Genetics of diabetes and its complications: a comprehensive review | Diabetology & Metabolic Syndrome

Types of diabetes

Type 1 diabetes mellitus (T1DM)

T1DM, is a complex long-term disorder characterised by insulin deficiency. The insulin deficiency results from autoimmune destruction of β-cells, which in turn leads to hyperglycemia [20]. T1DM is most prevalent among young individuals, particularly during puberty and early adulthood. According to an International Diabetes Federation report, approximately 1,211,900 individuals under the age of 20 are living with T1DM in 2021 worldwide [21]. Individuals with this condition may experience symptoms such as polyuria, polydipsia, nocturnal enuresis, blurred vision, polyphagia, fatigue, weakness and weight loss [22]. T1DM is primarily characterised by a loss of β-cell but another observation is loss in pancreatic mass. MRI scans have shown progressive decrease in pancreatic mass [23, 24].

One of the acute complications associated with T1DM is DKA [25]. DKA is characterised by metabolic acidosis, ketosis, hyperglycemia. Common contributing factors of DKA are non-compliance to insulin therapy, undiagnosed T1DM, and inadequate glycemic control [26]. In normal physiological conditions, when serum glucose levels rise, beta cells produce insulin. Insulin achieves glucose homeostasis by decreasing production of glucose (glycogenolysis and gluconeogenesis), while increasing glucose uptake in cells that utilize lowering blood glucose [27]. In T1DM patients there is an insulin deficiency, coupled with elevated counter-regulatory hormones resulting in accelerated gluconeogenesis, glycogenolysis, and impaired glucose uptake by body cells. This stimulates lipolysis, causing fats to increase in the bloodstream. These fatty acids are oxidised in the liver to produce ketone bodies, resulting in accumulation of ketones and metabolic acidosis. The condition is further exacerbated by osmotic diuresis induced by hyperglycemia, which leads to dehydration, hyperosmolarity, and electrolyte imbalances that can reduce glomerular filtration and impair renal function. Impaired renal function also causes electrolyte imbalance, especially potassium. Additionally, hyperglycemia triggers an inflammatory response in the body, caused by release of C-reactive protein, pro-inflammatory cytokines, reactive oxygen species (ROS), and peroxidation of lipoproteins [28, 29]. All these conditions can cause severe metabolic acidosis, cardiac arrhythmias, kidney failure, cerebral edema and eventually death if left untreated [28].

T1DM is influenced by a complex interaction of environmental, lifestyle, and genetic factors. In this dynamic context, understanding the genetics of T1DM is essential for uncovering its underlying pathophysiology. Genetics are a crucial component in the development of T1DM [30]. The hereditary component of the disease is evident, as individuals with a first-degree relative with T1DM have a 15-fold increased risk of developing the condition [31, 32]. Extensive GWAS have identified over 60 genetic loci linked to heightened risk of T1DM. CTLA4, IL2RA, PTPN22, genes are some of the notable genes implicated in development of T1DM [33]. The various genes linked to T1DM have been discussed in detail in Table 1. However, after decades of research the Human Leukocyte Antigen (HLA) gene has emerged as the strongest genetic link to T1DM. It has been attributed to 50% of the genetics associated with T1DM. The HLA gene system is highly polymorphic and contains a vast allele pool. The main genetic factors influencing T1DM are polymorphisms in class II HLA genes, specifically those encoding HLA-DQ and HLA-DR, with HLA-DP also playing a role to a lesser extent. Furthermore, specific alleles of the class I HLA-B gene show a strong association with increased T1DM risk. Class II genes have been associated with triggering autoimmune response while class I genes have been implicated in progressive autoimmune response and destruction of beta cells. [34].

A 2024 study aimed to explore the role of new HLA loci including HLA class 1 genes in T1DM. The study highlighted that there has been increasing evidence of involvement of new HLA loci including HLA class I gene in T1DM development and onset, but still the current HLA screening remains largely focused on detecting DR3 and DR4 haplotypes. The study employed high-resolution HLA typing, and found that 13% of T1DM patients did not have the classical halotypes (CH) HLA, further strengthening the argument that additional genetic factors beyond class II are involved in T1DM development. Among non-classical haplotypes (NCH), two class I alleles—HLA-B39:06:02 and HLA-C07:02:01—were more frequent compared to CH T1DM subjects. Notably, HLA-C*07:02:01 were linked to increased expression of T cell receptor genes, suggesting elevated immunological activity. The study also found that 38% of NCH T1DM subjects presented with DKA compared to 26 of CH T1DM subjects [35]. There is a need for extended HLA typing could thus uncover new alleles linked to DM susceptibility, though large sample sizes are needed to account for the significant allelic diversity within the HLA locus. Recent studies including the above study underscore a connection between specific HLA profiles and clinical features such as age of T1DM onset. NGS based HLA typing is feasible and accurate, and can enhance clinical outcomes. New studies are also emphasising that expanded HLA typing could aid in prevention, allowing for early identification of individuals at higher risk of developing T1DM and potentially avoiding a severe disease onset with DKA, which can lead to both acute and chronic complications [43].

Another important factor in T1DM is the age of onset and studies indicates that several genes are linked to an earlier onset of T1DM [27]. A 2020 study found two chromosomal regions associated with age at T1DM diagnosis. These regions included the HLA region on chromosome 6, which contains multiple independent genetic variants, and a locus on chromosome 17q12. Among the non-HLA genes, lower expression of Phenylethanolamine N-methyltransferase (PNMT) in whole blood, along with higher expression of IKZF3 and ZPBP2 and lower expression of ORMDL3 and GSDMB across various tissues, were linked to a younger age at T1DM diagnosis [44]. Incorporating these genetic markers into clinical practice for early detection of high-risk individuals can help prevent complications in children by enabling timely intervention and personalized care.

