**11. Etiology of type 2 diabetes mellitus**

We have covered the different types of diabetes, the cells that comprise the pancreas, glucose signaling, transcription, and some of the genes that govern pancreatic cellular behavior and differentiation, so we will now look more closely at the etiology of T2D, ultimately moving into the epigenetic layer.

The etiology of T2D is complex and multifactorial since it is affected by genetic predisposition [31] and behavioral influences, such as diet and physical activity [32]. As previously stated, T2D is often characterized by β-cell dysfunction, insulin resistance, and hyperinsulinemia [33]. These factors and symptoms depend on the disease phase and how insulin affects and regulates the bloodstream's high level of glucose [34]. Essentially, genetic, epigenetic, and non-genetic factors influence the pathogenesis of T2D [35].

Firstly, as far as genetics goes, genome-wide association studies have identified associations between single-nucleotide polymorphisms (SNPs) and disease in large case-control cohorts and family-based studies. However, although over a hundred genetic variants have been identified that are associated with T2D risk, they can explain only a modest portion of T2D heritability [36].

There also are non-genetic risk factors for T2D, such as age, physical inactivity, and energy-rich diets that result in obesity [35]. However, it is not necessary to be obese to have this type of DM. Most patients who have DM are not obese, have an incommensurable reduction of insulin secretion, and are less insulin resistant than obese individuals. It was discovered that T2D could also exist in the absence of an obese phenotype by studying non-obese rodent models [34].

There is also evidence that DM in adulthood can be caused by intrauterine or fetal malnutrition. This type of malnutrition is vital to comprehending adult DM because the genetic abnormalities and imbalances in the mother's uterus can affect the probability of her child developing DM even as an adult. Another study has shown that low birth weight leads to T2D development or insulin resistance. Moreover, factors such as the mother having DM, low birth weight of the child, and fetus malnutrition, work in a complex manner with a variety of epigenetic regulators (guided by α and β-cell-type-specific transcription factors such as Pdx1, mentioned earlier) and result in abnormal β-cell maturation and differentiation causing adult DM [ 37 ].

 Thus, other explanations for T2D heritability have been proposed, including alterations in epigenetic patterns [ 35 ]. We likely need a more holistic understanding of epigenetics to obtain a complete picture of the etiology of DM, especially environmental-epigenetic interactions.

 But what exactly does "epigenetic" mean? It is here that we can delve more into the molecular aspects of DNA and chromatin and how they relate to gene expression and disease etiology.
