Abstract
Today, both type 1 and type 2 diabetes mellitus affect 33.3 million people in the United States and nearly 500 million adults worldwide, and there is concern that this number may increase steadily in the future. Previous studies have linked the development of type 2 diabetes to multiple lifestyle factors, including physical activity level and diet, and biological characteristics, such as body composition, age, and race; however, current research suggests that gender may also have an impact on one’s risk of developing type 2 diabetes. Variations in type 2 diabetes diagnosis, prevalence, and progression have been found between males and females. These variations stem from distinctions in testosterone, estrogen, and leptin hormone levels, incongruity in health practices, differences in physical size and shape, and factors that only affect those who are biologically female, such as age of menstruation or menopause and the presence of gestational diabetes or polycystic ovary syndrome. This literature review aims to summarize the current literature discussing these factors. Using the search engine PubMed, and applicable search terms such as “type 2 diabetes,” “gender,” “sex hormones,” and “diabetes and age of menarche/menopause,” we found information about diabetes risk specific to females and general risk factors that vary for both males and females. Through our investigation, we have reasons to believe that the probability of developing type 2 diabetes has some association with one’s biological sex and specifically the hormones involved. It is our hope that this work will provide useful information to researchers of basic and public health sciences, physicians, nutritional practitioners, people with diabetes, and students in biomedical fields.
Keywords
Type 2 diabetes, Gender, Disease stages, Risk factors, Race, Lifestyle
Abbreviations
FPG: Fasting Plasma Glucose; GLUT: Glucose Transporter; IDF: International Diabetes Federation; OGTT: Oral Glucose Tolerance Test; BMI: Body Mass Index; PCOS: Polycystic Ovary Syndrome; SHBG: Sex-hormone Binding Globulin; T2D: Type 2 Diabetes
Background
The International Diabetes Federation (IDF) estimates that as of 2019, 463 million adults had diabetes worldwide [1] This is significantly higher than the 415 million reported by IDF in 2015 [2]. More recently, the Center for Disease Control and Prevention (CDC) reported 33.3 million people had diabetes in the U.S. These numbers show that diabetes is prevalent worldwide, and is increasing each year at a substantial rate [3]. By 2035 the number of diabetics worldwide is expected to be 592 million, and by 2045 the number may reach 693 million [2,4]. In the U.S. alone, the prevalence of diabetes is expected to be 34 million by 2030 and 36 million by 2045 [1]. These rates are concerning because diabetes leads to morbidity and mortality. In 2017, 5 million estimated deaths worldwide were attributable to diabetes [5].Furthermore, financial burden of diabetes management affects the societal medical expenditure. The American Diabetes Association (ADA) estimates the total cost of diagnosed diabetes in the United States was about $327 billion in 2017, an increase from $245 billion in 2012. The majority of this $327 billion was allocated towards direct medical care and a smaller percentage was due to loss of productivity [6]. Given the current state of diabetes prevalence in the U.S. and worldwide, and the detrimental effects associated with diabetes, a thorough understanding of the factors contributing to the risk of diabetes is necessary.
Diabetes Mellitus
Diabetes mellitus refers to conditions of elevated levels of blood glucose. Based on the pathophysiology of the disease and whom the disease may affect, diabetes mellitus is classified as type 1 diabetes, type 2 diabetes (T2D), or gestational diabetes [7]. Type 1 diabetes involves an autoimmune attack of pancreatic beta cells, which produce and secrete insulin. Destruction of these beta cells eventually leads to loss of insulin production [8]. To diagnose, the patient is screened for type 1 related autoimmune markers [9]. T2D involves impaired insulin action and, eventually, loss of insulin secretion in later stages due to insulin resistance. Insulin resistance occurs when a given amount of insulin produces less than normal physiological responses [10]. It contributes to reduced glucose uptake and utilization in organs and tissues such as muscle, the liver, and adipose tissue [7,11,12]. T2D is more common among adults; however, the prevalence rate in children is rising, especially for those of minority groups [13]. Gestational diabetes is diagnosed in women without preexisting diabetes during their 2nd or 3rd trimesters of pregnancy [14]. If diagnosed during the 1st trimester, it is considered preexisting T1D or T2D [14]. Following childbirth, women diagnosed as gestational diabetics are at an increased risk of developing T2D [15].
