Neuregulin-4 (Nrg-4) may have anti-inflammatory and anti-atherogenic properties. Egyptian researchers used Nrg-4 together with carotid intima-media thickness as a marker for subclinical atherosclerosis. Their finding: The addition of metformin to intensive insulin therapy improves Nrg-4 levels, glycemic control and subclinical atherosclerosis in adolescents with type 1 diabetes.
Cardiovascular disease (CVD) is the leading cause of death in type 1 diabetes mellitus and vascular dysfunction is an early and critical event in the development of CVD. Biguanides such as metformin sensitize body cells to insulin, which can lead to a reduction in atherogenic lipid fractions in patients with type 2 diabetes (T2D), Prof. Dr. Nancy Samir Elbarbary from the Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, recapitulated by way of introduction. Metformin monotherapy tends to reduce mortality as well as cardiovascular morbidity and mortality as it improves endothelial function. Many guidelines recommend metformin as first-line therapy for patients with T2D. However, metformin showed inconsistent improvement in some adults with type 1 diabetes, while in others HbA1c, BMI and insulin dose decreased.
Recently, neuregulin-4 (Nrg-4) was identified as an adipokine. It has been found in several organs, particularly in brown adipose tissue, and belongs to the epidermal growth factor (EGF) family of extracellular ligands. Overexpression of Nrg-4 can reduce chronic inflammation by affecting the gene expression of the macrophage marker (MCP1) and enhancing the expression of the M2 macrophage marker gene CD163. Therefore, Nrg-4 may have anti-inflammatory and anti-atherogenic properties. Lower Nrg-4 levels have been associated with obesity, insulin resistance, impaired glucose tolerance (IGT), T2D as well as non-alcoholic fatty liver disease (NAFLD) and subclinical cardiovascular disease
First study on the role of metformin in T1D adolescents
Prof. Elbarbary and colleagues conducted a study in which the effect of metformin was examined in adolescents with type 1 diabetes who suffered from microvascular complications. They measured both neuregulin-4 and carotid intima-media thickness as markers of subclinical atherosclerosis. This is the first study to investigate the role of metformin in adolescents with type 1 diabetes and microvascular complications.
This prospective randomized, double-blind, placebo-controlled study involved adolescents aged between 12 and 18 years with type 1 diabetes and a disease duration of ≥5 years and microvascular complications with relatively good glycemic control (HbA1c) ≤8.5% and regular insulin therapy. 100 patients were randomly assigned to two groups: either the intervention group, which took 500 mg metformin tablets once daily for 24 weeks, or the control group, which received no supplementation. After recording their medical and clinical characteristics, a laboratory examination of fasting blood glucose (FBG), HbA1c, lipid profile, urinary albumin excretion (UAE) and hsCRP was carried out. In addition, the thickness of the intima-media of the carotid artery (CIMT) was measured as a marker for subclinical atherosclerosis.
The primary endpoint of this study was the change in Nrg-4 levels. The secondary endpoint was the change in glycemic control, CIMT and the safety endpoint of the occurrence of adverse events during the study period.
Both groups were well matched in terms of baseline clinical characteristics and laboratory parameters (p>0.05). After 6 months, metformin therapy in the intervention group resulted in a significant decrease in FBG, HbA1c, total cholesterol, C-reactive protein (CRP), urinary albumin-to-creatinine ratio (UACR) and CIMT, while Nrg-4 levels were increased compared to baseline (p<0.001) and compared to the control group (p<0.001). Metformin therapy was well tolerated, with minor gastrointestinal disturbances (nausea, heartburn, bloating and diarrhea). Baseline Nrg-4 values correlated negatively with FBG, HbA1c, total cholesterol, CRP and CIMT (p<0.001 for all).
Low Nrg-4 levels associated with poor blood glucose control
Low Nrg-4 levels in adolescents with T1D and microvascular complications were associated with poor glycemic control and increased low-grade inflammation. Results showed that metformin therapy improved blood glucose levels, glycemic control, dyslipidemia, and Nrg-4 levels, thus reducing inflammation, microvascular complications, and subclinical atherosclerosis in this patient population.
However, further studies are needed to assess whether Nrg-4 could be a promising marker for monitoring disease progression, according to Prof. Elbarbary. In addition, further research into this adipokine could expand the understanding of the pathophysiology of atherosclerosis and lead to the development of new therapeutics.
| Take-Home-Messages Six months of metformin therapy in adolescents with T1D and microvascular complications… |
| …improved neuregulin-4 levels and glycemic control, |
| …reduced CRP, UACR and dyslipidemia, |
| …reduced CIMT as an index for subclinical atherosclerosis. |
| Metformin is a safe and effective adjuvant therapy for type 1 diabetics with vascular complications. |
Source: Elbarbary NS: Metformin added to intensive insulin therapy improves Neuregulin-4 level and subclinical atherosclerosis in youth with type 1 diabetes. Oral Presentation #975, Session SO 091: A new look at well-known drugs in type 2 diabetes. EASD, 10.09.2024.
InFo DIABETOLOGIE & ENDOKRINOLOGIE 2024; 1(4): 16 (published on 29.11.24, ahead of print)
CARDIOVASC 2024; 23(4): 15
