📘 Risk factors and causes of type 2 diabetes

Major non-modifiable risk factors include positive family history (3X with one affected parent, 5-6X for both), age over 45 years (incidence doubles with each decade), high-risk ethnicity (South Asians, Africans, Hispanics, Native Americans), history of gestational diabetes (risk reaches 50% long-term) and polycystic ovary syndrome (3X) [1]. Known genetic modifications explain only 20% of susceptibility, with TCF7L2 conferring the greatest individual risk [2].

The main modifiable factors are abdominal obesity (waist circumference over 102 cm in men and 88 cm in women => 5X), sedentary lifestyle (less than 150 minutes of moderate-intensity physical activity per week => 2X) and diet rich in refined carbohydrates and saturated fats [3]. The main predictive biochemical markers are prediabetes (10% annual progression to diabetes), triglycerides above 250 mg/dl (2.8 mmol/L) and HDL below 35 mg/dl (0.9 mmol/L) [1].

Obesity, especially visceral distribution of adipose tissue, gradually increases resistance to insulin action [4]. This is due to the release from adipose tissue of free fatty acids, which when reaching muscle and liver interfere with insulin signaling through accumulation of toxic lipid metabolites (e.g. ceramides, diacylglycerol). Hypertrophied (swollen) adipocytes secrete an altered profile of adipokines, creating an environment of low-grade chronic inflammation, which further disturbs glucose metabolism [5].

Diabetes risk increases with BMI. Generally, each extra kg increases risk by 5%, with wide individual variations [5]. Paradoxically, 10% of type 2 patients are normal weight, but have increased visceral adiposity detectable by DEXA or MRI. Some of them actually have type 1 diabetes, LADA form. Loss of 10% of weight significantly improves insulin sensitivity, and sustained loss of over 15 kg can induce remission in most recently diagnosed cases [6]. This is achieved through amelioration of lipotoxicity and recovery of beta cell function.

Type 2 diabetes has a strong hereditary component, with a 50% risk in twins (one already affected), concordance in monozygotic twins reaching 80% [7]. Lifetime risk is 40% with one affected parent (higher if it's the mother), 70% with both parents with diabetes and approximately 15% with an affected sibling (without parents). Genetic transmission is complex, with over 400 common genetic variants identified, but which explain only 20% of susceptibility, the rest being rare variants with large effect or gene-environment interactions still undiscovered [1].

Familial aggregation reflects not only common genes but also common environment, with similar eating habits, physical activity level, socioeconomic status and access to medical services. Epigenetics also plays an important role. Intrauterine exposure to maternal hyperglycemia programs fetal metabolism, increasing diabetes risk by 30% [1]. After birth, epigenetic modifications induced by diet and lifestyle can be transmitted to descendants. Screening of families with an affected member identifies the presence of prediabetes in up to half of first-degree relatives. This allows preventive intervention on lifestyle, which can reduce progression to diabetes by 58% [8].

Sedentary lifestyle, defined as less than 5000 steps daily or over eight hours of sitting, doubles diabetes risk, independent of physical activity performed in the rest of the time [9]. The main mechanisms would be decreased metabolically active muscle mass, reduced mitochondrial density and down-regulation of glucose transporters in muscle. Each additional hour spent watching television increases diabetes risk by 10% [20], and replacing 30 minutes of sedentary behavior with light walking reduces risk by at least 10% [9].

Physical inactivity significantly alters the body's metabolism. After just three days of immobilization insulin sensitivity decreases by 30%, and after two weeks you can already develop glucose intolerance (prediabetes) [3]. Muscle contraction activates insulin-independent pathways of glucose uptake, which persist subsequently 1-2 days, thus explaining why moderate-intensity physical exercise reduces diabetes incidence. Interrupting sedentary behavior every 30 minutes with three minutes of light activity improves glycemic control especially after meals [3].

Aging brings increased diabetes risk due to inevitable physiological processes, such as muscle mass decline by 1% annually after 30 years, progressive mitochondrial dysfunction and accumulation of senescent cells that secrete pro-inflammatory factors [10]. Beta cell function decreases by ~0.5% annually after 20 years.

Diabetes prevalence increases rapidly with age, being under 1% at 20 years, 5% at 40 years, 15% at 60 years and over 25% at 80 years [10]. Diabetes incidence has a peak between 65-74 years, when physiological decline converges with accumulation of risk factors. Diabetes in the elderly has as particularities an insidious onset, often masked by other morbidities, increased risk of hypoglycemia and greater risk of complications. Paradoxically, diabetes with onset after 75 years has better prognosis and can be managed with more relaxed glycemic targets (HbA1c 7.5-8%), prioritizing quality of life and avoiding hypoglycemia over strict control [10].

Ethnic differences in type 2 diabetes are a reality [12]. Compared to the Caucasian population, risk is double in African Americans, 2.5X in Hispanics, 3X in South Asians and Native Americans, reaching extreme prevalence, of 50%, in Pima Indians (USA). Asians present increased diabetes risk at BMI 5 kg/m² lower and age 10 years younger. They additionally have a distinct phenotype, with more visceral adiposity, more severe beta-secretory deficit and faster progression to insulin treatment [11].