Diagnosis of T2D using Fasting Plasma Glucose (FPG), Oral Glucose Tolerance Tests (OGTT), and Glycated Hemoglobin A1C (HbA1c)
T2D can be diagnosed by measuring a patient’s fasting plasma glucose (FPG) and by using an oral glucose tolerance test (OGTT) [7,16]. FPG shows the plasma’s glucose level after fasting for eight hours or more. The ADA defines a FPG of ≥126mg/dL as a means for a diabetes diagnosis [7]. An OGTT measures blood glucose before and 2 hours after ingestion of 75 grams of glucose dissolved in water. The ADA states an OGTT ≥ 200mg/dL is related to diabetes [7]. An HbA1c test assesses the percent of hemoglobin glycosylation [16]. High glycosylation signifies prolonged elevation of blood glucose. The measurement of HbA1c reflects how well blood glucose is managed over the past two to three months (the lifespan of red blood cells). An HbA1c of >6.5% is associated with diabetes [16]. Table 1 shows the values of HbA1c, FPG, and OGTT in normal, prediabetic and type 2 diabetic subjects [7,16-18]. The values of FPG, OGTT and HbA1c show different aspects of T2D, and are helpful for people with diabetes to manage and control the disease progression. The use of one or more of them should be under the discretion of one’s primary care provider [7].
|
|
HbA1c |
FPG |
OGTT |
|
Normal |
<5.7% |
<100mg/dL |
< 140mg/dL |
|
Prediabetes |
5.7% to 6.4% |
100mg/dL to 125mg/dL |
140mg/dL to 199mg/dL |
|
Diabetes |
> 6.5% |
≥ 126mg/dL |
≥ 200mg/dL |
Stages of T2D
Two methods of categorizing stages of T2D have been proposed. One method of tracing the progression of T2D is by assessing the changes in pancreatic beta-cell mass and functionality. At the onset of insulin resistance, the pancreatic beta-cells grow and overproduce insulin to overcome barriers to glucose uptake. As the condition progresses, the beta-cells decrease in size and the pancreas can no longer sufficiently produce insulin. T2D is diagnosed once blood glucose concentrations are elevated and the insulin produced by the pancreas can no longer lower these levels.
Figure 1 depicts five stages of T2D, as defined by the alteration of pancreatic beta-cell size, function, and appearance [19].
Figure 2. Proposed stages of T2D estimated by the increasing health complications resulting from the progression of the disease. T2D progression begins with prediabetes. As insulin resistance continues T2D is diagnosed, but no harmful complications are present. Stages 3 through 4 highlight increasing complications of T2D from less dangerous, to the inability to produce insulin, to severe and deadly complications of T2D [20].
Another proposed set of stages focuses on the increasing severity of diabetes-induced complications (Figure 2) [20]. At the onset of prediabetes, blood glucose levels are elevated but not to the degree that T2D may be diagnosed. As the disease develops, blood glucose levels increase and insulin secretion decreases. By stages 3 through 5, the person with diabetes will experience complications of increasing severity.
Results and Discussion
Age, body composition, and lifestyle behaviors including an unhealthy diet and low physical activity can be risk factors for T2D, especially when considered through the lens of gender differences (Figure 3) [21-30].
Figure 3. Lifestyle contributors to the development of T2D can be diet, adiposity, and a low physical activity level.
In 2012, 8.9% of U.S. males were reported to have diabetes, whereas 8.3% of U.S. females were reported to have diabetes [31]. Although these percentages are similar, research suggests that diabetes prevalence and risk may be influenced by gender-specific factors, such as the effects of hormones, differences in lifestyle, and physical variations between males and females.
Risk factors related to the development of T2D
Risk factors related to T2D development have been studied extensively.
