Version May 2024
INTRODUCTION — Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and relative impairment in insulin secretion. Its pathogenesis is only partially understood, but is heterogeneous and both genetic factors affecting insulin release and responsiveness and environmental factors, such as obesity, are important.
The prevalence of and risk factors for type 2 diabetes will be reviewed here. The pathogenesis, including genetic susceptibility, and the diagnostic criteria for diabetes are discussed elsewhere. (See "Pathogenesis of type 2 diabetes mellitus" and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
PREVALENCE — Diabetes is estimated to affect approximately 530 million adults worldwide, with a global prevalence of 10.5 percent among adults aged 20 to 79 years [1,2]. Type 2 diabetes represents approximately 98 percent of global diabetes diagnoses, although this proportion varies widely among countries [3]. In an analysis of data from the National Health Interview Survey (2016 and 2017), the prevalence of diagnosed type 2 diabetes among adults in the United States was 8.5 percent [4]. Other national databases, such as the Center for Disease Control and Prevention Diabetes Surveillance System, reported in 2022 a prevalence of diagnosed diabetes of approximately 11.3 percent of adults (37.3 million people; 28.7 million with diagnosed diabetes, an estimated 8.5 million undiagnosed, and 95 percent of whom have type 2 diabetes) [5,6]. Given the marked increase in childhood obesity, there is concern that the prevalence of diabetes will continue to increase substantially. Global data appear to substantiate this concern as the worldwide incidence rate of type 2 diabetes among adolescents and young adults (aged 15 to 39 years) rose from 117 to 183 per 100,000 population between 1990 and 2019 [7]. (See "Definition, epidemiology, and etiology of obesity in children and adolescents", section on 'Epidemiology'.)
The prevalence of diabetes is higher in certain populations [8,9]. As examples:
●Using data from a national survey for people aged 20 years or older, the prevalence of diagnosed type 2 diabetes in the United States (2018) was 7.5 percent in non-Hispanic White Americans, 9.2 percent in non-Hispanic Asian Americans, 12.5 percent in Hispanic Americans, 11.7 percent in non-Hispanic Black Americans, and 14.7 percent in Native Americans/Alaska Natives [8].
●In an analysis of data from the 2011 to 2014 Behavioral Risk Factor Surveillance System, the prevalence of self-reported diabetes was higher among Asian persons (9.9 percent) and Native Hawaiian or other Pacific Islander individuals (14.3 percent) than in White individuals (8 percent) [10].
●Outside the United States, type 2 diabetes is most prevalent in Polynesia and other Pacific islands (approximately 25 percent) with similarly high rates in the Middle East and South Asia (Kuwait and Pakistan, in particular) [11,12]. In China, the most populous country in the world, an estimated 13 percent of the adult population has diabetes, with approximately one-half undiagnosed [1,13].
ABNORMAL GLUCOSE METABOLISM — Abnormal glucose metabolism can be documented years before the onset of overt diabetes. Although the risk of developing type 2 diabetes follows a continuum across all levels of abnormal glycemia, when classified categorically, the individuals demonstrably at highest risk include those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or a glycated hemoglobin (A1C) level of 5.7 to 6.4 percent (39 to 46 mmol/mol) (table 1) [14,15]. The criteria for defining diabetes and impaired glucose regulation are reviewed in greater detail separately. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
Although the natural history of IFG and IGT is variable, approximately 25 percent of subjects with either will progress to diabetes over three to five years [14]. Individuals with isolated IFG have hepatic insulin resistance, whereas those with isolated IGT predominantly have muscle insulin resistance and normal or slightly reduced hepatic insulin sensitivity [14]. Individuals with abnormalities in both IFG and IGT have hepatic and muscle insulin resistance, which confers an even higher risk of progressing to diabetes compared with having only one abnormality. Individuals with additional diabetes clinical risk factors, including obesity and family history, are also more likely to develop diabetes. (See 'Clinical risk factors' below.)
Impaired glucose tolerance — The term IGT describes subjects who, during an oral glucose tolerance test (OGTT), have blood glucose values between those in normal subjects and those in patients with overt diabetes (140 to 199 mg/dL [7.8 to 11 mmol/L]) (table 1). The rate of progression from IGT to overt diabetes varies among different populations. In six prospective studies, for example, the incidence rates of type 2 diabetes among patients with IGT ranged from 36 to 87 per 1000 person-years [16]. The rates were higher among Hispanic, Pima, and Nauruan people than among White people. Estimates of obesity (including body mass index [BMI], waist-to-hip ratio, and waist circumference) were positively associated with the incidence of type 2 diabetes. In contrast, sex and family history of diabetes were not related to the rate of progression in most studies.
Subjects who have only IGT generally do not develop clinically significant microvascular complications of diabetes such as retinopathy and nephropathy [17]. They are, however, at substantially increased risk (when compared with matched subjects with normal glucose tolerance) for developing macrovascular disease (such as coronary artery disease). (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'A1C, FPG, and OGTT as predictors of cardiovascular risk'.)
