 82%.

· Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin.

· Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR, and serum albumin.

· Serum betatrophin is found to be a risk factor or predictor for diabetic nephropathy.

The findings showed that in patients with diabetic nephropathy, particularly those with macroalbuminuria, serum levels of betatrophin were markedly elevated compared to both other diabetic groups and the control group. Serum betatrophin showed significant positive correlations with age, fasting and postprandial glucose levels, BMI, triglycerides, total cholesterol, serum creatinine, blood urea, urine albumin-to-creatinine ratio (UACR), and significant negative correlations with estimated glomerular filtration rate (eGFR) and serum albumin levels. Consequently, serum betatrophin levels can serve as a significant predictor for diabetic nephropathy.

"Conversely, serum levels of Sestrin 2 were notably decreased, especially in patients with macroalbuminuria, but did not emerge as a significant predictor for diabetic nephropathy. However, targeting its restoration could represent a novel therapeutic approach aimed at reducing reactive oxygen species (ROS) accumulation and enhancing autophagy in diabetic nephropathy," the researchers wrote.

The main limitation of the study was that as a cross-sectional study, the sample size was comparatively small.

Reference:

Emara, A.M., El Bendary, A.S., Ahmed, L.M. et al. Evaluation of serum levels of sestrin 2 and betatrophin in type 2 diabetic patients with diabetic nephropathy. BMC Nephrol 25, 231 (2024). https://doi.org/10.1186/s12882-024-03663-2