It is believed that genetic factors can be triggered by environmental factors. The exogenous stressors range from infections, maternal age, dysbiosis, vitamin D deficiency, geographical location, and diet. Viral infections are widely recognized as a trigger for T1DM in susceptible individuals [30]. Key viruses that are implicated include enterovirus, Epstein-Barr virus, cytomegalovirus, parechovirus, parvovirus, norovirus, mumps virus, coxsackievirus B, influenza virus, rubella virus, and human endogenous retrovirus [23, 45]. A 2019 study by Perrett et al. [46], observed the role of rotavirus in development of T1DM by triggering pancreatic apoptosis. Studies suggest that molecular mimicry by T-cell epitopes on rotavirus initiate an autoimmune response in genetically predisposed individuals. The immune system recognizes the viral peptides as a threat, it activates T cells that may also recognize similar structures in the β cells. As a result, this can lead to the destruction of these insulin-producing cells, contributing to the onset of T1DM [46, 47]. These viral infections may initiate autoimmune responses in genetically predisposed individuals, potentially leading to the development of T1DM. Understanding the interplay between genetic predisposition and environmental triggers is crucial for identifying preventative measures and treatment strategies for this condition.

The pathophysiology of T1DM at its core is autoimmune, T-cell and auto-antibody directed pancreatic β cell destruction. The numerous environmental, lifestyle and genetic factors stress out the β cell and cause them to produce β-cell antigens. These antigens are recognised and processed by antigen presenting cells (APCs). The APCs then migrate to lymph nodes and present these to CD4 + T cells that become activated. In turn CD4 + cells activate Cytotoxic T cells (CD8+) and B cells. CD8 + cells move to pancreas and destroy β-cells. B cells produce antibodies that cause destruction of β cell. CD4 + cells also activate macrophages and natural killer (NK) cells that further destroy β cell [48]. The process is further accelerated by production of proinflammatory cytokines (Il-1, TNF a, IL 2, IL 4) and ROS from immune cells like NK cells, macrophages, and neutrophils. The regulatory cells of our body’s immune system, regulatory T-cells (Tregs), do not inhibit the self-attacking immune cells leading to damage of β-cells [34]. This coordinated attack by the body’s immune cells, i.e., causes the destruction of β cells and consequently insulin deficiency. Recent studies have identified β cells not as a bystander being attacked by T-cells but a potential trigger or accelerator of T-cell mediated autoimmunity. It has been suggested that the exceptionally high rate of insulin production β-cells and protein processing makes them particularly vulnerable to endoplasmic reticulum stress and the unfolded protein response. This susceptibility is further exacerbated by cytokines released from infiltrating immune cells. Immune cells have easy access to the pancreas due to profuse vascular supply [49]. Figure 1 represents the role immune cells play in the autoimmune mechanism of T1DM.

In conclusion, T1DM is associated with the dysregulation of a wide range of genes, particularly those involved in immune function. These genetic factors influence various aspects of T1DM, including the severity of the disease and the age of onset. Recent advances in genetic research have identified additional alleles linked to T1DM susceptibility, such as PTPN22, CTLA4 and IL2RA, providing valuable insights into the disease’s development and progression. Moreover, genes like PNMT and PHF20L1 are associated with earlier disease onset. Early genetic screening for these genes can help identify individuals at high risk, enabling timely preventive interventions that may reduce the risk of severe disease onset and complications, such as DKA. Furthermore, recent studies, including those focused on HLA class I genes, highlight the importance of expanding genetic screening beyond traditional HLA class II haplotypes [35]. These genetic markers can also serve as biomarkers, aiding in clinical diagnosis and paving the way for personalized healthcare strategies. Ultimately, integrating genetic typing into T1DM research and clinical practice has the potential to improve prevention, diagnosis, and treatment, enhancing the quality of life for those affected by this autoimmune disorder.

Type 2 diabetes mellitus (T2DM)

The underlying mechanism of T2DM is IR or impaired insulin secretion caused by dysfunction of β-cells of pancreas. T2DM represents a significant global health burden making up 90% of the cases of DM globally [50].

In T2DM, β-cell dysfunction results from an interplay of metabolic and stress pathways. Excessive nutritional intake and obesity, leads to high blood glucose and altered lipid profile, promoting IR and persistent inflammation [51]. This exerts toxic pressure on β-cells, including inflammation, endoplasmic reticulum stress, ROS, and amyloid stress, which disrupt islet integrity. Lipotoxicity and glucotoxicity activate the unfolded protein response, triggering β-cell apoptosis [52, 53]. High levels of free fatty acids impair ER calcium signalling and exacerbate stress, while sustained hyperglycemia increases proinsulin and islet amyloid polypeptides, further promoting oxidative stress and inflammation. These factors disrupt cell-to-cell communication within the pancreatic islets, impair insulin secretion, and contribute to the progressive β-cell failure central to T2DM [54].

IR also plays a central role in the development of T2DM. IR is marked by a diminished cellular and systemic response to insulin, leading to hyperglycemia [55]. Several mechanisms contribute to IR, including diminished insulin secretion by β-cell, the presence of insulin antagonists such as counter-regulatory hormones, and factors that disrupt insulin receptor signalling [56]. Insulin action is further modulated by molecules like growth hormone and IGF-1 during the fed state, while glucagon, glucocorticoids, and catecholamines help prevent hypoglycemia during fasting. An imbalance in the insulin/glucagon ratio can exacerbate metabolic disturbances, with catecholamines promoting lipolysis and glycogen breakdown, while glucocorticoids stimulate muscle catabolism, gluconeogenesis, and lipolysis. Excessive secretion of these hormones can worsen IR. Additionally, impaired insulin action in key tissues, including skeletal muscle, adipose tissue, and the liver, often precedes systemic IR and contributes to the progression of T2DM [54].

Genetic predisposition and metabolic and environmental factors are major causes of the autoimmune trigger and contribute to the many pathophysiological changes that are leading to impaired glucose homeostasis in T2DM. Lifestyle factors—like lack of exercise, smoking, high-fat and high-sugar diets, and poor sleep—greatly increase the risk of T2DM. Obesity, in particular, is closely linked to IR, forming a crucial connection between excessive body weight and T2DM [57]. Sedentary lifestyle and lack of exercise contribute to this relationship and are associated with heightened markers of chronic inflammation in the body. In this inflammatory state, proinflammatory molecules are released into the bloodstream and specific tissues. This phenomenon, referred to as metabolic inflammation, plays a pivotal role in the progression of T2DM. Notably, IL-1 is implicated in the autoimmune response against β-cells, leading to impaired β-cell function and promoting their apoptosis. This cascade of events further exacerbates the dysregulation of glucose homeostasis in individuals with T2DM. Figure 2 illustrates the various risk factors associated with T2DM.