Impaired fasting glucose — IFG is defined as a fasting blood sugar of 100 to 125 mg/dL (5.6 to 7 mmol/L) (table 1). IFG increases the risk of developing type 2 diabetes [18].
Although fasting glucose levels less than 100 mg/mL (5.55 mmol/L) are considered normal by the 2003 criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, subjects with fasting glucose values in the higher quintiles of normal range are at increased risk for developing type 2 diabetes. In a prospective cohort study (over 46,500 subjects followed for a mean of 81 months), the overall incidence of diabetes in those with normal fasting glucose was low (4 percent) [19]. However, there was an increased risk of diabetes incidence in those with fasting plasma glucose of 95 to 99 mg/dL (5.3 to 5.5 mmol/L) compared with <85 mg/dL (4.7 mmol/L) (hazard ratio [HR] 2.33, 95% CI 1.95-2.79) [19].
Similar results were reported in a study of 13,163 healthy male Israeli army recruits [20]. There was a progressive increased risk of diabetes for those with fasting plasma glucose levels greater than 87 mg/dL (4.83 mmol/L) compared with those in the lowest quintile with fasting glucose levels less than 81 mg/dL (4.5 mmol/L). The risk of diabetes was even greater (HR 8.23, 95% CI 3.6-19.0) in those with high normal glucose levels (91 to 99 mg/dL) in combination with elevated serum triglycerides (greater than 150 mg/dL) and elevated BMI (>30 kg/m2), and may indicate subjects for whom preventive measures would be most effective.
Glycated hemoglobin — A1C measurements are also helpful in predicting diabetes (table 1) [15,21-23]. In a systematic review of 16 prospective studies examining the relationship between A1C and future incidence of diabetes mellitus, risk of diabetes increased sharply with A1C across the range of 5 to 6.5 percent (31 to 48 mmol/mol) [24]. For persons with A1C between 5.5 to 6.0 percent and 6.0 to 6.5 percent, the projected five-year risk of diabetes ranged from 9 to 25 and 25 to 50 percent, respectively. In the largest prospective cohort study of 26,563 women without diagnosed diabetes followed for 10 years, baseline A1C, at levels considered to be within the normal range, was an independent predictor of future type 2 diabetes [22]. In those individuals with baseline A1C in the highest quintile (A1C >5.22 percent [34 mmol/mol]), the adjusted relative risk (RR) of diabetes was 8.2, 95% CI 6.0-11.1.
The international standardization of the A1C assay and biological and patient-specific factors (eg, low red cell turnover in iron deficiency anemia, rapid red cell turnover in patients treated with erythropoietin, hemoglobinopathies) that may cause misleading results are reviewed in detail elsewhere. (See "Measurements of chronic glycemia in diabetes mellitus", section on 'Glycated hemoglobin (A1C)'.)
CLINICAL RISK FACTORS
Family history — Compared with individuals without a family history of type 2 diabetes, individuals with a family history in any first degree relative have a two to three-fold increased risk of developing diabetes [25,26]. The risk of type 2 diabetes is higher (five- to sixfold) in those with both a maternal and paternal history of type 2 diabetes [25,26]. The risk is likely mediated through genetic, anthropometric (body mass index [BMI], waist circumference), and lifestyle (diet, physical activity, smoking) factors. The genetics of type 2 diabetes is reviewed separately. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Genetic susceptibility'.)
Ethnicity — Data from the prospective Nurses' Health Study (NHS) collected over 20 years found that the risk for developing diabetes in women, corrected for BMI, was increased for Asian, Hispanic, and Black Americans (relative risk [RR] 2.26, 1.86, and 1.34, respectively) compared with White Americans [27]. In an analysis of 2011 to 2012 data from the National Health and Nutrition Examination Survey (NHANES), the age-standardized prevalence of total diabetes (using the A1C, fasting plasma glucose, or two-hour oral glucose tolerance test [OGTT] definition) was higher among non-Hispanic Black, non-Hispanic Asian, and Hispanic individuals (21.8, 20.6, and 22.6 percent, respectively) than among non-Hispanic White individuals (11.3 percent) [28].
The ethnic disparity in diabetes incidence may be related in part to modifiable risk factors. As an example, in a retrospective analysis of a cohort study of 4251 Black and White young adults without diabetes at baseline (median follow-up 30 years), the racial disparity in diabetes risk was primarily associated with biological risk factors (eg, BMI, waist circumference, blood pressure) but also with neighborhood, psychosocial, socioeconomic, and behavioral factors during young adulthood [29].
Obesity — The risk of impaired glucose tolerance (IGT) or type 2 diabetes rises with increasing body weight (figure 1) [30-34]. In an analysis of five NHANES spanning over thirty years, increase in BMI over time was the most important of the three covariates studied (age, race/ethnicity, BMI) for the increase in diabetes prevalence, accounting for approximately 50 percent of the increase in diabetes prevalence in males and 100 percent in females [35]. In addition, the NHS demonstrated an approximately 100-fold increased risk of incident diabetes over 14 years in nurses whose baseline BMI was >35 kg/m2 compared with those with BMI <22 kg/m2 [36].