Differences between various ethnicities reflect complex interaction between genetic predisposition, evolutionary adaptations (thrifty genes historically advantageous become disadvantageous in modern environment), epigenetic factors (e.g. fetal programming through maternal malnutrition followed by postnatal caloric excess) and socioeconomic determinants (unequal access to healthy food, medical services and education) [1]. Treatment response also varies between ethnicities. Asians respond better to DPP-4 inhibitors, and Native Americans have increased risk of diabetic chronic kidney disease, requiring intensified screening for this [11].

Ultra-processed foods, rich in added sugars, trans fats and sodium increase diabetes risk by at least 10% for each 10% increase in caloric intake from this category [12]. The explanation consists in high glycemic index leading to chronic hyperinsulinemia, high caloric density promoting overeating and additives that disturb the intestinal microbiome. Sugary drinks (including 100% natural ones) increase diabetes risk by 25% per daily serving, through massive fructose intake [13]. Fructose induces increased hepatic lipid production, with their local deposition and consequently, insulin resistance at hepatic level.

Processed red meat (bacon, salami, sausages) increases diabetes risk by 50% per 50g daily through intake of heme iron, nitrates/nitrites and advanced glycation products, which induce oxidative stress and inflammation [12]. Refined cereals and white rice (over 5 servings weekly) double risk compared to whole grains through loss of fibers and B vitamins. Industrial trans fats (margarine, fast-food fried foods) increase risk by 40%, even at moderate consumption [14]. At the opposite pole, Mediterranean diet or DASH diet reduce diabetes incidence by 20-23% [22].

Chronic psychosocial stress activates the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, increasing cortisol and catecholamines [15]. These hormones induce insulin resistance through stimulation of hepatic glucose production, inhibition of muscle glucose uptake, release of free fatty acids from adipose tissue and redistribution of adiposity towards visceral pattern (dangerous) [15]. Chronically elevated cortisol is associated with doubling of diabetes risk.

Behavioral adaptation mechanisms can amplify diabetes risk. Chronic stress leads to emotional eating, with preference for calorie-dense foods ("comfort foods"), sedentary behavior through fatigue and lack of motivation, insufficient or fragmented sleep (alters glucose metabolism) and reduced compliance with healthy lifestyle recommendations [14]. Occupational stress increases diabetes incidence, and depression also doubles diabetes risk. Interestingly, diabetes onset doubles the risk of subsequent depression appearance (the effect seems bidirectional) [15]. Stress reduction interventions (e.g. mindfulness) improve glycemic control by 0.5% on HbA1c, thus demonstrating the therapeutic potential of stress management.

Smoking increases type 2 diabetes risk by 40-60% in active smokers, reaching doubling in heavy smokers (over 25 cigarettes/day), and increases it by 14-20% in former smokers [16]. The effect is dose-proportional. Nicotine induces resistance to insulin action through sympathetic activation and release of free fatty acids from adipose tissue, carbon monoxide induces mild chronic tissue hypoxia, and cadmium and polycyclic hydrocarbons induce oxidative stress at pancreatic level [17]. Smoking cessation can initially temporarily increase diabetes risk through weight gain, but long-term benefit exceeds this transient risk [16].

Alcohol has a U-shaped relationship with diabetes [18]. It appears that moderate consumption (maximum one unit daily) reduces diabetes risk through improvement of insulin sensitivity and increase of adiponectin, but excessive consumption (over two units daily or much at once) increases risk through chronic pancreatitis, hepatic steatosis and malnutrition. Beer and sweet alcoholic drinks confer greater risk through added carbohydrates. Red wine appears protective through polyphenols [21]. Alcohol cessation in former heavy consumers gradually reduces diabetes risk, but it will remain higher compared to general population for the rest of their lives. Mediterranean consumption pattern (constant, very small) slightly decreases alcohol-associated risk compared to Nordic pattern (episodic, excessive) [18].

Glucocorticoids are the most diabetogenic, slightly raising blood glucose in two-thirds of patients and inducing diabetes in 20% of them [19]. The main mechanisms through which glucocorticoids raise blood glucose include stimulation of hepatic glucose production, inhibition of insulin secretion and action and redistribution of fat towards Cushingoid pattern (on trunk and neck). Diabetes risk increases with dose (from 7.5 mg prednisolone or equivalent) and duration (from 3 months). Glucocorticoid-induced diabetes may persist after their discontinuation in approximately one quarter of cases [19]. Statins slightly increase diabetes risk through reduction of insulin secretion and muscle glucose uptake, but cardiovascular benefits are so great that their uninterrupted administration is very useful [19].

Atypical antipsychotics (olanzapine, clozapine, quetiapine) increase risk three times through weight gain (average 10 kg) and direct beta cytotoxic effect [19]. Thiazide diuretics in high doses (over 25 mg hydrochlorothiazide) increase risk by 30% through potassium loss. Non-selective beta-blockers mask hypoglycemia and slightly reduce insulin sensitivity. Protease inhibitors (HIV treatment), tacrolimus (post-transplant medication) and nicotinic acid in pharmacological doses are other classes with associated diabetes risk requiring glycemic monitoring at initiation and possibly dose adjustments [19].