Genetics are significantly linked to T2DM [58]. Individuals with family history especially those with first degree relatives having T2DM face 2–3 times greater risk of T2DM. The risk significantly increases, approximately 5–6 times greater, for those with both maternal and paternal histories of T2DM. Ethnicity also is linked to risk of T2DM with specific ethnic group facing higher risks [59]. A study in the US found that black individuals were twice as likely to develop T2DM compared to white individuals [60].

In the current landscape, genetics significantly influence the development of T2DM. Recent GWAS have identified over 50 genetic variants associated with T2DM. Notable genes linked to the condition include PON1, LCAT, APOE, FTO, and TCF7L2 genes [61]. The genes linked to T2DM have been discussed in detail in Table 2. The TCF7L2 gene has attracted significant attention due to its strong association with T2DM [62]. It is considered the most significant genetic locus for T2DM risk, with its role being replicated in multiple studies [62]. A 2022 study, which analysed data from five clinical research cohorts—including African, Asian, and Brazilian populations—found a strong association between TCF7L2 alleles (specifically the rs7903146 T allele) and T2DM. The key finding from the study was that a single factor cannot be fully implicated in development of T2DM. Rather, the condition results from a complex interplay of genetic and environmental factors [63, 64]. While certain genetic variants, such as those in TCF7L2, may increase susceptibility, environmental exposures—fat-rich diet, high BMI, smoking, and physical inactivity—can further exacerbate the risk of developing T2DM [65]. A 2021 case–control study by Aboelkhair et al. [66], included 180 individuals divided in 3 groups including 60 healthy controls (HC), 60 T2DM without complications and 60 T2DM with microvascular complications. The study showed that the T allele of TCF7L2 gene had a high susceptibility to development of T2DM. Additionally, the T allele was significantly linked to increased risk of complication compared to other alleles of TCF7L2 specifically TT and CT genotypes.

Another gene under scrutiny due to its link to T2DM is PON1. A 2020 case–control study by Wamique et al. [67], with 250 DM patients and 250 HC analysed the link between PON1 & SRB1 genes and T2DM. The genes were significantly associated with T2DM and the frequency of their polymorphic allele was greater among DM patients. Admiringly the researchers found higher LDL and lower HDL levels among gene carriers. The researchers concluded that PON1 and SRB1 can act as biomarkers for T2DM. Dyslipidemia is linked to inflammation in the body and is a major contributor for T2DM development.

T2DM poses the most significant burden of disease among all types of diabetes. Given the severity of consequences linked to T2DM, it is critical that all avenues for its prevention, treatment, and management be exhausted. Genetics is a key factor to further T2DM treatment. Early genetic testing, particularly in families with a history of T2DM, can facilitate early detection. As previously discussed, genes such as PON1 and SRB1 can serve as valuable biomarkers. Proactive management of individuals at high risk is crucial for delaying or preventing the onset of T2DM [6]. Additionally, studying risk genes like LCAT, APOE, FTO, and TCF7L2, which are associated with obesity and inflammation, can lead to improved treatment options by targeting these pathways.

Type 3c diabetes mellitus (T3cDM)

T3cDM, is a form of diabetes secondary to a pancreatic disorder. The prevalence of T3cDM is 10–15% among individuals diagnosed with DM [75]. Pancreatic pathologies that cause damage to the Islets of Langerhans lead to endocrine pancreatic dysfunction and consequently T3cDM. Pancreatitis is the most frequently associated cause for T3cDM. Additional conditions implicated in the development of T3cDM include acute pancreatitis, pancreatic cancer, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, genetic disorders [76,77,78]. Surgical procedures such as in pancreatic resections and total pancreatectomy can also lead to T3cDM [75].

T3cDM is characterized by structural and functional loss of pancreatic cells including α-cells (reduced glucagon), β-cell (reduced insulin) and γ cells (decreased pancreatic polypeptide). Furthermore, there is decreased incretin production, and low serum levels of fat-soluble vitamins [75].

Pancreatitis is the most common cause of T3cDM, and a wide range of genes are involved in development of pancreatitis, and consequently contributing to the onset of T3cDM. Key genes associated with pancreatitis include PRSS1, SPINK1 and CFTR [79]. Other genetic risk factors for pancreatitis identified through sequencing include CASR, CPA, CTRC, SBDS, and UBR1 [80]. The various genes linked to T3cDM have been discussed in detail in Table 2. The development of chronic pancreatitis often involves multiple genes, indicating the need for extensive research to fully understand these complex genetic interactions [81]. A 2017 study analysing a GWAS conducted in 2 stages, identified and successfully replicated PRSS1-PRSS2 and CLDN2 as potential loci. Variants in CLDN2 may interact with alcohol consumption, suggesting a gene-environment interaction. While alcohol was historically considered the primary cause of pancreatitis, genetic factors have become increasingly recognized, especially after discovering that rare variants of PRSS1, SPINK1 and CFTR genes are associated with a higher risk of pancreatitis. This underscores that pancreatitis is rarely caused by a single factor. Many patients with recurrent episodes of acute or chronic pancreatitis possess multiple genetic variants, or undergo epistatic interactions between different genes. The condition can be exacerbated by environmental exposures like pollution and lifestyle choices e.g. alcohol consumption. [81]. The various genes linked to T3cDM have been discussed in detail in Table 3.

In clinical conditions, pancreatic cancer-associated T3cDM is often mistaken for conventional T2DM. Misdiagnosis or delay in the diagnosis and treatment of pancreatic cancer can lead to serious consequences for patients. Therefore, accurate and early identification of pancreatic ductal adenocarcinoma (PDA) associated T3cDM and its differentiation from conventional T2DM is essential for improving survival rates in patients with pancreatic cancer [87]. Genetic testing and emerging technologies have the potential to play a key role in the diagnosis and early detection of PDA-associated T3cDM, enabling more timely and effective interventions.