The risk of diabetes associated with body weight appears to be modified by age. In a prospective cohort study of over 4000 males and females >65 years of age, the risk of diabetes associated with BMI in the highest tertile was greater in subjects less than 75 years of age compared with those 75 years and older (hazard ratio [HR] 4.0 versus 1.9) [37].
Obesity acts at least in part by inducing resistance to insulin-mediated peripheral glucose uptake, which is an important component of type 2 diabetes, likely unmasking the part of the population with limited insulin secretion [38-40]. Reversal of obesity decreases the risk of developing type 2 diabetes and, in patients with established disease, improves glycemic management and can lead to remission. (See "Prevention of type 2 diabetes mellitus", section on 'Lifestyle intervention' and "Nutritional considerations in type 2 diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Weight management'.)
Fat distribution — The distribution of excess adipose tissue is another important determinant of the risk of insulin resistance and type 2 diabetes. The degree of insulin resistance and the incidence of type 2 diabetes are highest in those subjects with central or abdominal obesity, as measured by waist circumference or waist-to-hip circumference ratio (figure 2) [34,37,41,42]. Intra-abdominal (visceral) fat rather than subcutaneous or retroperitoneal fat appears to be of primary importance in this regard. This 'male' type obesity is different from the typical 'female' type, which primarily affects the gluteal and femoral regions and is not as likely to be associated with glucose intolerance or cardiovascular disease. Why the pattern of fat distribution is important and the relative roles of genetic and environmental factors in its development are not known [41,42]. (See "Obesity in adults: Prevalence, screening, and evaluation", section on 'Waist circumference' and "Obesity: Genetic contribution and pathophysiology", section on 'Body fat distribution'.)
Birth and childhood weight — There is an apparent U-shaped relationship between birth weight and risk of type 2 diabetes. This issue is discussed in detail elsewhere. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Role of intrauterine development'.)
Above-average childhood BMI also is a risk factor for diabetes, independent of birth weight [43,44]. Remission of overweight or obesity before puberty appears to negate the risk. In a population-based study from Denmark, men who had been overweight at seven years of age, but who were normal weight by 13 years of age (and remained normal weight), had a similar risk of developing type 2 diabetes in adulthood as men who had never been overweight as children or in early adulthood [44]. Remission of overweight after age 13 years but before early adulthood (17 to 26 years) was associated with increased risk, but risk was lower than that among men who were overweight at every age. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Risk factors'.)
Lifestyle factors — Although insulin resistance and, in particular, impaired insulin secretion in type 2 diabetes have a substantial genetic component, they can also be influenced, both positively and negatively, by behavioral factors, such as physical activity, diet, smoking, alcohol consumption, body weight, and sleep duration. Improving these lifestyle factors can reduce the risk of diabetes mellitus [45].
Exercise — A sedentary lifestyle lowers energy expenditure, promotes weight gain, and increases the risk of type 2 diabetes [46]. Among sedentary behaviors, prolonged television watching is consistently associated with the development of obesity and diabetes [47].
Physical inactivity, even without weight gain, appears to increase the risk of type 2 diabetes. In a cohort study of Swedish men, low aerobic capacity and muscle strength at 18 years of age was associated with an increased risk of type 2 diabetes 25 years later, even among men with normal BMI [48].
Physical activity of moderate intensity reduces the incidence of new cases of type 2 diabetes, regardless of the presence or absence of IGT. (See "Prevention of type 2 diabetes mellitus", section on 'Exercise'.)
Smoking — Several large prospective studies have raised the possibility that cigarette smoking increases the risk of type 2 diabetes [49-57]. In a meta-analysis of 25 prospective cohort studies, current smokers had an increased risk of developing type 2 diabetes compared with nonsmokers (pooled adjusted RR 1.4, 95% CI 1.3-1.6) [58]. The risk appears to be graded, with increasing risk as the number of cigarettes smoked per day and pack-year history rises. In one study, the risk was also increased for non-smokers who have been exposed to secondhand smoke, compared with those who have not been exposed [55].
While a definitive causal association has not been established, a relationship between cigarette smoking and diabetes mellitus is biologically possible based upon a number of observations:
●Smoking increases the blood glucose concentration after an oral glucose challenge [59].
●Smoking may impair insulin sensitivity [60].
●Cigarette smoking has been linked to increased abdominal fat distribution and greater waist-to-hip ratio that, as mentioned above, may have an impact upon glucose tolerance [61,62].
The effect of smoking cessation on diabetes risk is variable and may depend upon individual patient factors. Smoking cessation may reduce diabetes risk by reducing systemic inflammation. On the other hand, smoking cessation is often associated with weight gain, which will increase the risk of diabetes. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Role of diet, obesity, and inflammation'.)
