Risk factors of T2D

Almost all populations share same risk factors for the development of type 2 diabetes. These risk factors are broadly categorized as non-modifiable risk factors and modifiable risk factors. Age, gender and heredity are non-modifiable risk factors. Modifiable risk factors include obesity, diet, physical inactivity, smoking, alcohol consumption, psychological stress and depression (Zimmet 2011). In addition, low birth weight is associated with T2D (Vaag et al. 2012) and those persons who develop any impairment in glucose metabolism, such as gestational diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) are at a very high risk of developing T2D in future (Nathan et al. 2007).

Numerous studies have found that the risk of diabetes increases with age. The majority of people with diabetes in developed countries are more than 64 years old, whereas in the developing countries most of the patients are between 45 to 64 years of age. A study estimating the global prevalence of diabetes found that the prevalence of T2D is higher in men than in women (Wild et al. 2004). A Swedish study found that men tend to have T2D at a lower BMI and 3-4 years earlier than women. Unhealthy lifestyles and tendency of developing abdominal obesity, partly explains this gender difference (Wandell & Carlsson 2014).

Heredity is related to the development of T2D (Poulsen et al. 1999). It is established earlier that family history of T2D increases the risk of T2D. The increased risk with the positive family history is around 2.4-fold (Wada et al. 2006, Valdez et al. 2007). Association of genetic variation with diabetes has been well established and various susceptible genes that contribute to the development of diabetes have been identified. Gene-environment interaction is found to modulate the risk of T2D (Franks 2011). This is seen as environment induced chemical modifications of the genome, which is known as epigenetic modification. Gene expression is found to be regulated by the influence of epigenetic modifications, DNA methylation and histone modifications, so any alteration in these processes is believed to have influence on phenotype transmission and the development of T2D (Ling & Groop 2009). Epigenetic modifications are found to be associated with exposure to heavy metals, smoking, folate deficiency and methionine deficiency during

embryogenesis and thus suspected to influence the development of T2D in later life (Dayeh et al.

2014).

Obesity is one of the most important modifiable factors related to the risk of T2D. Researchers have found that unhealthy lifestyles and obesity contribute most to the increase in the prevalence of T2D. Studies have found a parallel increase of obesity and the prevalence of T2D in the societies (Berghofer et al. 2008, Hu 2011, Hill et al. 2013). After the age of 18, weight gain raises the risk of T2D for both sexes approximately by 25% for an additional unit of BMI over 22 kg/m² (Colditz et al. 1990, Chan et al. 1994). A 13-year follow-up study conducted among 27270 US male health professionals examined the relationship of abdominal adiposity and general obesity with the risk of T2D. The study concluded that both overall obesity and central obesity are strongly associated with T2D (Wang et al. 2005). Another study conducted among female nurses to observe the association between diet, lifestyle, and the risk of T2D found that, overweight and obesity were the most important predictors of T2D (Hu et al. 2001).

According to world health organization (WHO), every 1 in 4 adults around the world are not physically active enough which may be a major risk factor for non-communicable diseases (NCDs) such as diabetes (WHO 2016b). A Chinese study investigated the relationship between physical activity, smoking and alcohol consumption with the incidence of T2D among 51464 middle-aged and elderly men. They found that physical activity and moderate alcohol intake are inversely related to the risk of T2D (Shi et al. 2013). It is also observed in many studies that physical inactivity increases the risk of T2D (Hu et al. 2004, Waller et al. 2010).

Western dietary pattern, including high fat and sugar intake are found to increase the risk of diabetes. A prospective cohort study with 12 years follow up was conducted among 42504 male health professionals, to assess the role of major dietary patterns with the risk of T2D. The study found that the western dietary pattern was connected with a considerably elevated risk for the development of T2D (Van Dam et al. 2002). A study conducted among 4304 Finnish men and women aged between 40 to 69 years to observe the association between dietary patterns and the incidence of T2D found that the food rich in butter, potatoes, red meat, and whole milk is associated with a higher risk of T2D (Montonen et al. 2005). Intake of saturated fat or trans fatty acids has been linked with the risk of T2D in several studies (Van Dam et al. 2002). A prospective cohort

study conducted in USA among 69554 women aged between 38 to 63 years to examine the association between dietary patterns and risk of T2D found that higher intake of processed meats was associated with increased risk of T2D (Fung et al. 2004). Other important macronutrients that play vital role in the development of diabetes are carbohydrates. Quality of carbohydrates has been found to be associated with the risk of diabetes (AlEssa et al. 2015). A study in USA found that the diet with high glycemic load increases the risk of T2D (Hu 2011).

Cigarette smoking is found to be an independent risk factor for the development of T2D (Foy et al.

2005, Patja et al. 2005, Willi et al. 2007). A prospective study showed a strong association of smoking with the risk of T2D, even after controlling for age and other major risk factors (Patja et al. 2005). A systemic review and meta-analysis reported that, active smoking is associated with an increased risk of T2D (Willi et al. 2007). It is observed that the risk of developing T2D in smokers is 45% higher than in nonsmokers (Hu 2011). Not only active, but also passive smoking is found to increase the risk of T2D (Hayashino et al. 2008).

Psychosocial stress is also found to be associated with the risk of developing T2D (Eriksson et al.

2008, Mantyselka et al. 2011). A cohort study of US men and women found a modest association between depressive symptoms and incidence of T2D (Golden et al. 2008).

A substantial number of women have gestational diabetes during their pregnancy. Subsequently, gestational diabetes inclines women to the development of T2D (Kaaja et al. 1996, Baptiste et al.

2009). It is observed that women with GDM and their offspring, have an increased risk for the development of metabolic syndrome and T2D after delivery (Kaaja & Ronnemaa 2008). A study in Iran examined the risk factors and incidence of abnormal glucose level and metabolic syndrome (MetS) in women with a history of GDM. The study found that within 1 to 6 years after delivery 32.7% women developed T2D, 10% had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) and 20% had developed Metabolic syndrome (Valizadeh et al. 2015).

Intrauterine growth retardation and low birth weight (< 2.5 kg) are connected with the development of T2D in offspring (Wei et al. 2003, Whincup et al. 2008). A systematic review on the association of birth weight and risk of T2D reported that the birth weight is inversely associated with the risk of T2D (Whincup et al. 2008). Two genes among the 45 known T2D susceptible genes were found to be associated with low birthweight (Vaag et al. 2012). It is also observed that there is an

association between preterm birth and risk of T2D (Kajantie et al. 2010). A systematic review and meta-analysis was conducted to assess the relationship between preterm birth and both types of diabetes (T1D and T2D). The study found that, preterm birth is a significant and independent risk factor for both T1D and T2D (Li et al. 2014).