Genetic testing can play a critical role in the prevention and early detection of T3cDM particularly in individuals with a high genetic susceptibility to chronic pancreatitis and diabetes. By identifying those at increased risk early on, genetic screening enables personalised management strategies, allowing for timely lifestyle modifications and targeted medical interventions. Early identification of high-risk individuals can prevent or delay the onset of T3cDM and its associated complications, ultimately improving long-term health outcomes [88]. Reducing modifiable risk factors, such as alcohol consumption and smoking, is crucial in managing chronic pancreatitis, as both behaviours exacerbate pancreatic inflammation, fibrosis, and pain. Avoiding alcohol consumption is beneficial for management of DM, as it can disrupt liver glucose production and cause hypoglycemia, particularly in individuals on insulin therapy [89]. Furthermore, engaging in a minimum of 150 min of moderate aerobic exercise each week can be beneficial for health. In diabetes associated with chronic pancreatitis, the primary objectives of medical nutrition therapy include preventing and managing malnutrition, addressing steatorrhea symptoms, and controlling post-meal hyperglycemia. Patients are advised to eat meals rich in soluble fibre and low in fat [90]. For those with pancreatic exocrine insufficiency, oral pancreatic enzyme replacement therapy (PERT) is recommended to aid in fat digestion, improve nutrient absorption, and enhance incretin hormone secretion, which helps with glucose tolerance. PERT also alleviates steatorrhea symptoms, prevents fat-soluble vitamin deficiencies, and supports overall nutritional balance [91]. Vitamin D deficiency is common in chronic pancreatitis, even among patients with normal exocrine function, and osteoporosis affects 34% of these individuals—three times more than in the general population. In cystic fibrosis-related T3cDM, the main treatment goals are maintaining proper nutrition and stable blood glucose levels. A balanced diet is encouraged, without restrictions on calories, fat, or carbohydrates, due to the increased energy expenditure and malabsorption seen in cystic fibrosis. Routine supplementation with fat-soluble vitamins is crucial [90].

Conclusively, incorporating genes into clinical practice to treat T3cDM improve the current situation. Integrating genetic insights into clinical practice for treating T3cDM can significantly enhance current approaches. The genes discussed, including PRSS1, SPINK1, CFTR, CASR, CPA, CTRC, SBDS, and UBR1, have the potential to serve as early biomarkers. Detecting these genes through advanced genotyping can aid in the early prevention and management of the disease, thereby reducing its harmful effects. Proper management of T3cDM is essential for maintaining glucose control and preventing both microvascular and macrovascular complications. Ongoing glucose monitoring and insulin therapy are crucial to prevent hyperglycemic episodes, which may lead to further complications [77]. By focusing on genetics can pave the way for more effective T3cDM management and treatment.

Gestational diabetes mellitus (GDM)

GDM is abnormal glucose tolerance with the onset of pregnancy. Currently GDM is the most prevalent medical complication related to pregnancy [92]. Gestational diabetes affects around 5–20% of the pregnancies around the globe and a further increasing trend of cases is seen [93].

GDM is influenced by many modifiable and nonmodifiable factors, with body mass index (BMI) being a significant factor [94]. High pre-pregnancy BMI is a strong risk factor associated with GDM. High pre-pregnancy BMI, classified as overweight (BMI > 25 kg/m2) or obese (BMI > 30 kg/m2) by the WHO, is strongly linked to GDM. With the rise of the epidemic of obesity, particularly among women of reproductive age, the number of overweight (38.9 million) and obese (14.6 million) pregnant women globally is substantial. Diet is another key modifiable factor. Diet high in processed foods, sugars, and fats contributes to obesity and the development of GDM. Additional dietary factors, such as vitamin D deficiency and a high dietary acid load, can also elevate the risk of GDM [95]. Other contributing factors include metabolic disorders like dyslipidemia, medical conditions such as polycystic ovary syndrome (PCOS) and pre-eclampsia, and lifestyle factors like chronic stress, use of antidepressant, hypertension, smoking, and chronic sleep disturbances. Addressing these factors through improved lifestyle choices can help reduce the risk of GDM and enhance maternal and fetal health outcomes [96, 97].

Advanced maternal age is one of the most common non-modifiable risk factors for GDM, with the risk increasing as women aged. Other key factors include gravidity and parity, where a higher number of pregnancies and births may elevate GDM risk, and ethnicity, with certain groups, such as South Asian, Hispanic, African, and Indigenous populations, showing higher prevalence. Genetics and family history of hyperglycemia also play a significant role, as women with relatives who have diabetes or a history of GDM are at greater risk. Additionally, socioeconomic and geographic factors can impact GDM development [98]. Differences in climate and geographical location may contribute to variations in prevalence due to lifestyle, diet, and healthcare access, while education and socio-economic status influence risk by affecting access to health information and prenatal care [99]. Lower socio-economic status and education levels may limit awareness and resources, increasing the likelihood of GDM. Clinical factors such as HbA1C levels of ≥5.7% and a history of delivering a baby weighing over 4000 g is also associated with a heightened risk of GDM, reflecting underlying metabolic disturbances that contribute to the condition [96, 97].

GDM can lead to significant complications for both the mother and the offspring, with effects that extend beyond pregnancy. For mothers, GDM increases the risk of endothelial damage and vascular dysfunction, which can lead to hypertension during and after pregnancy. Women who have experienced GDM are also at a 50% higher risk of developing T2DM later in life, and there is a substantial likelihood of GDM recurring in future pregnancies [100].

For the offspring, complications associated with GDM include asphyxia, hypoglycemia, jaundice, bacterial infections, and neonatal respiratory distress syndrome. Additionally, infants may experience birth trauma, such as shoulder dystocia and brachial plexus injury, due to macrosomia. Neonatal hypoglycemia is particularly concerning, as it arises from the abrupt loss of the maternal glucose supply at birth, compounded by fetal hyperinsulinemia induced by GDM, requiring careful management if hypoglycemia persists [101].

The risks for children extend into later life, as maternal GDM is strongly associated with hyperglycemia, obesity, and CVDs in children. Children born to mothers with GDM are 29% more likely to develop cardiovascular conditions early in life, including heart failure, DVT, hypertension, and pulmonary embolism. This increased risk is linked to a combination of genetic and the intrauterine environment factors, which can alter metabolic pathways and predispose the offspring to chronic health conditions from an early age. These findings underscore the importance of early diagnosis and management of GDM to mitigate long-term health consequences for mother and child [97].