Age: Age is not a gender specific factor for T2D development. T2D can occur in youths and in the elderly, although it is more common in adults compared to children. There are multiple contributing factors to adolescent diabetes including exposure to maternal diabetes and/or obesity in utero, being a member of a racial or ethnic minority group, and not being breastfeed as a newborn [32]. T2D rarely occurs in pre-pubertal children, as such, T2D is more commonly diagnosed during, or following, puberty. This is thought to be related to the decline in insulin sensitivity that occurs during puberty, around the same time that early-onset T2D is often diagnosed [33]. T2D has been known to be prevalent among the elderly. According to the ADA, 22-33% of U.S. adults aged 65 or older are diagnosed with diabetes [34]. Additional findings claim insulin secretion decreases by about 0.7% per year of life [35]. This decrease in secretion may contribute to insulin resistance which leads to T2D. It is important to know that the elderly have an increased risk of having diabetes, since they are also prone to have worse complications than younger people living with diabetes do. As such, it is recommended that adults 45 years of age and older are regularly screened for T2D using FPG, OGTT, or HbA1c [34].
According to a study analyzing data from the National Health Interview Survey (NHIS) conducted in 2016 and 2017, about 9.7% of U.S. adults have diabetes; an estimated 0.8% of this total is the prevalence for type 1 diabetes and other subtypes of diabetes, and 8.5% of the total represents type 2 diabetes prevalence [36]. Although T2D was prevalent at all ages in the study (20 to greater than 65 years of age), the majority of the studied adults with T2D were older than 65 years of age [36]. Essentially, any age can develop T2D, though the majority of those with the disease are older in age.
Dietary intake: Research suggests that diet is associated with T2D, specifically diets that are lacking in a variety of healthful foods yet are high in calories. Diets consisting of processed meats are associated with an increased risk of developing T2D [21]. Additionally, drinking sugar-sweetened drinks, especially those with real sugar, increases incidence of T2D [22]. The adoption of a Mediterranean diet and an increase in intake of fruit, whole grains, and dairy products, however, may be associated with a decreased risk of T2D [23,24]. Diets may vary significantly between men and women, which can increase or decrease one’s risk of developing T2D. In a study of younger adults from 23 different countries, less men reported attempting to eat according to healthy eating recommendations than women [37]. As addressed previously, healthier diets may serve as a protective factor against T2D. If it is possible that men are not making comparable food choices to women, and T2D risk is linked to diet, then the less-healthy food choices men may make could increase the risk of T2D among males. Furthermore, the study found that women consumed less fats and more fiber than men did, and most of the women studied ate more fruit – only a portion of this disparity was attributed to dieting in women [37]. Since it is possible that men and women may sustain different diets, it may be important to conduct further research on how this may impact each genders risk of developing T2D.
Body composition and physical differences: Obesity is a leading contributor to T2D risk. Adiposity, specifically in the abdomen, and the onset age of weight gain are associated with T2D development. Visceral fat located in the abdominal cavity is more greatly associated with the development of T2D than general adiposity that is less localized in the abdomen [28]. Research suggests that obesity leads to insulin resistance and impaired pancreatic beta-cell functioning [38]. When these complications develop, diabetes risk increases, often leading to an eventual diagnosis [38]. Additionally, childhood obesity may be linked to T2D in adulthood [27].
Results from multiple randomized clinical trials (RCTs) demonstrate that bariatric surgery treatments correct obesity and T2DM in human subjects [39]. These procedures reduce body weight and lower blood glucose more efficiently when compared to other interventions in people with T2DM [40-47]. Surgery treatments have been recommended for people with T2DM and obesity to control blood glucose [48]. Men are diagnosed with diabetes at younger ages and lower BMIs based on the results from a 2011 study [49]. Furthermore, diabetes onset for men appears to begin at a younger age than women [49]. Women have been found to have higher OGTT results than men, despite having lower fasting glucose levels [50]. This may be caused by the physical differences in height and muscle mass between men and women, and because each gender is given the same amount of glucose during the OGTT [50]. Using the same amount of glucose can potentially complicate screening results since men and women uptake glucose at different rates regardless of insulin resistance. More muscle mass equates faster glucose uptake, even if uptake is impaired overall. Physical differences between genders may suggest a need for specialized screening tactics based on gender, in order to produce accurate results.
Physical activity: Low physical activity is associated with an increased risk of T2D. Studies demonstrate that replacing sedentary activities with physical activities can increase insulin sensitivity [30]. T2D risks due to physical activity can be lessened with small changes such as being physically active during leisure time, walking more, and doing cardiorespiratory workouts [25,29].