In an analysis of three cohort studies in the United States (mean follow-up 19.6 years), smoking cessation was associated with an increased risk of type 2 diabetes compared with continuing to smoke (HR 1.22, 95% CI 1.12-1.32) [63]. The risk peaked five to seven years after cessation and did not drop to that among individuals who had never smoked until 30 years after quitting. The increased risk of diabetes was directly proportional to weight gain. Nevertheless, quitters had significantly lower rates of overall and cardiovascular mortality compared with current smokers, irrespective of weight gain.
Similar findings were noted in other cohort studies [64,65]. The increased risk of type 2 diabetes after smoking cessation does not outweigh the overall benefits of giving up smoking. Smoking cessation efforts should be accompanied by additional lifestyle interventions, such as increasing physical activity and reducing weight.
Sleep duration — Sleep quantity, quality, and chronotype may be associated with development of type 2 diabetes mellitus, but causality is uncertain [66]. In a meta-analysis of 10 prospective observational studies, compared with approximately eight hours/day of sleep, short (≤5 to 6 hours/day) and long (>8 to 9 hours/day) duration of sleep were significantly associated with an increased risk of type 2 diabetes (RR 1.28 and 1.48, respectively) [67]. Difficulty initiating and maintaining sleep were also associated with an increased incidence. In a subsequent report from the European Prospective Investigation into Cancer and Nutrition (EPIC) study of more than 23,000 participants across Europe, short sleep duration (<6 hours/day compared with 7 to <8 hours/day) was associated with an increased risk of chronic disease, including type 2 diabetes (6.7 cases versus 4.2 cases per 1000 person-years, HR 1.44, 95% CI 1.10-1.89) [68]. However, this association lost statistical significance after adjusting for BMI and waist-to-hip ratio (HR 1.08, 95% CI 0.82-1.42).
Very limited data support a causal relationship between short sleep duration and development of diabetes. In a crossover study in 38 women aged 20 to 75 years with baseline sleep duration of seven to nine hours nightly, the effect of reduced sleep duration on insulin sensitivity was examined [69]. Participants underwent sequential, six-week phases of sleep maintenance (usual sleep time maintained) and sleep restriction (sleep time reduced by 1.5 hours nightly). Sleep restriction led to increases in fasting insulin concentration and homeostasis model assessment of insulin resistance (HOMA-IR), indicating diminished insulin sensitivity. These changes were independent of changes in adiposity and more pronounced in postmenopausal compared with premenopausal participants.
One possible mechanism whereby short sleep duration increases the risk of diabetes is through its effect on melatonin secretion. Sleep disruption is associated with decreased melatonin secretion, and in an observational study, lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes [70].
DIETARY PATTERNS — Dietary patterns affect the risk of type 2 diabetes mellitus. Consumption of red meat, processed meat, and sugar sweetened beverages is associated with an increased risk of diabetes, whereas consumption of a diet high in fruits, vegetables, nuts, whole grains, and olive oil is associated with a reduced risk [71-74]. A healthy cardiac diet (high in cereal fiber and polyunsaturated fat, and low in trans fat and glycemic load) had more impact on diabetes risk in Asian, Hispanic, and Black than among White Americans (relative risk [RR] 0.54 versus 0.77) in a 20-year prospective study [27]. It is important to recognize that most studies have used food frequency questionnaires to capture dietary patterns and that none of the food stuffs examined can be considered in isolation. For example, higher meat intake always means more saturated fat intake, relatively lower fruit and vegetable intake, and frequently, higher body mass index (BMI). Although some lifestyle and dietary factors are considered in multivariable analysis, other unmeasured lifestyle or dietary factors may account for the findings in the observational studies described below.
Increased risk
Western versus prudent diet — In a study of over 42,000 male health professionals, a western diet (characterized by high consumption of red meat, processed meat, high fat dairy products, sweets, and desserts) was associated with an increased risk of diabetes independent of BMI, physical activity, age, or family history (RR 1.6, 95% CI 1.3-1.9) [72,73]. The risk was markedly increased (RR 11.2) among subjects who ate a western diet and were obese (BMI ≥30 kg/m2 versus <25 kg m2) [72]. In contrast, men who ate a prudent diet (characterized by higher consumption of vegetables, fruit, fish, poultry, and whole grains) had a modest reduction in risk (RR 0.8, 95% CI 0.7-1.0).
Similar results have been described in women [75,76] and in European populations [77]. (See "Nutritional considerations in type 2 diabetes mellitus" and "Healthy diet in adults".)
Sugar-sweetened beverages — Sugar-sweetened beverages, in particular soft drinks, have been associated with obesity in children. Most [78-85], but not all [86], studies report an increased risk of diabetes with consumption of sugar-sweetened beverages. As examples:
●In a prospective, cohort study of adult women, higher consumption of sugar-sweetened beverages was associated with both greater weight gain and risk of type 2 diabetes [78]. After adjustment for potential confounders, women consuming one or more sugar-sweetened soft drinks per day had a higher risk of developing type 2 diabetes when compared with women who had less than one soft drink per month (RR 1.83, 95% CI 1.4-2.4).