A variety of genes are involved in the development of GDM. Research has highlighted several gene variants as prominent candidates, including TCF7L2, MTNR1B, CDKAL1, IRS1, and KCNQ1, associated with GDM risk [102]. Additionally, other genes linked to increased susceptibility to GDM include IGF2BP2, GCK, KCNJ11, GCKR, HNF4A, SLC30A8, PPARG, and FTO. These genes play crucial roles in pathways related to insulin secretion, glucose metabolism, and insulin sensitivity, which are central to the pathogenesis of GDM [93]. The various genes linked to GDM have been discussed in detail in Table 4.

Several GWAS have found MTNR1B implicated in development of GDM. MTNR1B is a gene that codes for melatonin receptors, strongly expressed in various cells including brain, retina, and β-cells, and MT2. This important gene is involved in circadian rhythm, insulin secretion and glucose regulation through the melatonin pathway [103]. Mutation of this gene can lead to impaired secretion of melatonin and subsequently impaired secretion of Insulin. This eventually leads to IR and β cell dysfunction [104]. A study by Alharbi et al. [105], consisting of a cohort of 400 pregnant women (200 GDM, and 200 HC), showed a strong correlation between MTNR1B gene and GDM. The variants rs1387153 and rs10830963 were identified as being strongly associated with GDM in the dominant genotype. A 2021 study by Popova et al. [103], analysed MTNR1B genes correlation with GDM among Russian women. The study had a total of 1,142 patients (688 GDM vs 454 HC). Two variants of the MTNR1B gene showed significantly increased risk of GDM. The researchers concluded that addition of genetic information can complement clinical diagnosis and help in predicting GDM.

Another major gene involved in pathogenesis of GDM is IRS1, which encodes the IRS-1 protein, crucial for transmitting signals between the insulin receptor and PI3K [104]. Dysregulation of IRS-1 expression or function has been shown to disrupt the insulin signalling pathway, contributing to the development of IR and DM [105]. A 2024 meta-analysis by Shen et al. [106], analysed the relation between IRS1 gene and risk of GDM. The study included 4777 patients (2661 HC vs 2116 GDM). The study found that IRS1 (rs1801278) gene was significantly accosted with GDM.

The insights above underscore that GDM has profound implications for both mother and child, affecting fetal development and posing risks even after birth. Complications such as preeclampsia and eclampsia can endanger maternal and fetal health, sometimes with life-threatening outcomes [105]. Despite decades of research, effective treatment for GDM remains elusive. Preventing and managing GDM requires a comprehensive approach that combines lifestyle changes, medical intervention, and continuous monitoring [107]. Central to this approach is prevention and early detection, which can be enhanced through advanced techniques, including genetic testing. Although biochemical analysis are currently used to diagnose GDM in pregnant women, no molecular tests have been established or validated as specific disease markers for GDM or other forms of diabetes. Similar trends are observed in T1DM and T2DM, as well as in diabetes newly onset after transplantation. However, certain genetic polymorphisms have been identified that help explain the differences in susceptibility to these conditions [108]. Recent studies have highlighted genetic factors that influence pregnancy outcomes, treatment responses, and complications, which can be identified using molecular techniques [105]. Identifying women who are genetically predisposed to GDM allows for preconception counselling and early intervention, enabling healthcare providers to recommend personalised, preventive strategies well before pregnancy. This proactive approach can significantly reduce GDM risk and improve maternal and fetal health outcomes. Advances in genetic knowledge can significantly improve GDM management during pregnancy by guiding a more tailored approach. Effective strategies include lifestyle modifications, medical interventions, and continuous monitoring. Recent studies emphasise preventive measures, such as maintaining a diet high in whole grains, lean proteins, and fibre, along with regular physical activity to enhance insulin sensitivity and support healthy weight [109, 110].

During pregnancy, GDM management involves regular glucose monitoring, meal planning based on personal needs, and moderate exercise to maintain normal glucose levels. If lifestyle adjustments are inadequate, medications such as insulin or metformin may be prescribed, with recent research confirming metformin’s safety and effectiveness in controlling GDM [111]. This comprehensive approach enhances the control and outcomes of GDM for both the mother and child. The genetic insights from recent research open the door for developing personalised risk prediction models, offering valuable information about the genetic underpinnings of GDM. Incorporating genetic markers into these models holds great promise for the early identification and management of GDM cases. By combining genetic data with traditional risk factors healthcare providers can improve the accuracy of risk assessments, leading to more tailored and effective interventions [112]. Postpartum care involves glucose monitoring, as women with GDM are at an elevated risk for developing T2DM, along with ongoing lifestyle interventions to prevent GDM recurrence and the onset of T2DM. Education, support groups, and regular follow-up visits are essential for guiding women in managing their long-term health [111].

Integration of genetic knowledge clinical management of GDM holds significant promise for improving health outcomes. Genes such as TCF7L2, MTNR1B, CDKAL1, IRS1, and KCNQ1 play pivotal roles in the pathogenesis of GDM and can serve as biomarkers for risk assessment. Integrating these genetic markers can enhance the precision of risk prediction, allowing healthcare providers to tailor prevention and management strategies for GDM. TCF7L2, shared between GDM and T2DM, highlights the common genetic pathways involved in both conditions, offering insights for targeted interventions. MTNR1B, with its role in circadian rhythm and insulin secretion, directly influences glucose regulation and insulin sensitivity, making it a key target for therapeutic strategies. IRS1 gene is essential for insulin signalling, contributes to IR, while CDKAL1 and KCNQ1 are involved in glucose metabolism and insulin secretion. Understanding these genetic factors allows for personalized approaches to manage GDM, ultimately improving maternal and fetal health outcomes while mitigating long-term risks of developing T2DM.

Diseases related to diabetes

Macrovascular complications

Macrovascular complications are the damage to larger blood vessels, which are associated with increased risk of heart attack, stroke and peripheral artery disease [119].