Research findings reflect that physical activity rates and types of physical activity can vary between men and women. According to a study of the European nations, men reported higher physical activity than women did [51]. This is notable as lower amounts of physical activity are associated with higher risk of T2D risk, which may increase risk of T2D among less-active women.
Race: Race is associated with an increased risk of T2D, but is not a gender specific factor for T2D development. According to the National Health Interview Survey (2012) certain races have higher rates of diabetes prevalence than others [31]. Native Americans and Alaskan Natives have the highest percentage of diabetes among U.S. adults at 17.9% (Table 2) [31]. Furthermore, the percentages of diabetes prevalence appear to be rising, evident from the 1.4% increase in prevalence from 2008 to 2012 [31,52]. Diabetes prevalence of Native Americans may vary based on the location of the tribal group. It is the highest in the Plains, the Southwest, and the Woodlands, with Pacific Coastal tribes maintaining the lowest rates [53].
|
Ethnicity
|
Native American and Alaskan Native
|
Black or African American |
Latino |
Mexican American
|
Asian American
|
Native Hawaiian and other Pacific Islanders
|
White |
|
Diabetes Rate |
17.9% |
13.1% |
12.2% |
13.1% |
8.9% |
7.9% |
7.3% |
The Pima Indians of Arizona and the Sierra Madre Mountains of Mexico serve a notable example of the effects of environmental and dietary habits on diabetes prevalence [54]. The U.S. Pima Indians have the highest recorded rates of diabetes of any group in the U.S. [55]. Although genetically similar, U.S. Pima Indians had lower physical activity and higher obesity than Mexican Pima Indians, which contributed to higher rates of diabetes [54]. Nonetheless, newer research suggests that increased insulin resistance among U.S. Pima Indians is much greater than Mexican Pima Indians, which implies that lifestyle is not the only contributor to the U.S. Pima’s increased prevalence of diabetes [56]. Black or African Americans have the second highest percentage at 13.1% (Table 2) [31]. A meta-analysis reflects that African Americans have HbA1c levels about 0.65% higher than non-Hispanic white individuals [57]. Researchers have tried to explain the higher HbA1c level of African Americans through differences in socioeconomic status and obesity/central adiposity [58-60]. Increased rates of T2D among 40 to 70-year-old African American women may be due to economic disadvantages [60]. However, diabetes rate disparities between African Americans and non-Hispanic white adults differ the most at the lowest economic level, which implies lower economic status is not the greatest contributor to African American T2D prevalence [59]. Regarding adiposity, a study of premenopausal women indicates that African American women have higher prevalence of insulin resistance than white females. The study conjectures that this difference is partially due to a higher skeletal muscle mass among African American women. Regardless, the difference in skeletal muscle mass and adipose tissue amounts are not enough to provide the ultimate cause in insulin resistance disparity [58].
Latino individuals and Mexican or Mexican Americans have diabetes percentages of 12.2%, and 13.1%, respectively (Table 2) [31]. A meta-analysis shows that the HbA1c level among Hispanic persons with diabetes was about 0.5% higher than that of non-Hispanic white subjects, showing the effects of genetics, healthcare access, and adherence to diabetes regimens [61]. Furthermore, Hispanic individuals have an increased risk of developing diabetes throughout their lifetime. Hispanic individuals born in the year 2000 have a 1 in 2 risk of developing diabetes. These are greater odds than the risk that all men born in 2000 have, which is 1 in 3, and the risk that all women born in 2000 have, which is 2 in 5 [62]. Country of origin affects diabetes risk for Latinos as well [63]. Compared to non-Hispanic white adults, Cubans have the second-lowest risk. Risk increases for South Americans, Central Americans, Mexicans, Puerto Ricans, and Dominicans in that order from the lowest to the highest [63]. Asian American adults have the third-highest percentage of T2D equating to 8.9% (Table 2) [31]. Increased rates of diabetes are found for Asian Americans versus Asian individuals living in China, Korea, and Vietnam. These disparities are thought to be linked to increased consumption of high caloric foods and less physical activity among Asian Americans [64]. Nonetheless, genetics contribute significantly to the increased diabetes prevalence of Asian Americans versus non-Hispanic white Americans. When BMI is included in calculating diabetes prevalence, Asian Americans have a much greater chance of developing diabetes than non-Hispanic white Americans [65]. Despite higher education, abstinence from drinking and smoking, and lower BMIs, Asian individuals were found to have a 30% higher risk of developing diabetes compared to non-Hispanic white individuals [66]. As a result, it is recommended that screening for T2D in Asian Americans begins at a BMI of 23 or higher [67]. Genetics, acculturation, and a predisposition to have more visceral fat at any BMI are considered contributors to Asian Americans’ increased risk [66]. Native Hawaiian and other Pacific Islanders have a diabetes prevalence of 7.9% (Table 2) [31]. This group has a higher risk of developing diabetes at the age of 35 and older than non-Hispanic whites who have a prevalence of 7.3% [68]. When recording diabetes prevalence rates, ethnicities are often grouped by their regional association; however, this practice may mask the higher rates of diabetes found in the subgroups. It has been proposed that Pacific Islander, South Asian, and Filipino Americans have the highest incidences of diabetes compared to any other ethnicity group, but this outcome is disguised by the differential rates of subgroups with larger populations [69]. These findings may reflect a necessity for altered methods of obtaining diabetes records in the future. Globally, diabetes rates vary significantly among different countries. Once adjusted for age, the Middle East and North Africa had the highest prevalence of diabetes at a rate of 10.9%. In the Middle East and North Africa, there were 34.6 million adults at 18 years old to 79 years old diagnosed with diabetes in 2013 [4]. North America and the Caribbean had the second-highest prevalence rate of 9.6%, which equates to 36.7 million diagnosed adults. South East Asia had a prevalence of 8.7% and 72.1 million diagnosed diabetics, followed by South and Central American which had a prevalence of 8.2% and 24.1 million diagnosed. The Western Pacific region had a prevalence rate of 8.1% with 138.2 million diagnosed diabetics. Europe had a percentage of 6.8% for diabetes prevalence, which equates to 56.3 million diagnosed diabetics. Africa had the lowest prevalence rate for diabetes, 5.7%, of all the regions studied, and had the least amount of diagnosed diabetes, at 19.8 million. However, it is estimated that Africa will have a large increase in cases by 2035 [4]. Africa’s rapid increase in diabetes prevalence poses significant complications for Africa’s populations. Sub-Saharan Africa’s lack of knowledge and resources for its treatment needs to be addressed [70]. Epidemiology studies of T2D risk factors have identified lifestyle [71172], age [73], and race [74-76] as major determinants. The purpose of this review is to provide a comprehensive analysis of the effect of gender – or one’s biological sex – on T2D risk and development.
Hormones: Current research connects insulin resistance and T2D with abnormal levels of hormones. Hyperandrogenicity, an excess of androgens, is measured by plasma sex-hormone-binding globulin (SHBG) levels and associated with T2D risk [77,78]. Since testosterone has a higher affinity for SHBG than estradiol does, SHBG’s availability greatly affects testosterone amounts [77]. Increased SHBG levels means that more testosterone and estradiol are available. In women, low SHBG levels predict higher T2D risk, regardless of weight, age, or blood glucose [78]. Causality may be attributed to low SHBG levels that may lower insulin sensitivity of muscles in women. Conversely, other researchers claim that hyperandrogenicity is a result of high insulin levels, and not a cause [78].
The increased binding of testosterone associated with elevated SHBG levels can reduce the risk of T2D in women and increase risk in men because of the decrease in available testosterone [77]. Research suggests that low testosterone affects obese males more than nonobese men [79,80]. Low levels of SHBG and excess testosterone can increase T2D risk in women, and decrease risk in men [77,81]. Lower estradiol in men predicts lower risk of T2D [79]. However, free testosterone unbound to SHBG is not an accurate marker for insulin resistance and diabetes independent of obesity [82,83]. Testosterone therapy has successfully lowered HbA1c percentages of men. HbA1c levels of men with over 7.5% HbA1c, decreased by 0.41% within six weeks and decreased by 0.46% after a year of testosterone therapy [84]. Bioavailable estradiol may predict insulin resistance in women [81]. As women experience menopause, their estrogen levels drop, which may increase abdominal weight gain [85]. Postmenopausal women form estradiol through the aromatization of testosterone. Higher estrogen may result from higher androgen levels, which is known to predict diabetes risk [86]. Additionally, hormone replacement therapy in postmenopausal women may lower fasting glucose but it impairs glucose tolerance [87]. Leptin may be used to predict T2D risk among men only. Leptin regulates appetite and energy expenditure [88]. Its level increases with the development of obesity. Increased leptin levels in men seem to be associated with greater insulin resistance. However, this is not true for women, possibly due to higher levels of subcutaneous fat, which produces more leptin in women than in men. As a result, changes in leptin levels because of weight gain may affect men more so than women, since males are not accustomed to elevated levels of leptin [89]. In one clinical trial, androgen therapy increased insulin sensitivity and lessened male leptin levels [90].