●Similar findings were noted in a prospective study of 59,000 African American women [79]. Compared with women who consumed less than one sugar-sweetened soft drink per month, women who had two or more drinks each day had a higher risk of developing type 2 diabetes (incidence rate ratio [IRR] 1.24, 95% CI 1.06-1.45). For fruit drinks (fortified fruit drinks, Kool-Aid, and fruit juices other than orange or grapefruit), the IRR was 1.31, 95% CI 1.13-1.52. Consumption of orange or grapefruit juice and diet soft drinks did not increase risk of diabetes.
It is unclear whether the described association is due to increased caloric intake and weight gain, other lifestyle factors (smoking, exercise, other food choices), or excess consumption of refined carbohydrates, such as high-fructose corn syrup (used to sweeten beverages) [87]. In the two studies described above, women who increased their consumption of soft drinks over the study period experienced greater weight gain than women with stable consumption patterns, suggesting that the primary mechanism for increased diabetes risk is weight gain [78,79].
Vitamin D deficiency — Several prospective observational studies have shown an inverse relationship between circulating 25-hydroxyvitamin D levels and risk of type 2 diabetes. The causality of this relationship remains unclear as interventional trials have failed to demonstrate a significant benefit of vitamin D therapy on the risk of developing diabetes [88]. Obesity is also associated with low 25-hydroxyvitamin D concentrations, and a relationship between vitamin D deficiency and type 2 diabetes may be related to obesity, rather than vitamin D deficiency. This topic is reviewed in detail elsewhere. (See "Vitamin D and extraskeletal health", section on 'Diabetes'.)
Selenium — Although animal models suggest that low doses of the antioxidant selenium may improve glucose metabolism, these findings have not been demonstrated in humans [89]. In an exploratory analysis of the Nutritional Prevention of Cancer trial, 1202 individuals who did not have diabetes at baseline and who were randomly assigned to selenium (200 mcg daily) or placebo were evaluated for incident type 2 diabetes [90]. After 7.7 years of follow-up, the cumulative incidence of diabetes was higher in those taking selenium than placebo (incidence 12.6 versus 8.4 cases per 1000 person-years, respectively, hazard ratio [HR] 1.55, 95% CI 1.03-2.33). Thus, selenium supplementation does not confer benefit and may increase the risk of type 2 diabetes. Potential mechanisms for this association are unknown, but may be related to the effects of selenium on glucagon (stimulatory) and insulin-like growth factor 1 (IGF-1) (inhibitory) [91].
Other
●Iron intake – An association between serum ferritin levels [92,93], high iron intake [94], and type 2 diabetes has been reported, but the association is not well understood. Low iron diets are not recommended.
●Chromium deficiency – Chromium deficiency is generally limited to hospitalized patients with increased catabolism and metabolic demands in the setting of malnutrition. Other patients at risk for chromium deficiency include patients with short bowel syndrome, burns, traumatic injuries, or those on parenteral nutrition without appropriate trace mineral supplementation. An association has been suggested between low chromium levels and impaired glucose tolerance (IGT) and unfavorable lipid profiles. Randomized trials on this subject are of fair quality and have conflicting results, but generally suggest that chromium supplementation improved glycemia among patients with diabetes, but not among those with normal glucose tolerance [95]. (See "Overview of dietary trace elements", section on 'Chromium'.)
Reduced risk
Mediterranean diet — In prospective cohort study of over 13,000 Spanish graduate students without diabetes at baseline, high versus low adherence to a Mediterranean diet (high in fruits, vegetables, nuts, whole grains, and olive oil) was associated with a lower risk of diabetes over 4.4 years (median) of observation [96]. Similar findings were noted in a large European case-cohort study [97]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Diet'.)
Dairy products — There is an inverse association between consumption of dairy products and the metabolic syndrome (obesity, glucose intolerance, hypertension, dyslipidemia) in overweight, but not lean adults. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, overweight subjects with the highest consumption of dairy products (≥35 per week) had a significantly lower risk of the metabolic syndrome as compared with those with the lowest dairy consumption (<10 per week, adjusted odds ratio [OR] 0.3, 95% CI 0.1-0.6) [98]. In other prospective studies, low-fat, but not high-fat dairy intake, was associated with a lower risk of type 2 diabetes (independent of BMI) in men [99] and in women [100].
The beneficial effects of dairy product consumption on diabetes risk may be mediated by trans-palmitoleic acid, a fatty acid derived primarily from naturally occurring dairy and ruminant trans fats. In a subset of subjects participating in the Cardiovascular Health Study, higher plasma trans-palmitoleic acid levels were associated with lower risk for new onset diabetes [101].