Cardiovascular disease (CVD)

Cardiovascular diseases are a significant health issue for individuals with DM [120]. The increased risk of CVD in individuals with DM is largely due to the complex interplay of metabolic abnormalities, including IR, hyperglycemia, and dyslipidemia. Moreover, diabetes accelerates the development of atherosclerosis and other cardiovascular complications [121].

CVD is a primary cause of death among individuals with DM. Evidence suggests T2DM can double the risk of CVD in individuals [122]. This increased risk of CVD in diabetes can be largely attributed to several key risk factors common in diabetic patients, including obesity, hypertension (HTN), and elevated cholesterol levels—each of which significantly raises the likelihood of developing conditions such as coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and stroke. Among these complications, heart failure stands out as particularly prevalent and is often the first manifestation of CVD, affecting approximately 22% of individuals with diabetes [123].

One of the most significant studies to see the prevalence of CVD in patients with DM was conducted by Einarson et al. [124], in 2018. In which he extracted and analysed data from fifty-seven studies published between 2007 and March 2017 with a massive sample size of 4,549,481 T2DM patients. The study found that the prevalence of CVD in patients with DM was 32.2% globally. Among complications, atherosclerosis was the most common CVD, accounting for 29.1% of the cases. Other complications included CHD at 21.2%, HF at 14.9%, angina at 14.6%, MI at 10.0%, and stroke at 7.6%. CVD was a major contributor to mortality, responsible for 9.9% of deaths among individuals with T2DM, accounting for 50.3% of all deaths in this group. In a 2021 study, Mosenzon et al. [125], further examined CVD prevalence in adults with T2DM, finding an overall prevalence of 34.8%, with 31.8% of individuals affected by atherosclerotic CVD.

The role of genetics in the development of CVD among individuals with DM is undeniably profound, and recent research has illuminated several key genetic factors contributing to this elevated risk. Thus, studying these genes is crucial for identifying polymorphisms that help us predict susceptibility to CVD in DM patients [126]. Ma et al. [127], highlighted the association between ACE and PCSK9 genes with increased risk of CHD in T2DM. Elevated plasma levels of ACE induce overexpression of IL-6 and KLK1, which in turn heighten the vulnerability for coronary plaques. This leads to plaque ulceration and thrombosis, which significantly increase the risk and mortality associated with CVD [128]. Trends suggest a strong link between occurrence of pre-diabetes or T2DM and plasma levels of PCSK9. Insulin regulates the levels of PCSK9 through a dual mechanism: it upregulates the SREBP-1c transcription factor, which stimulates the expression of PCSK9. Simultaneously, it suppresses PCSK9 expression by inhibiting HNF-1α [129]. A 2022 study by Zarkasi et al. [130], investigated the involvement of the APOE gene in the development of CHD in individuals with T2DM. The APOE gene, expressed in the liver, encodes apolipoprotein E, an important protein involved in lipoprotein metabolism. There are three main variants of the APOE gene. The E2 variant produces an apo-E protein that has been shown to exhibit a reduced ability to bind to LDL receptors, potentially contributing to the development of CHD.

GWAS have linked atherosclerosis and related conditions, such as CHD, to over 60 genetic loci. However, the lncRNA ANRIL gene located on chromosome 9p21 is regarded as the most significant of these loci [131]. Goodarzi et al. [132], arrived at a similar conclusion regarding the ANRIL gene and its role in CHD in diabetic patients, acknowledging that its associated locus may be the most significant genetic signal identified for CHD. The CHD-associated genotype at 9p21 enhances the expression of linear ANRIL, which exerts pro-atherogenic effects by altering the expression of target genes. Conversely, it reduces the expression of circular ANRIL, which has anti-atherogenic properties through its impact on ribosomal RNA processing. Thus, abnormal expression of ANRIL contributes to the development of various atherosclerosis-related complications, including vascular endothelial damage, dysfunction of vascular smooth muscle cells, imbalances in mononuclear cell adhesion and proliferation, disturbances in glycolipid metabolism, DNA damage, and the disruption of competing endogenous RNAs [133].

The genetic landscape of cardiovascular disease in diabetes is complex, involving multiple genes that regulate lipid metabolism, inflammation, endothelial function, and vascular health. Genetic studies have identified several key genes, including ACE, PCSK9, APOE, and ANRIL, that play essential roles in the onset and progression of CVD in individuals with T2DM [134]. Understanding the genetic mechanisms underlying these associations is crucial for improving risk prediction, early detection, and the development of targeted therapies. By exploring these genetic markers, we can better identify individuals at higher risk of CVD and tailor prevention and treatment strategies to reduce the burden of cardiovascular complications in diabetes.

Microvascular complications

Microvascular complications related to DM are caused due to damage to small blood vessels in retina, kidneys, skin and brain. The microvascular complications have been attributed to activation of pathways like protein kinase C pathway, inflammation and oxidative stress that all ultimately damage vessels in these vital organs and cause their dysfunction [135].

Diabetic kidney disease (DKD)

DKD is a microvascular complication caused by DM. Hyperglycemia causes damages to blood vessels in the kidneys. This leads to impaired filtering and kidney function overtime. It is a leading cause for End Stage Renal Disease (ESRD) [136]. Currently, DKD affects approximately 30–40% of individuals with diabetes [137]. However, as the global prevalence of diabetes is expected to rise, the number of patients developing DKD is also projected to increase, leading to a growing burden of the disease [121]. DKD is clinically characterised by proteinuria, microalbuminuria, hematuria, decreased glomerular filtration rate (GFR) [138]. Proteinuria is the presence of proteins, and is present in 15–40% of patients with T1DM while it ranges from 5–20% in patients with T2DM. Microalbuminuria is present in 12–33% of T1DM patients [19]. Hematuria is a microvascular complication of DM, linked to podocyte damage, glomerular injury, and tubular dysfunction, ultimately causing a reduction in GFR [139].

The pathophysiology of DKD involves the disruption of metabolic, inflammatory, and hemodynamic pathways [140]. Chronic hyperglycemia causes the production of ROS and activates several key pathways such as protein kinase C that lead to inflammation. DKD is characterised by elevated levels of inflammatory molecules such as MCP-1, TGF-beta, and VEGF. This inflammation contributes to fibrosis and increased vascular permeability. As a result, podocyte damage occurs, leading to albuminuria. Systemic and intraglomerular hypertension further exacerbate proteinuria [137].

