SUGAR DOESN'T DIRECTLY CAUSE TYPE 2 DIABETES BUT EPIGENETIC CHANGES DO

 

As a prevalent non-infectious disease, Type 2 diabetes (T2D) is identified by high blood sugar levels (hyperglycemia) due to insufficient insulin secretion from pancreatic islets or the body's incapability to effectively use insulin, known as insulin resistance. Moreover, 88 million people have prediabetes, a precursor of T2D and still, there is no cure for it and only medications.

Global diabetes mellitus (DM) statistics for individuals aged 20 to 79 years old in 2019, along with forecasts for the years 2030 and 2045

An epigenetic mechanism, DNA methylation regulates the cell function and gene regulation in prokaryotes and eukaryotes. However, dysregulation in epigenetics can cause disease and there are several evidence proving that and has been seen as associated with T2D. Several researchers have shown that DNA methylation differs in T2D patients' pancreatic islets when compared with non-diabetic controls. Further, experiments in beta-cells of T2D candidates have shown differential DNA methylation and expression in genes like CDKN1A, PDE7B, PARK2, and SOCS2 influences the secretion of insulin in beta cells of pancreatic islets which enhance the linking of epigenetic dysregulation in pancreatic islets to ineffective insulin secretion. In addition, DNA methylation increases in islets of T2D patients' genes, such as INS, PDX1, GLP1R, and PPARGC1A have been shown to reduce the expression of genes. 

Although these many statements have been proven to link the DNA methylation in the T2D genes with the cause of the disease, they did not identify whether these epigenetic alterations predispose a person to the disease. This information on the predisposing cause of T2D was now published in Nature Communications as “Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes”.

Through epigenetic analysis in the islets of T2D patients and patients previously not diagnosed with T2D, an HbA1c test (a blood test that measures the average amount of glucose (sugar) attached to haemoglobin in your blood over the past three months) was conducted and differences in the HbA1c level were observed in both population. Through additional epigenetic marks and transcriptional activity, subsequently dissecting cellular function and metabolism in human islets, clonal β-cells, and a diabetic rat model, they have discovered that RHOT1 has a key role in the functioning of islet and T2D pathogenesis and DNA methylation of the RHOT1 in blood was connected with the future T2D.

Through the study, it has been shown that T2D and HbA1c (Hemoglobin A1C ) have control over the DNA methylation of the sites in human islets. These sites are rich with pathways like Calcium signalling, Type II diabetes mellitus, and Pancreatic secretion which play a prominent role in the development of T2D. Additionally, it was shown that alternation due to methylation in T2D is found in promoters and enhancers.

In conclusion, the study reveals significant alterations in DNA methylation at 5,584 sites within pancreatic islets of individuals with Type 2 diabetes (T2D) compared to non-diabetic controls, with these changes also correlating with HbA1c levels in individuals without T2D. These methylation variations primarily occur in enhancer regions and regions bound by β-cell-specific transcription factors, resulting in decreased expression of key genes associated with insulin secretion, including CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. Notably, RHOT1 emerges as a critical regulator of insulin secretion in human islets, with RHOT1 deficiency in β-cells leading to impaired insulin secretion and mitochondrial dysfunction, characterized by alterations in ATP/ADP ratio, mitochondrial mass, calcium levels, and respiration, as well as changes in regulators of mitochondrial dynamics and metabolites. These findings are further supported by observations of RHOT1 deficiency in islets from diabetic GK rats and the association of RHOT1 methylation in blood with future T2D development.

Still, researchers suggest that the mechanism of perturbing islet insulin secretion should be understood better to develop new drug targets. Furthermore, if epigenetic modifications indeed increase an individual's susceptibility to diabetes, leveraging this knowledge could significantly benefit preventive healthcare efforts. By delaying the onset and progression of the disease, as well as mitigating long-term complications and patient distress, such interventions hold considerable promise. 

REFERENCE

Rönn, T. et al. (2023) ‘Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes’, Nature Communications, 14(1). doi:10.1038/s41467-023-43719-9. 

IMAGE CREDITS

Healthline, https://images.app.goo.gl/zFZbvoBjBu24t5ie7

Clinical Epigenetics, https://images.app.goo.gl/y8GPYBA1GXhSKyzQ9