Nuts — Nut and peanut butter consumption may lower the risk of type 2 diabetes in women. In a prospective cohort study of over 83,000 women, increasing nut consumption was inversely associated with the risk of type 2 diabetes (for ≥5 one-ounce servings per week compared with no nut consumption, RR 0.7, 95% CI 0.6-0.9) [102]. In addition, women consuming more than five servings of peanut butter per week had a similar reduction in risk compared with those who never/rarely ate peanut butter (RR 0.8, 95% CI 0.7-0.9).
Whole grains and cereal fiber — There appears to be an inverse association between whole grain consumption and the risk of type 2 diabetes [85,103,104]. As an example, among males and females participating in the Health Professionals Follow-up Study and the Nurses' Health Study (NHS), high brown rice intake was associated with a lower risk of type 2 diabetes (RR 0.89, 95% CI 0.81-0.97 for two or more servings per week versus less than one serving per month) [105]. In contrast, consumption of white rice was associated with a higher risk of type 2 diabetes (RR 1.17, 95% CI 1.02-1.36). A meta-analysis of prospective cohort studies showed that high intake of white rice was more strongly associated with risk of type 2 diabetes in Asian than Western populations (RR 1.55, 95% CI 1.20-2.01 versus 1.12, 95% CI 0.94-1.33, for highest versus lowest category of white rice intake) [106]. Consumption levels of white rice were much lower overall in the Western populations (112.9 versus 5.3 g/day for high and low intake groups compared with ≥750 versus <500 g/day for Asian populations). The meta-analysis was limited by significant heterogeneity in the size of the effect estimates obtained.
Some of the beneficial reduction in type 2 diabetes associated with intake of whole grains may be mediated by cereal fiber [104]. Cereal fiber is linked to a reduced risk of type 2 diabetes [107-109]. Increased insoluble fiber consumption for three days improved insulin sensitivity in a randomized cross-over study of 17 overweight subjects with normal glucose metabolism [110].
Fruit — Increased consumption of fruit has not been associated consistently with a decreased risk of developing type 2 diabetes [111,112]. The heterogeneity in the findings may be due to the differences in patient populations, study design, or even to the type of fruit consumed. In one study, greater consumption of specific fruits (blueberries, grapes, apples, bananas, and pears) was significantly associated with a reduced risk of type 2 diabetes, whereas greater consumption of strawberries, cantaloupe, peaches, and oranges was not [113]. The glycemic index of the individual fruits did not account for the differences in the associations.
Coffee and caffeinated beverages — Long-term coffee consumption may be associated with a decreased risk of type 2 diabetes [86,114-118]. In a systematic review of nine cohort studies (combined n = 193,473), compared with those with minimal coffee consumption (less than two cups per day), diabetes risk was lowest in subjects who drank greater than six cups daily (RR 0.65, 95% CI 0.54-0.78) and significantly reduced for subjects who consumed four to six cups daily (RR 0.72, 95% CI 0.62-0.83) [116]. These associations did not differ by sex, obesity, or region including the United States, Europe, and Asia. A modest inverse association was also seen for decaffeinated coffee.
A prospective study of over 88,000 women aged 26 to 46 years in the NHS found that the risk of diabetes was lower even for small amounts of daily coffee consumption [119]. RR was 0.87 (95% CI 0.73-1.03) for one cup per day, 0.58 (0.49-0.68) for two to three cups, and 0.53 (0.41-0.68) for four or more cups, compared with non-drinkers. Associations were similar for non-caffeinated and caffeinated coffee; tea consumption did not affect risk.
In contrast, in a survey of over 17,000 subjects age 40 to 65 years of age from Japan, where diabetes prevalence has increased twofold in the past two decades, participants who frequently drank green tea (six or more cups daily) were less likely to develop diabetes over a five year follow-up period (odds ratio [OR] 0.67, 95% CI 0.47-0.94) [120]. The correlation with green tea consumption was dose-related and reflected caffeine intake.
These observational data do not prove a cause-and-effect relationship, and we do not recommend increasing coffee or green tea intake as a prevention strategy.
Other
●In meta-analyses of prospective cohort studies, there was a lower risk of type 2 diabetes in both males and females with higher magnesium intake [108,121]. Sources of dietary magnesium include nuts, whole grains, and green leafy vegetables.
●Moderate alcohol intake (defined for females and males as <2 and <3 drinks per day, respectively) has also been associated with a lower risk of type 2 diabetes. (See "Overview of the risks and benefits of alcohol consumption", section on 'Diabetes mellitus'.)
ENVIRONMENTAL EXPOSURES — Epidemiologic studies have reported an increased risk of type 2 diabetes after exposure to some environmental toxins and contaminants [122-125]. As examples:
●Chronic exposure to inorganic arsenic in drinking water (adjusted odds ratio [OR] 3.58, 95% CI 1.18-10.83, for type 2 diabetes in individuals at the 80th versus the 20th percentiles for the level of total urinary arsenic) [126]. (See "Arsenic exposure and chronic poisoning".)