Several genes have been associated with the development of DKD including PPP1R3A, TTN, and ZNF136. Furthermore, the DPY6, FRMD4A, and CROCC genes are linked to the development of DKD and are linked to related comorbidities such as T2DM and obesity. These genes play pivotal roles in glycogen synthesis, glycogen regulation, encode protein in maintenance of glomerulus and ensuring proper functioning of kidneys [141]. Other risk factors of DKD are hyperglycemia, elevated, HbA1c, dyslipidemia, hypertension, obesity, smoking which are common to risk factors of diabetes [140].

A 2020 meta-analysis extensively examined the genetic relationships between DM and kidney disease, identifying 66 gene loci involved in the development of DKD. These genes are implicated in six important signalling pathways, and polymorphisms within these genes can disrupt these pathways, contributing to the progression of DKD. Among the many genes identified, ACACB, ACE, ADIPOQ, and AGT stood out as key contributors. These genes affect critical pathways such as the adipocytokine signalling pathway and pyruvate metabolism, both of which are essential for maintaining renal function [142]. Dysfunction of these genes can lead to development of DKD.

In 2021, Li C et al. [143], examined several genes associated with DKD and their relationship with hypoxia and immunity. The researchers identified 16 genes involved in regulating the hypoxic response. Notably, genes such as TGFBR3, APOLD1, CPEB1, and KDR were positively correlated with glomerulopathy and demonstrated high specificity for renal tubulopathy. Additionally, the study found that T cells play a central role in the immune response in DKD. These genes hold great clinical significance due to high diagnostic accuracy for DKD, offering promising potential for early detection and targeted treatment.

Furthermore, in a study conducted by Feng et al. [144], in 2021 the researchers explored potential genes for development of new biomarkers for DKD. They highlighted that LUM and FMOD were significantly linked to development of DKD as they play a role in ECM accumulation. The researchers highlighted that these genes are highly specific for DKD and can act as biomarkers. In 2021, Hu et al. [145], conducted a bioinformatics analysis of genes associated with ferroptosis in DKD. The study highlighted the crucial role of iron homeostasis in maintaining normal kidney cell function, with excessive iron accumulation contributing to tissue dysfunction. In DKD patients, iron death-related factors such as ACSL4, PTGS2, and NOX1 were significantly elevated, marking an important finding in the disease’s pathophysiology.

DKD is a significant health challenge related to DM. Early detection of patients at increased risk for DKD is essential for effective management. In this domain, genetics can play a crucial role by providing diagnostic markers and therapeutic targets. As highlighted in previous studies, genes such as TGFBR3, APOLD1, CPEB1, and KDR exhibit high sensitivity and specificity, making them valuable markers for kidney damage. Additionally, genes like ACACB, ACE, ADIPOQ, and AGT are integral to the development of DKD. Targeting these genes through gene editing or pharmacological therapies offers a promising approach to improve the treatment and management of DKD, ultimately enhancing patient outcomes and slowing the progression of kidney damage.

Diabetic neuropathy (DN)

DN is a distinctive neurodegenerative disorder that impacts the peripheral nervous system (PNS). It primarily impacts sensory and autonomic axons and later, motor axons to some extent [146]. A 2020, meta-analysis with 50,112 participants showed that the 30% of T2DM patients have DN. Additionally the study found that painful DN occurs in 13–26% of people with DM [147]. A 2021 research showed the global prevalence of diabetic peripheral neuropathy (DPN) ranges from 21.3 to 34.5% in T2DM and between 7 to 34.2% in T1DM [148]. Shiferaw et al., in his research in 2020 stated the regional prevalence of DPN is 8.4% in China, 48.1% in Sri Lanka, 29.2% in India, 56.2% in Yemen, 39.5% in Jordan, 71.1% in Nigeria, 16.6% in Ghana, and 29.5% in Ethiopia [149].

Diabetes and obesity have been implicated as the top 2 causes of neuropathy, respectively. The condition is typically characterised by a range of symptoms, including: tingling sensation, numbness, pain and weakness especially in the distal lower extremities [150, 151]. Management of glucose level has been effective in preventing neuropathy in T1DM but has not been effective in T2DM with the majority suffering from T2DM [152]. New studies provide a new perspective into various risk factors of neuropathies and show encouraging evidence on how to better manage DM in order to prevent complications such as DN. Several genes have been identified that contribute to the development of DN. These genes are ACE, APOE, MTHFR, NOS3 and vascular endothelial growth factor (VEGF). Although all these genes are involved in the progression of DN, polymorphisms in ACE and MTHFR genes are considered most important in relation to DN and have been the most extensively studied genes across multiple populations, including large scale cohorts [153, 154]. MTHFR plays a crucial role in the remethylation of homocysteine thus its reduced activity is associated with hyper-homocysteinemia, which can damage blood vessels, impair lipid metabolism, and affect neuronal function leading to DN. Similarly, NOS3 is also an important gene that helps maintain endothelial cell function and maintain vascular supply. The APOE gene is associated with disorders affecting both the CNS and PNS in DN. In addition to these genes, meta-analyses have also confirmed links between the GPx-1 gene and the CAT gene with DN [154].

DN pain is a common complication seen in people with DN. It is marked by sensations such as tingling, burning, sharp or shooting pains, throbbing, and even electric shock-like feelings. The pain is typically classified as moderate to intense and tends to intensify at night, often leading to sleep disturbance [155]. Genetically, this neuropathic pain in DPN is linked to chromosome 1 and 8, with a stronger association observed in women [154].

Study conducted by Guo et al. [156], in 2020 showed a strong link between the genes PLCG2 and GPR17 and DPN. A 2024 study highlighted a strong link between neuropathic pain and genes involved in circadian rhythm. Tac1 gene is an important gene encoding substance P, a neuropeptide, plays a critical role in pain signalling. Furthermore the study showed that the CLOCK:BMAL1 complex regulates the expression of these genes suggesting a direct connection between circadian rhythm and neuropathic pain [157].