T2D screening differences: Women are more likely than men to utilize T2D screening tests, according to a study conducted in the U.S. Potential causes of this disparity may be that women, in their years of fertility, are screened more often than men and that women view diabetes as a greater hindrance in their daily lives than men do. Since women are more attuned to the negative impacts of diabetes, they may seek screenings more often than men [91]. The fact that women are more likely than men to seek T2D screening suggests that screening approaches could potentially be altered to include men that do not seek screening on their own.
Female-specific predictors of T2D
Women have some gendered risk factors of T2D involving the age of menarche, the prevalence of polycystic ovary syndrome (PCOS), and the age of menopause.
Early menarche: Early age of menarche has been linked to increased diabetes risk; however, this is most likely due to a higher BMI throughout the lifespan [92].
Gestational diabetes: Having a history of gestational diabetes has been linked to an increased risk of developing T2D in the future. Of women who had a history of gestational diabetes and were not given metformin or provided lifestyle interventions, 48% developed T2D within 10 years [93].
PCOS: PCOS develops due to sex hormone imbalances. This disease causes waterfilled cysts to form on an ovary, which prevents the egg from releasing to be fertilized and prevents ovulation. PCOS involves many of these cysts forming on the ovary [94]. Women diagnosed with PCOS typically have significant insulin resistance, regardless of body weight [95]. This insulin resistance can progress to T2D. One study shows that a significant number (54%) of women who previously had impaired glucose tolerance progressed to T2D in less than 10 years [96]. Additionally, research suggests that those with PCOS secrete increased amounts of insulin in compensation for increased insulin resistance due to the disease [97].
Early menopause: Diabetes risk increases for women entering menopause before the age of 40. One study claims that among those studied, early onset menopause was associated with a 32% increase in risk of T2D versus women entering menopause from 50 to 54 years old [98].
Conclusion and Perspectives
T2D has sexually dimorphic risk factors ranging from differences in hormone levels, lifestyle, physical appearance, and female menstrual/hormonal factors. The prevalence of testosterone and estrogen can be detrimental or beneficial to diabetes risk depending on the gender of the subject. Lifestyle, which has been known to affect T2D risk, is also influenced by gender differences, with women eating healthier and men participating in higher amounts of physical activity. Height, obesity and adipose depots, and muscle mass all impact T2D risk in men and women, and these factors are often influenced by gender differences. Furthermore, women have unique risks for diabetes, such as gestational diabetes and PCOS. With these findings, the need for increased research on gender influences on diabetes risk and progression is obvious. Further research may assess the effectiveness of hormone therapy on prediabetics and diabetics, so hormone therapy may one day be a treatment for T2D caused due to this dimorphism. Likewise, continued research may find ways to adapt lifestyle adjustments for men and women, based on the knowledge that men are less likely to be nutritionally conscious, while women are less likely to be physically active. With the global obesity epidemic, future research should further analyze why obesity impacts T2D risk differently amongst women and men [99]. Lastly, studies should look further into how menstruation and menopause onset, PCOS, and gestational diabetes manifest. Moreover, researchers must decipher whether these traits are diabetes risk factors in and of themselves, or whether there is another outside factor that makes women more likely to have these traits and develop diabetes.
Acknowledgements
I wish to thank my family for supporting me throughout my academic career, and for always nurturing my desire to learn. Additionally, I would like to thank the University of Tennessee for providing me the resources I needed to achieve my goals. To all involved, thank you for believing in me.
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