●Exposure to bisphenol A, a monomer used to make hard, polycarbonate plastics, and some epoxy resins (adjusted OR 1.39, 95% CI 1.21-1.60, per one standard deviation increase in urinary bisphenol A concentration) [127]. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Bisphenol A and other phenols'.)
●Chronic exposure to organophosphate and chlorinated pesticides (OR 1.17, 95% CI 0.99-1.38, for type 2 diabetes in those with the highest quartile of cumulative days of use compared with lowest quartile) [128].
MEDICATIONS — A large number of drugs can impair glucose tolerance or cause overt diabetes mellitus; they act by decreasing insulin secretion, increasing hepatic glucose production, or causing resistance to the action of insulin (table 2). This topic is reviewed elsewhere. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Drug-induced hyperglycemia'.)
MEDICAL CONDITIONS ASSOCIATED WITH INCREASED RISK
Gestational diabetes — The risk for type 2 diabetes is higher in women who have had gestational diabetes [129-132]. These women have defects in both insulin secretion and insulin action, the severity of which correlate with the future risk of diabetes [129,130]. In a meta-analysis of observational studies, the cumulative incidence of type 2 diabetes in women with and without gestational diabetes was 16 and 2 percent, respectively, by 10 years (RR 8.09, 95% CI 4.34-15.08) [132]. (See "Gestational diabetes mellitus: Glucose management and maternal prognosis", section on 'Maternal prognosis'.)
Cardiovascular disease — Heart failure and myocardial infarction (MI) appear to be associated with an increased risk of type 2 diabetes. In one study of 2616 nondiabetic patients with coronary artery disease, those with advanced heart failure (New York Heart Association [NYHA] class III) had nearly twice the risk of developing diabetes during 6 to 12 years of follow-up (17 versus 8 percent in NYHA class I patients; relative risk [RR] 1.7, 95% CI 1.1-2.6) [133]. Worsening obesity is an unlikely explanation, as weight loss is common in severe heart failure. (See "Heart failure: Clinical manifestations and diagnosis in adults".)
Similar findings were noted in a retrospective analysis of 8291 nondiabetic patients with MI [134]. During a mean observation period of three years, 12 percent developed diabetes, representing an annual incidence rate of 3.7 percent compared with 0.8 to 1.6 percent in population-based cohorts. Independent predictors of diabetes included markers of metabolic dysfunction (body mass index [BMI], hypertension, high triglycerides, low high-density lipoprotein [HDL], smoking) and medications (diuretics, beta blockers, lipid-lowering drugs).
In some studies, there has also been an association between elevated blood pressure and increased risk of developing type 2 diabetes [135,136]. As an example, in one large prospective cohort study, women with self-reported high-normal (130 to 139/85 to 89 mmHg) and elevated (≥140/90 mmHg or on antihypertensive therapy) blood pressure were at increased risk of developing diabetes compared with women with normal blood pressure (multivariate adjusted hazard ratios [HRs] 1.4 [95% CI 1.2-1.7] and 2.0 [95% CI 1.8-2.3] for high-normal and elevated blood pressure, respectively) [136]. The association persisted after adjustment for several metabolic dysfunction variables, such as BMI, hypercholesterolemia, age, exercise, smoking, and family history of diabetes. However, these results do not prove causality, and other confounders not controlled for during statistical analysis (insulin resistance or other genetic polymorphisms linking endothelial dysfunction, inflammation, and type 2 diabetes) may explain the observed association.
Hyperuricemia — Several prospective studies have found an association between higher levels of serum uric acid and an increased risk of developing type 2 diabetes [137-141]. After controlling for other diabetes risk factors (eg, BMI, alcohol consumption, smoking, physical activity) the RR was attenuated but remained significant. Proposed mechanisms for such an increase in risk include development of endothelial dysfunction, oxidative stress, and insulin resistance [87]. Although the association is plausible, these observational studies do not prove causality.
Polycystic ovary syndrome — Polycystic ovary syndrome is associated with an increased risk for type 2 diabetes, independent of BMI, particularly in women with a first degree relative with type 2 diabetes. This topic is reviewed separately. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'IGT/type 2 diabetes'.)
Metabolic syndrome — Patients with the metabolic syndrome, including those without hyperglycemia as an element of the definition, are at particularly high risk for type 2 diabetes. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Risk of type 2 diabetes'.)
OTHER
Breastfeeding — Breastfeeding has been associated with a decreased risk of maternal type 2 diabetes [142,143]. As an example, in two large cohorts from the Nurses' Health Study (NHS), with data collected prospectively in 83,585 parous women and retrospectively in 73,418, each additional year of lactation reduced the risk of diabetes in women who had been pregnant within the prior 15 years by 14 to 15 percent [142]. Risk reduction began to accrue with a minimum of six months of lactation, and longer durations of breastfeeding per pregnancy were associated with a greater benefit. In this study, the incidence of diabetes in women with a history of gestational diabetes was not affected by lactation. However, in a subsequent prospective study of women with recent gestational diabetes, breastfeeding reduced the two-year incidence of type 2 diabetes mellitus [144]. (See "Gestational diabetes mellitus: Obstetric issues and management", section on 'Breastfeeding'.)