One of the major problems related to DN is the neuropathic pain which has not been addressed adequately. Recent studies have shown that neuropathic pain may have its basis in genetics. In his 2022 study, Hall et al. [158], analysed neurons for genes that could lead to inflammation, intra-ganglionic pathologies and neuropathic pain. They performed transcriptome analysis and identified 844 genes with mutation. They saw a down-regulation of several neuron regulated genes. Furthermore, mutations were seen in genes involved in macrophage function leading to development of inflammation and hypersensitivity linked to neuropathic pain. The researchers found that downregulation of KCNQ2, KCNN1, and KCNT1 genes were linked to pain in DN. The study shows that emphasis on genetic studies can help address the complications related to DM.

DN is a multidimensional condition influenced by both metabolic and genetic factors. The genetic landscape of diabetic neuropathy is complex, involving multiple genes that affect vascular function, inflammation, neurotransmission, and circadian rhythms. Key genes involved in DN include ACE, MTHFR, NOS3, APOE, and VEGF, which influence vascular function, oxidative stress, and inflammation [159]. In addition, circadian genes, immune-associated genes, and neuronal markers are important in the development and progression of neuropathic pain. Understanding the genetic underpinnings of DN opens new avenues for personalised medicine, where targeted therapies can be developed to manage and potentially prevent neuropathy in diabetes. While managing blood glucose remains crucial, early identification of genetic risks and personalised therapeutic approaches may improve the intervention and management strategies for treatment of DN, particularly in T2DM patients, who are most at risk for developing this debilitating complication.

Diabetic retinopathy (DR)

DR is a slowly progressing microvascular condition associated with DM. It is characterized by retinal ischemia, macular edema, and retinal neovascularization. If left undiagnosed and untreated, DR can lead to significant vision loss. In DM, hyperglycemia and disrupted metabolic processes produce oxidative stress, which result in neurodegeneration as one of the initial consequences. The key indicators of DR include vascular endothelial damage, the formation of microaneurysms, and dot-shaped intraretinal haemorrhages. As it progresses, vasoconstriction and capillary blockages lead to distorted capillaries and retinal ischemia. In the late stages, acute hypoxia drives neovascularization, causing complications like vitreous haemorrhage and retinal detachment [160, 161]. Untreated DR can result in irreversible blindness [64]. Approximately one in five diabetic patients is affected by DR [162]. The prevalence of DR was 13.1% among the newly diagnosed patients of T2DM. It was found most prevalent in African 19.2%, South‐East Asia 15.4% and European 15.0% regions. Another significant finding of this study showed a much greater incidence of DR in males as compared to females [64]. A similar study by Teo et al. [163], showed global prevalence of 22% for DR in patients with T2DM. In 2020, the number of adults worldwide with DR were estimated to be 103.12 million.

Genetics are a key factor in the development of DR, influencing various aspects such as its incidence, progression, heritability, and underlying mechanisms. While evidence indicates a hereditary component to DR, no single gene has been definitively linked to the condition. Candidate gene studies have identified several genes linked to the development of DR, including AKR1B1, VEGFA, AGER, EPO, and NOS3 [164]. However, the associations vary across different ethnic groups, underscoring the complex interaction between genetics and environmental factors in the disease. KLF17, ZNF395, CD33, and COL18A1 are among the recently identified genes linked to proliferative DR. Several of these potential genes are recognized for their role in regulating VEGF [165].

A study by Wong et al., showed that several genetic alterations can lead to the development of DR. These alterations include overexpression of the genes like ENPP1 and IL-6, as well as rs3844492 polymorphism in the protein ARHGAP22. The E2F3 gene disrupted re-epithelialization, the Tacl gene-encoded substance P was reduced, resulting in persistent inflammation, and the expression of the MMp-9 contributed to the impairment of healing. While downregulation of TLR2 enhances the severity of wounds in diabetic foot ulcer patients, a decrease in HIF-1a gene expression increases the likelihood of pathogenesis. Research also shows a significant correlation between genetic predispositions for T2DM and AD with specific SNP alleles. Altered DNA methylation of the CLOCK gene may contribute to the development of AD, while the APOE4 gene appears to exacerbate the condition through its influence on dyslipidemia. [63, 166]. A study conducted by Wang et al. [167], in 2022 used genetic analysis to identify 23 genes related to autophagocytosis that play a role in DR. Among these, 9 genes were seen to be up-regulated while 14 genes were down-regulated. Tissue expression analysis showed that these gene polymorphisms were present mainly in the retina of the eye. Findings of the bioinformatics analysis of the mRNA expression profile verified role of MAPK3 expression in development of DR. Numerous studies of laser-induced hypoxia have confirmed the immense role of VEGF in ocular neovascularization with elevated levels in aqueous fluid causing severe neovascularization [168]. This occurs as VEGF induces the expression of pro-inflammatory mediators. These molecules, particularly ICAM-1, VCAM-1, and VEGF, play a role in disruption of the vascularization of the retina, leading to the formation of microaneurysms and retinal leakage [169].

Understanding the genetic basis of DR is crucial for improving early detection and developing more effective treatments for individuals with DM. Research on genes such as VEGF has led to the development of anti-VEGF therapies, that treat the disease in its late stage, when there is significant damage and was previously considered untreatable. Leading anti-VEGF drugs, including ranibizumab, and aflibercept, have revolutionized the management of DR patients [169]. Additionally, the creation of a genome-wide polygenic score could help identify individuals with a high susceptibility to DR, enabling earlier intervention and more personalized care [165]. Genetics play a pivotal role in the incidence, progression, heritability, and underlying mechanisms of DR. A number of genes have been linked to the disease, contributing to its development and progression. These include genes involved in metabolic and vascular regulation, such as AKR1B1, VEGFA, AGER, EPO, and NOS3 [170]. Figure 3 shows different genes involved in diabetes. The genetic research on these genes has also been instrumental in the development of anti-VEGF treatments, which specifically target ocular neovascularization, a hallmark of advanced DR, and have been proven effective in halting disease progression. As personalized medicine and gene-targeted therapies continue to evolve, they hold great promise for better managing and potentially preventing this debilitating diabetic complication.