Endogenous sex hormones — Levels of endogenous sex hormones may influence the risk of type 2 diabetes differently in males and females. A systematic review found that, after adjusting for body mass index (BMI), high testosterone levels were associated with an increased risk for type 2 diabetes in women but a decreased risk in men [145]. Decreased levels of sex hormone-binding globulin (SHBG) were associated with an increased risk for type 2 diabetes; this association was stronger in women than in men. In a subsequent study that included a genotype analysis, SHBG polymorphisms were associated with plasma levels of SHBG and were predictive of risk of type 2 diabetes in males and females [146]. Carriers of an rs6257 allele had lower plasma levels of SHBG and increased risk of type 2 diabetes, whereas carriers of an rs6259 variant allele had higher plasma levels and lower risk. Sex differences in the action of testosterone on lipolysis, and the production of cytokines such as tumor necrosis factor alpha, have been suggested.
PREDICTION MODELS — There are several diabetes-prediction models that incorporate clinical risk factors and/or metabolic factors to generate a prediction score [147]. These models vary in complexity and most have not been validated in varied populations.
Simple clinical models may be more effective in predicting diabetes than complex models [148,149]. As an example, in the Framingham Offspring Study, several models to predict incident diabetes were compared [149]. The simple clinical model included information typically available at clinic evaluations, such as age, parental history of diabetes, body mass index (BMI), blood pressure, high-density lipoprotein (HDL), triglycerides, and impaired fasting glucose (IFG). Each of the metabolic syndrome traits (elevated blood pressure and triglyceride concentrations, low HDL levels, and IFG), obesity, and parental history were highly associated with developing diabetes. Adding more complex measurements (oral glucose tolerance, insulin sensitivity, insulin resistance) did not improve the model, nor did adding a genotype score based upon the presence of a number of risk alleles confirmed to be associated with type 2 diabetes [150].
In other models, the addition of genetic data to the simple clinical model (and other clinical models) had a minimal effect on prediction of type 2 diabetes [151,152]. In one such model, genetic data were incorporated based upon low and high genetic risk groups (quintiles with the lowest and highest number of risk alleles, respectively) [151]. The improvement in prediction was too small to allow for individual risk prediction. Thus, at the current time, there is insufficient evidence to support genotyping for risk assessment in clinical practice.
The genetics of type 2 diabetes, including a discussion of the risk alleles confirmed to be associated with it, are reviewed elsewhere. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Genetic susceptibility'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Diabetes mellitus in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Type 2 diabetes (The Basics)" and "Patient education: Treatment for type 2 diabetes (The Basics)" and "Patient education: Lowering your risk of prediabetes and type 2 diabetes (The Basics)")
●Beyond the Basics topics (see "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and "Patient education: Exercise and medical care for people with type 2 diabetes (Beyond the Basics)")
SUMMARY
●Abnormal glucose metabolism – Patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or a glycated hemoglobin (A1C) level of 5.7 to 6.4 percent (39 to 46 mmol/mol) are at increased risk of developing type 2 diabetes (table 1). Patients with both IFG and IGT have hepatic and muscle insulin resistance, which confers an increased risk of progressing to diabetes compared with having only one abnormality. Although most of the high-risk groups have been defined categorically (eg, IFG or IGT), the risk for developing diabetes follows a continuum across the entire spectrum of subdiabetic glycemic values. Higher fasting or two-hour oral glucose tolerance test (OGTT) values or higher A1C values convey higher risk than lower values. (See 'Abnormal glucose metabolism' above.)
●Clinical risk factors
•Obesity – Obesity is the most important modifiable risk factor for type 2 diabetes. (See 'Obesity' above.)
•Genetic susceptibility – Genetic susceptibility is an important contributor to the risk of developing diabetes. Insulin resistance and impaired insulin secretion in type 2 diabetes have a substantial genetic component. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Genetic susceptibility'.)
•Lifestyle factors – Insulin resistance and impaired insulin secretion can also be influenced, both positively and negatively, by behavioral factors, such as physical activity, diet, smoking, alcohol consumption, body weight, and sleep duration. (See 'Lifestyle factors' above and 'Dietary patterns' above.)
●Dietary patterns – Adherence to a diet high in fruits, vegetables, nuts, whole grains, and olive oil is associated with a lower risk of type 2 diabetes. (See 'Mediterranean diet' above.)
●Medical conditions – Medical conditions associated with an increased risk of type 2 diabetes include gestational diabetes, polycystic ovary syndrome, and metabolic syndrome. (See 'Medical conditions associated with increased risk' above.)
●Prevention – Identification of individuals at risk for diabetes is important as lifestyle modification (predominantly exercise and weight loss) successfully decreases the development of diabetes. (See "Prevention of type 2 diabetes mellitus".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.
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